Hematology Times

Tumor cells producing p53

Credit: A.T. Tikhonenko

A novel sequencing technique has allowed researchers to identify direct targets of p53, providing new insight into this gene’s anticancer activity.

The research, published in eLife, revealed nearly 200 genes that were directly regulated by p53, and many of these had never been identified before.

The study’s authors said this work lays the foundation for investigations into which of these genes are necessary for p53’s cancer-killing effects and how cancer cells evade these genes.

The researchers noted that all cancers must deal with p53’s antitumor effects. Generally, there are 2 ways they do this: by mutating p53 directly or by producing the protein MDM2, which inhibits p53 function. With the current study, the team explored the second strategy.

“MDM2 inhibitors, which are through phase 1 human trials, effectively activate p53 but manage to kill only about 1 in 20 tumors,” said study author Joaquín Espinosa, PhD, of the University of Colorado in Boulder.

“The question is why. What else is happening in these cancer cells that allow them to evade p53?”

According to the researchers, the answer is in the downstream effects of p53. The gene sets in motion a cascade of events that lead to cancer cell destruction. But it has been unclear exactly which other genes are directly activated by p53.

To identify genetic targets of p53, Dr Espinosa and his colleagues used a technique called Global Run-On Sequencing (GRO-Seq). Unlike other methods, GRO-Seq measures new RNA being created, not overall RNA levels.

“Many teams around the world have been getting cancer cells, treating them with MDM2 inhibitors, and waiting hours and hours to see what genes turn on, and then, only imprecisely,” Dr Espinosa said. “GRO-Seq lets us do it in minutes, and the discoveries are massive.”

The technique generates a large quantity of data because it requires counting tens of thousands of RNA molecules before and after p53 activation. So this research required designing algorithms to sort through the data, as well as a computational biologist driving a supercomputer.

But the researchers were able to pinpoint new genes directly regulated by p53. And they believe this could aid the future development of cancer-fighting strategies.

Tumor cells producing p53

Credit: A.T. Tikhonenko

A novel sequencing technique has allowed researchers to identify direct targets of p53, providing new insight into this gene’s anticancer activity.

The research, published in eLife, revealed nearly 200 genes that were directly regulated by p53, and many of these had never been identified before.

The study’s authors said this work lays the foundation for investigations into which of these genes are necessary for p53’s cancer-killing effects and how cancer cells evade these genes.

The researchers noted that all cancers must deal with p53’s antitumor effects. Generally, there are 2 ways they do this: by mutating p53 directly or by producing the protein MDM2, which inhibits p53 function. With the current study, the team explored the second strategy.

“MDM2 inhibitors, which are through phase 1 human trials, effectively activate p53 but manage to kill only about 1 in 20 tumors,” said study author Joaquín Espinosa, PhD, of the University of Colorado in Boulder.

“The question is why. What else is happening in these cancer cells that allow them to evade p53?”

According to the researchers, the answer is in the downstream effects of p53. The gene sets in motion a cascade of events that lead to cancer cell destruction. But it has been unclear exactly which other genes are directly activated by p53.

To identify genetic targets of p53, Dr Espinosa and his colleagues used a technique called Global Run-On Sequencing (GRO-Seq). Unlike other methods, GRO-Seq measures new RNA being created, not overall RNA levels.

“Many teams around the world have been getting cancer cells, treating them with MDM2 inhibitors, and waiting hours and hours to see what genes turn on, and then, only imprecisely,” Dr Espinosa said. “GRO-Seq lets us do it in minutes, and the discoveries are massive.”

The technique generates a large quantity of data because it requires counting tens of thousands of RNA molecules before and after p53 activation. So this research required designing algorithms to sort through the data, as well as a computational biologist driving a supercomputer.

But the researchers were able to pinpoint new genes directly regulated by p53. And they believe this could aid the future development of cancer-fighting strategies.

Tumor cells producing p53

Credit: A.T. Tikhonenko

A novel sequencing technique has allowed researchers to identify direct targets of p53, providing new insight into this gene’s anticancer activity.

The research, published in eLife, revealed nearly 200 genes that were directly regulated by p53, and many of these had never been identified before.

The study’s authors said this work lays the foundation for investigations into which of these genes are necessary for p53’s cancer-killing effects and how cancer cells evade these genes.

The researchers noted that all cancers must deal with p53’s antitumor effects. Generally, there are 2 ways they do this: by mutating p53 directly or by producing the protein MDM2, which inhibits p53 function. With the current study, the team explored the second strategy.

“MDM2 inhibitors, which are through phase 1 human trials, effectively activate p53 but manage to kill only about 1 in 20 tumors,” said study author Joaquín Espinosa, PhD, of the University of Colorado in Boulder.

“The question is why. What else is happening in these cancer cells that allow them to evade p53?”

According to the researchers, the answer is in the downstream effects of p53. The gene sets in motion a cascade of events that lead to cancer cell destruction. But it has been unclear exactly which other genes are directly activated by p53.

To identify genetic targets of p53, Dr Espinosa and his colleagues used a technique called Global Run-On Sequencing (GRO-Seq). Unlike other methods, GRO-Seq measures new RNA being created, not overall RNA levels.

“Many teams around the world have been getting cancer cells, treating them with MDM2 inhibitors, and waiting hours and hours to see what genes turn on, and then, only imprecisely,” Dr Espinosa said. “GRO-Seq lets us do it in minutes, and the discoveries are massive.”

The technique generates a large quantity of data because it requires counting tens of thousands of RNA molecules before and after p53 activation. So this research required designing algorithms to sort through the data, as well as a computational biologist driving a supercomputer.

But the researchers were able to pinpoint new genes directly regulated by p53. And they believe this could aid the future development of cancer-fighting strategies.

MRI scanner

Results of a new study indicate that MRI and mammography can detect invasive breast tumors at very early stages in female survivors of Hodgkin lymphoma (HL).

Researchers said the findings underscore the need for at-risk childhood HL survivors and their physicians to be aware of screening guidelines.

The guidelines recommend survivors undergo breast MRI screening beginning at age 25 or 8 years after they received chest radiation, whichever is later.

“Female survivors of childhood HL who had chest radiation should speak with their family doctor about after-care assessment and breast cancer screening,” said David Hodgson, MD, of Princess Margaret Cancer Centre in Toronto, Canada.

“We estimate that 75% of women who are at high risk because of prior radiotherapy to the chest are not being screened. So my hope is that this new evidence will encourage these survivors to discuss early screening with their doctors.”

Dr Hodgson and his colleagues reported this evidence in Cancer.

The researchers evaluated the results of breast MRI and mammography screening among 96 female survivors of childhood HL who had been treated with chest radiotherapy.

The median patient age at first screening was 30 years, and the median number of MRI screening rounds was 3. Ten breast cancers—half of them invasive tumors—were diagnosed in 9 women during 363 person-years follow up.

The median age at breast cancer diagnosis was 39 years (range, 24 to 43 years), and the median latency period between HL diagnosis and age at breast cancer diagnoses was 21 years (range, 12 to 27 years).

“This illustrates the young age at which these cancers can occur,” Dr Hodgson said. “For some of these women, if they had been screened starting at age 40 or 50, like average-risk women, it would have been too late.”

MRI alone detected tumors with 80% sensitivity and 93.5% specificity. Mammography alone detected tumors with 70% sensitivity and 95% specificity. And both modalities combined detected tumors with 100% sensitivity and 88.6% specificity. All invasive tumors were detected by MRI.

In other words, of the 10 breast tumors, 5 were visible on both MRI and mammogram, 3 were visible only on MRI, and 2 were detected via mammogram alone (but were non-invasive). The median size of invasive tumors size was 8 mm (range, 3-15 mm), and none had spread to the lymph nodes.

The researchers noted that these results are substantially better than prior studies using only mammographic screening in young patients.

Dr Hodgson also pointed out that, because MRI screening is so much more sensitive to small changes in the appearance of the breast tissue than mammography, up to a third of patients may be called back for further testing of suspicious findings. But many of these are benign or not clinically significant and, therefore, require no treatment.

MRI scanner

Results of a new study indicate that MRI and mammography can detect invasive breast tumors at very early stages in female survivors of Hodgkin lymphoma (HL).

Researchers said the findings underscore the need for at-risk childhood HL survivors and their physicians to be aware of screening guidelines.

The guidelines recommend survivors undergo breast MRI screening beginning at age 25 or 8 years after they received chest radiation, whichever is later.

“Female survivors of childhood HL who had chest radiation should speak with their family doctor about after-care assessment and breast cancer screening,” said David Hodgson, MD, of Princess Margaret Cancer Centre in Toronto, Canada.

“We estimate that 75% of women who are at high risk because of prior radiotherapy to the chest are not being screened. So my hope is that this new evidence will encourage these survivors to discuss early screening with their doctors.”

Dr Hodgson and his colleagues reported this evidence in Cancer.

The researchers evaluated the results of breast MRI and mammography screening among 96 female survivors of childhood HL who had been treated with chest radiotherapy.

The median patient age at first screening was 30 years, and the median number of MRI screening rounds was 3. Ten breast cancers—half of them invasive tumors—were diagnosed in 9 women during 363 person-years follow up.

The median age at breast cancer diagnosis was 39 years (range, 24 to 43 years), and the median latency period between HL diagnosis and age at breast cancer diagnoses was 21 years (range, 12 to 27 years).

“This illustrates the young age at which these cancers can occur,” Dr Hodgson said. “For some of these women, if they had been screened starting at age 40 or 50, like average-risk women, it would have been too late.”

MRI alone detected tumors with 80% sensitivity and 93.5% specificity. Mammography alone detected tumors with 70% sensitivity and 95% specificity. And both modalities combined detected tumors with 100% sensitivity and 88.6% specificity. All invasive tumors were detected by MRI.

In other words, of the 10 breast tumors, 5 were visible on both MRI and mammogram, 3 were visible only on MRI, and 2 were detected via mammogram alone (but were non-invasive). The median size of invasive tumors size was 8 mm (range, 3-15 mm), and none had spread to the lymph nodes.

The researchers noted that these results are substantially better than prior studies using only mammographic screening in young patients.

Dr Hodgson also pointed out that, because MRI screening is so much more sensitive to small changes in the appearance of the breast tissue than mammography, up to a third of patients may be called back for further testing of suspicious findings. But many of these are benign or not clinically significant and, therefore, require no treatment.

MRI scanner

Results of a new study indicate that MRI and mammography can detect invasive breast tumors at very early stages in female survivors of Hodgkin lymphoma (HL).

Researchers said the findings underscore the need for at-risk childhood HL survivors and their physicians to be aware of screening guidelines.

The guidelines recommend survivors undergo breast MRI screening beginning at age 25 or 8 years after they received chest radiation, whichever is later.

“Female survivors of childhood HL who had chest radiation should speak with their family doctor about after-care assessment and breast cancer screening,” said David Hodgson, MD, of Princess Margaret Cancer Centre in Toronto, Canada.

“We estimate that 75% of women who are at high risk because of prior radiotherapy to the chest are not being screened. So my hope is that this new evidence will encourage these survivors to discuss early screening with their doctors.”

Dr Hodgson and his colleagues reported this evidence in Cancer.

The researchers evaluated the results of breast MRI and mammography screening among 96 female survivors of childhood HL who had been treated with chest radiotherapy.

The median patient age at first screening was 30 years, and the median number of MRI screening rounds was 3. Ten breast cancers—half of them invasive tumors—were diagnosed in 9 women during 363 person-years follow up.

The median age at breast cancer diagnosis was 39 years (range, 24 to 43 years), and the median latency period between HL diagnosis and age at breast cancer diagnoses was 21 years (range, 12 to 27 years).

“This illustrates the young age at which these cancers can occur,” Dr Hodgson said. “For some of these women, if they had been screened starting at age 40 or 50, like average-risk women, it would have been too late.”

MRI alone detected tumors with 80% sensitivity and 93.5% specificity. Mammography alone detected tumors with 70% sensitivity and 95% specificity. And both modalities combined detected tumors with 100% sensitivity and 88.6% specificity. All invasive tumors were detected by MRI.

In other words, of the 10 breast tumors, 5 were visible on both MRI and mammogram, 3 were visible only on MRI, and 2 were detected via mammogram alone (but were non-invasive). The median size of invasive tumors size was 8 mm (range, 3-15 mm), and none had spread to the lymph nodes.

The researchers noted that these results are substantially better than prior studies using only mammographic screening in young patients.

Dr Hodgson also pointed out that, because MRI screening is so much more sensitive to small changes in the appearance of the breast tissue than mammography, up to a third of patients may be called back for further testing of suspicious findings. But many of these are benign or not clinically significant and, therefore, require no treatment.

Micrograph showing AML cells

Credit: Lance Liotta

New research has revealed a mechanism of drug resistance in acute myeloid leukemia (AML) that may also occur in other cancers.

Investigators found evidence suggesting that glioma-associated protein 1 (GLI1) and the UDP glucuronosyltransferase (UGT1A) family of enzymes drive resistance to 2 drugs—ribavirin and cytarabine—in AML.

But the researchers were able to overcome this resistance by genetic or pharmacologic inhibition of GLI1.

They described this research in a letter to Nature.

“By studying drug-resistant cancer cells from AML patients and head and neck tumors, we found that a gene called GLI1 is dramatically overactive in these cells,” said study author Hiba Zahreddine, a doctoral student at the University of Montreal in Canada.

“[W[e were then able to show that this results in a specific chemical change to the drugs that prevents their toxicity toward the cancer cells,” said author Kathy Borden, PhD, of the University of Montreal’s Institute for Research in Immunology and Cancer.

Specifically, the investigators found that UGT1A enzymes add glucuronic acid to the drugs, thereby modifying their activity. And GLI1 alone is sufficient to drive UGT1A-dependent glucuronidation of ribavirin and cytarabine, which fuels drug resistance.

Fortunately, the researchers found that inhibiting GLI1, either genetically or with pharmacologic inhibitors, could force cancer cells to revert to a treatment-sensitive state.

The team therefore hopes that using GLI1 inhibitors in combination with ribavirin, cytarabine, or other therapies can overcome treatment resistance in patients with AML. The investigators have received approval from Health Canada to conduct a new clinical trial to test this theory.

“If this new approach is successful, it could have very broad applications, since the mode of action of ribavirin suggests that it could be effective against up to 30% of all cancers, including some types of breast, prostate, colon, stomach, and head and neck cancers, in addition to AML,” said Morris Goodman, co-founder and Chairman of the Board of Pharmascience Inc., the company that manufactured the ribavirin for this research.

Micrograph showing AML cells

Credit: Lance Liotta

New research has revealed a mechanism of drug resistance in acute myeloid leukemia (AML) that may also occur in other cancers.

Investigators found evidence suggesting that glioma-associated protein 1 (GLI1) and the UDP glucuronosyltransferase (UGT1A) family of enzymes drive resistance to 2 drugs—ribavirin and cytarabine—in AML.

But the researchers were able to overcome this resistance by genetic or pharmacologic inhibition of GLI1.

They described this research in a letter to Nature.

“By studying drug-resistant cancer cells from AML patients and head and neck tumors, we found that a gene called GLI1 is dramatically overactive in these cells,” said study author Hiba Zahreddine, a doctoral student at the University of Montreal in Canada.

“[W[e were then able to show that this results in a specific chemical change to the drugs that prevents their toxicity toward the cancer cells,” said author Kathy Borden, PhD, of the University of Montreal’s Institute for Research in Immunology and Cancer.

Specifically, the investigators found that UGT1A enzymes add glucuronic acid to the drugs, thereby modifying their activity. And GLI1 alone is sufficient to drive UGT1A-dependent glucuronidation of ribavirin and cytarabine, which fuels drug resistance.

Fortunately, the researchers found that inhibiting GLI1, either genetically or with pharmacologic inhibitors, could force cancer cells to revert to a treatment-sensitive state.

The team therefore hopes that using GLI1 inhibitors in combination with ribavirin, cytarabine, or other therapies can overcome treatment resistance in patients with AML. The investigators have received approval from Health Canada to conduct a new clinical trial to test this theory.

“If this new approach is successful, it could have very broad applications, since the mode of action of ribavirin suggests that it could be effective against up to 30% of all cancers, including some types of breast, prostate, colon, stomach, and head and neck cancers, in addition to AML,” said Morris Goodman, co-founder and Chairman of the Board of Pharmascience Inc., the company that manufactured the ribavirin for this research.

Micrograph showing AML cells

Credit: Lance Liotta

New research has revealed a mechanism of drug resistance in acute myeloid leukemia (AML) that may also occur in other cancers.

Investigators found evidence suggesting that glioma-associated protein 1 (GLI1) and the UDP glucuronosyltransferase (UGT1A) family of enzymes drive resistance to 2 drugs—ribavirin and cytarabine—in AML.

But the researchers were able to overcome this resistance by genetic or pharmacologic inhibition of GLI1.

They described this research in a letter to Nature.

“By studying drug-resistant cancer cells from AML patients and head and neck tumors, we found that a gene called GLI1 is dramatically overactive in these cells,” said study author Hiba Zahreddine, a doctoral student at the University of Montreal in Canada.

“[W[e were then able to show that this results in a specific chemical change to the drugs that prevents their toxicity toward the cancer cells,” said author Kathy Borden, PhD, of the University of Montreal’s Institute for Research in Immunology and Cancer.

Specifically, the investigators found that UGT1A enzymes add glucuronic acid to the drugs, thereby modifying their activity. And GLI1 alone is sufficient to drive UGT1A-dependent glucuronidation of ribavirin and cytarabine, which fuels drug resistance.

Fortunately, the researchers found that inhibiting GLI1, either genetically or with pharmacologic inhibitors, could force cancer cells to revert to a treatment-sensitive state.

The team therefore hopes that using GLI1 inhibitors in combination with ribavirin, cytarabine, or other therapies can overcome treatment resistance in patients with AML. The investigators have received approval from Health Canada to conduct a new clinical trial to test this theory.

“If this new approach is successful, it could have very broad applications, since the mode of action of ribavirin suggests that it could be effective against up to 30% of all cancers, including some types of breast, prostate, colon, stomach, and head and neck cancers, in addition to AML,” said Morris Goodman, co-founder and Chairman of the Board of Pharmascience Inc., the company that manufactured the ribavirin for this research.

Researchers in the lab

Credit: Rhoda Baer

A scientist’s chances of landing a faculty position at an academic institution are predictable based solely on his or her publication record, according to a study published in Current Biology.

Chances depend mostly on the number of publications the scientist has, the impact factor of the journals in which those papers are published, and the number of papers that receive more citations than expected based on the journal in which they were published, the researchers said.

“We’d like to start a discussion on what factors are taken into account when people are selected to become a principal investigator,” said study author David van Dijk, PhD, of the Weizmann Institute of Science in Rehovot, Israel.

“On the one hand, these results are encouraging, because they suggest that people are promoted based on merit. On the other hand, many of the most groundbreaking papers were not published in high-impact-factor journals and did not initially receive a high number of citations. This filtering method will certainly miss some phenomenal and ahead-of-their time scientists.”

Dr Van Dijk said he and his colleagues were motivated by endless conversations with fellow graduate students and post docs, who were dreaming of their first paper in a prestigious journal. There was the sense that those publications were the tickets to success.

So Dr van Dijk and his colleagues wanted to see if they could find evidence to that effect. And, indeed, they could.

The researchers generated publication record data for more than 25,000 scientists and used a machine-learning approach to generate a model of each individual’s chances of moving from the first-author position, typically reserved for trainees, to the last-author position, a place most often held by principal investigators (PIs).

“We find that whether or not a scientist becomes a PI is largely predictable by their publication record, even taking into account only the first few years of publication,” the researchers reported. “Our model is able to predict with relatively high accuracy who becomes a PI and is also able to predict how long this will take.”

To calculate your own likelihood of success using this model, visit: http://www.pipredictor.com.

Dr Van Dijk said the study results suggest the current system is working. Understanding how it works might be useful for those thinking through their careers or for those on hiring committees who might like to allow factors outside of the publication record to factor more significantly in hiring decisions.

The authors don’t recommend that scientists make decisions about their futures based solely on their PI prediction scores, of course. There are surely plenty of other harder-to-quantify factors that can also play a role. And there is some hopeful news for those who are persistent, even if they haven’t landed that stellar paper just yet.

“There is an element of luck in getting a paper in Nature, Cell, or Science, so it can be frustrating if you think you are a good scientist and want to succeed, but that high-impact-factor paper just doesn’t happen,” Dr van Dijk said.

“It’s encouraging that we find that doing good-quality science on a consistent basis—as evidenced by multiple first-author papers of reasonable impact factor—does seem to be rewarded in the end.”

Researchers in the lab

Credit: Rhoda Baer

A scientist’s chances of landing a faculty position at an academic institution are predictable based solely on his or her publication record, according to a study published in Current Biology.

Chances depend mostly on the number of publications the scientist has, the impact factor of the journals in which those papers are published, and the number of papers that receive more citations than expected based on the journal in which they were published, the researchers said.

“We’d like to start a discussion on what factors are taken into account when people are selected to become a principal investigator,” said study author David van Dijk, PhD, of the Weizmann Institute of Science in Rehovot, Israel.

“On the one hand, these results are encouraging, because they suggest that people are promoted based on merit. On the other hand, many of the most groundbreaking papers were not published in high-impact-factor journals and did not initially receive a high number of citations. This filtering method will certainly miss some phenomenal and ahead-of-their time scientists.”

Dr Van Dijk said he and his colleagues were motivated by endless conversations with fellow graduate students and post docs, who were dreaming of their first paper in a prestigious journal. There was the sense that those publications were the tickets to success.

So Dr van Dijk and his colleagues wanted to see if they could find evidence to that effect. And, indeed, they could.

The researchers generated publication record data for more than 25,000 scientists and used a machine-learning approach to generate a model of each individual’s chances of moving from the first-author position, typically reserved for trainees, to the last-author position, a place most often held by principal investigators (PIs).

“We find that whether or not a scientist becomes a PI is largely predictable by their publication record, even taking into account only the first few years of publication,” the researchers reported. “Our model is able to predict with relatively high accuracy who becomes a PI and is also able to predict how long this will take.”

To calculate your own likelihood of success using this model, visit: http://www.pipredictor.com.

Dr Van Dijk said the study results suggest the current system is working. Understanding how it works might be useful for those thinking through their careers or for those on hiring committees who might like to allow factors outside of the publication record to factor more significantly in hiring decisions.

The authors don’t recommend that scientists make decisions about their futures based solely on their PI prediction scores, of course. There are surely plenty of other harder-to-quantify factors that can also play a role. And there is some hopeful news for those who are persistent, even if they haven’t landed that stellar paper just yet.

“There is an element of luck in getting a paper in Nature, Cell, or Science, so it can be frustrating if you think you are a good scientist and want to succeed, but that high-impact-factor paper just doesn’t happen,” Dr van Dijk said.

“It’s encouraging that we find that doing good-quality science on a consistent basis—as evidenced by multiple first-author papers of reasonable impact factor—does seem to be rewarded in the end.”

Researchers in the lab

Credit: Rhoda Baer

A scientist’s chances of landing a faculty position at an academic institution are predictable based solely on his or her publication record, according to a study published in Current Biology.

Chances depend mostly on the number of publications the scientist has, the impact factor of the journals in which those papers are published, and the number of papers that receive more citations than expected based on the journal in which they were published, the researchers said.

“We’d like to start a discussion on what factors are taken into account when people are selected to become a principal investigator,” said study author David van Dijk, PhD, of the Weizmann Institute of Science in Rehovot, Israel.

“On the one hand, these results are encouraging, because they suggest that people are promoted based on merit. On the other hand, many of the most groundbreaking papers were not published in high-impact-factor journals and did not initially receive a high number of citations. This filtering method will certainly miss some phenomenal and ahead-of-their time scientists.”

Dr Van Dijk said he and his colleagues were motivated by endless conversations with fellow graduate students and post docs, who were dreaming of their first paper in a prestigious journal. There was the sense that those publications were the tickets to success.

So Dr van Dijk and his colleagues wanted to see if they could find evidence to that effect. And, indeed, they could.

The researchers generated publication record data for more than 25,000 scientists and used a machine-learning approach to generate a model of each individual’s chances of moving from the first-author position, typically reserved for trainees, to the last-author position, a place most often held by principal investigators (PIs).

“We find that whether or not a scientist becomes a PI is largely predictable by their publication record, even taking into account only the first few years of publication,” the researchers reported. “Our model is able to predict with relatively high accuracy who becomes a PI and is also able to predict how long this will take.”

To calculate your own likelihood of success using this model, visit: http://www.pipredictor.com.

Dr Van Dijk said the study results suggest the current system is working. Understanding how it works might be useful for those thinking through their careers or for those on hiring committees who might like to allow factors outside of the publication record to factor more significantly in hiring decisions.

The authors don’t recommend that scientists make decisions about their futures based solely on their PI prediction scores, of course. There are surely plenty of other harder-to-quantify factors that can also play a role. And there is some hopeful news for those who are persistent, even if they haven’t landed that stellar paper just yet.

“There is an element of luck in getting a paper in Nature, Cell, or Science, so it can be frustrating if you think you are a good scientist and want to succeed, but that high-impact-factor paper just doesn’t happen,” Dr van Dijk said.

“It’s encouraging that we find that doing good-quality science on a consistent basis—as evidenced by multiple first-author papers of reasonable impact factor—does seem to be rewarded in the end.”

Blood samples

Credit: Jeremy L. Grisham

MILAN, ITALY—New research suggests exome sequencing does not always produce high-quality results with regard to subsets of genes.

The American College of Medical Genetics and Genomics (ACMG) recommends physicians inform patients of clinically actionable genetic findings in the course of clinical exome testing.

Specifically, mutations in 56 specific genes with known clinical importance should be reported, even when they are incidental to the patient’s medical condition.

However, an analysis of 44 exome datasets from 4 different testing kits showed that they missed a high proportion of clinically relevant regions in the 56 ACMG genes.

“At least 1 gene in each exome method was missing more than 40% of disease-causing genetic variants, and we found that the worst-performing method missed more than 90% of such variants in four of the 56 genes,” said Eric Londin, PhD, of Thomas Jefferson University in Philadelphia, Pennsylvania.

He and his colleagues presented these findings at the European Society of Human Genetics Conference 2014 (abstract C07.6).

A central question, according to the researchers, is not how often a clinical diagnosis can be made using exome sequencing, but how often it is missed. And this study suggests there is a high false-negative rate using existing sequencing kits.

“Our concern is that when a clinical exome analysis does not report a disease-causing genetic variant, it may be that the location of that variant has not been analyzed, rather than the patient’s DNA being free of a disease-causing variant,” Dr Londin said.

“Depending on the method and the laboratory, a significant fraction (more than 10%) of the exome may be untested, and this raises concerns as to how results are being communicated to patients and their families.”

A total of 17,774 disease-causing genetic variants are annotated in the Human Gene Mutation Database for the 56 genes mentioned in the ACMG recommendations. The researchers examined the coverage of the exome datasets for the locations where the 17,774 disease-causing variants can occur.

Although the exome datasets are comparable in quality to other published clinical and research exome data sets, the coverage of the disease-causing locations was very heterogeneous and often poor.

The researchers believe that clinical labs that implement the ACMG reporting guidelines should recognize the substantial possibility of reporting false negative results.

The team said one potential improvement would be to have clinical exome sequencing use methods designed to provide a maximum yield of all clinically relevant genes.

“Many of the currently used exome kits are designed to provide a very broad dataset including genomic features that do not yet have a well-established clinical association,” Dr Londin said.

“There is a need to develop new kits and methods which provide adequate and reliable coverage of genes with known disease associations. If adequate performance cannot be obtained across the exome, then further use of targeted disease-specific panels of genes should be explored.”

The researchers also found that exome datasets generated from low amounts of sequence data (fewer than 6 gigabases) performed much worse than datasets that were generated from higher amounts of sequence data (more than 10 gigabases).

This finding is consistent with previous studies showing that exome methods do not have a linear relationship between sequence-generated and nucleotide coverage. Instead, a minimum threshold of sequencing data needs to be met before optimum nucleotide coverage is obtained.

“Current consensus and regulatory guidelines do not prescribe a minimum data requirement for clinical exome tests,” Dr Londin said. “The result is that when a causative variant cannot be identified, it does not necessarily imply that the variant is not present, rather that there may be a technical issue with the exome technology used.”

“In other words, a clinical ‘whole-exome’ study may not be ‘wholesome’ in coverage. Patients and their families should be made aware of this problem and of the implications of the genomic findings of clinical exome sequencing in its current state.”

Blood samples

Credit: Jeremy L. Grisham

MILAN, ITALY—New research suggests exome sequencing does not always produce high-quality results with regard to subsets of genes.

The American College of Medical Genetics and Genomics (ACMG) recommends physicians inform patients of clinically actionable genetic findings in the course of clinical exome testing.

Specifically, mutations in 56 specific genes with known clinical importance should be reported, even when they are incidental to the patient’s medical condition.

However, an analysis of 44 exome datasets from 4 different testing kits showed that they missed a high proportion of clinically relevant regions in the 56 ACMG genes.

“At least 1 gene in each exome method was missing more than 40% of disease-causing genetic variants, and we found that the worst-performing method missed more than 90% of such variants in four of the 56 genes,” said Eric Londin, PhD, of Thomas Jefferson University in Philadelphia, Pennsylvania.

He and his colleagues presented these findings at the European Society of Human Genetics Conference 2014 (abstract C07.6).

A central question, according to the researchers, is not how often a clinical diagnosis can be made using exome sequencing, but how often it is missed. And this study suggests there is a high false-negative rate using existing sequencing kits.

“Our concern is that when a clinical exome analysis does not report a disease-causing genetic variant, it may be that the location of that variant has not been analyzed, rather than the patient’s DNA being free of a disease-causing variant,” Dr Londin said.

“Depending on the method and the laboratory, a significant fraction (more than 10%) of the exome may be untested, and this raises concerns as to how results are being communicated to patients and their families.”

A total of 17,774 disease-causing genetic variants are annotated in the Human Gene Mutation Database for the 56 genes mentioned in the ACMG recommendations. The researchers examined the coverage of the exome datasets for the locations where the 17,774 disease-causing variants can occur.

Although the exome datasets are comparable in quality to other published clinical and research exome data sets, the coverage of the disease-causing locations was very heterogeneous and often poor.

The researchers believe that clinical labs that implement the ACMG reporting guidelines should recognize the substantial possibility of reporting false negative results.

The team said one potential improvement would be to have clinical exome sequencing use methods designed to provide a maximum yield of all clinically relevant genes.

“Many of the currently used exome kits are designed to provide a very broad dataset including genomic features that do not yet have a well-established clinical association,” Dr Londin said.

“There is a need to develop new kits and methods which provide adequate and reliable coverage of genes with known disease associations. If adequate performance cannot be obtained across the exome, then further use of targeted disease-specific panels of genes should be explored.”

The researchers also found that exome datasets generated from low amounts of sequence data (fewer than 6 gigabases) performed much worse than datasets that were generated from higher amounts of sequence data (more than 10 gigabases).

This finding is consistent with previous studies showing that exome methods do not have a linear relationship between sequence-generated and nucleotide coverage. Instead, a minimum threshold of sequencing data needs to be met before optimum nucleotide coverage is obtained.

“Current consensus and regulatory guidelines do not prescribe a minimum data requirement for clinical exome tests,” Dr Londin said. “The result is that when a causative variant cannot be identified, it does not necessarily imply that the variant is not present, rather that there may be a technical issue with the exome technology used.”

“In other words, a clinical ‘whole-exome’ study may not be ‘wholesome’ in coverage. Patients and their families should be made aware of this problem and of the implications of the genomic findings of clinical exome sequencing in its current state.”

Blood samples

Credit: Jeremy L. Grisham

MILAN, ITALY—New research suggests exome sequencing does not always produce high-quality results with regard to subsets of genes.

The American College of Medical Genetics and Genomics (ACMG) recommends physicians inform patients of clinically actionable genetic findings in the course of clinical exome testing.

Specifically, mutations in 56 specific genes with known clinical importance should be reported, even when they are incidental to the patient’s medical condition.

However, an analysis of 44 exome datasets from 4 different testing kits showed that they missed a high proportion of clinically relevant regions in the 56 ACMG genes.

“At least 1 gene in each exome method was missing more than 40% of disease-causing genetic variants, and we found that the worst-performing method missed more than 90% of such variants in four of the 56 genes,” said Eric Londin, PhD, of Thomas Jefferson University in Philadelphia, Pennsylvania.

He and his colleagues presented these findings at the European Society of Human Genetics Conference 2014 (abstract C07.6).

A central question, according to the researchers, is not how often a clinical diagnosis can be made using exome sequencing, but how often it is missed. And this study suggests there is a high false-negative rate using existing sequencing kits.

“Our concern is that when a clinical exome analysis does not report a disease-causing genetic variant, it may be that the location of that variant has not been analyzed, rather than the patient’s DNA being free of a disease-causing variant,” Dr Londin said.

“Depending on the method and the laboratory, a significant fraction (more than 10%) of the exome may be untested, and this raises concerns as to how results are being communicated to patients and their families.”

A total of 17,774 disease-causing genetic variants are annotated in the Human Gene Mutation Database for the 56 genes mentioned in the ACMG recommendations. The researchers examined the coverage of the exome datasets for the locations where the 17,774 disease-causing variants can occur.

Although the exome datasets are comparable in quality to other published clinical and research exome data sets, the coverage of the disease-causing locations was very heterogeneous and often poor.

The researchers believe that clinical labs that implement the ACMG reporting guidelines should recognize the substantial possibility of reporting false negative results.

The team said one potential improvement would be to have clinical exome sequencing use methods designed to provide a maximum yield of all clinically relevant genes.

“Many of the currently used exome kits are designed to provide a very broad dataset including genomic features that do not yet have a well-established clinical association,” Dr Londin said.

“There is a need to develop new kits and methods which provide adequate and reliable coverage of genes with known disease associations. If adequate performance cannot be obtained across the exome, then further use of targeted disease-specific panels of genes should be explored.”

The researchers also found that exome datasets generated from low amounts of sequence data (fewer than 6 gigabases) performed much worse than datasets that were generated from higher amounts of sequence data (more than 10 gigabases).

This finding is consistent with previous studies showing that exome methods do not have a linear relationship between sequence-generated and nucleotide coverage. Instead, a minimum threshold of sequencing data needs to be met before optimum nucleotide coverage is obtained.

“Current consensus and regulatory guidelines do not prescribe a minimum data requirement for clinical exome tests,” Dr Londin said. “The result is that when a causative variant cannot be identified, it does not necessarily imply that the variant is not present, rather that there may be a technical issue with the exome technology used.”

“In other words, a clinical ‘whole-exome’ study may not be ‘wholesome’ in coverage. Patients and their families should be made aware of this problem and of the implications of the genomic findings of clinical exome sequencing in its current state.”

Lab mouse

Researchers say they’ve found a way to target myeloid-derived suppressor cells (MDSCs) while sparing other immune cells.

In preclinical experiments, the team showed they could deplete MDSCs—and shrink tumors—using peptide antibodies.

These “peptibodies” wiped out MDSCs in the blood, spleen, and tumor cells of mice without binding to other white blood cells or dendritic cells.

The researchers described this work in Nature Medicine.

“We’ve known about [MDSCs] blocking immune response for a decade but haven’t been able to shut them down for lack of an identified target,” said the paper’s senior author, Larry Kwak, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston.

“This is the first demonstration of a molecule on these cells that allows us to make an antibody—in this case, a peptide—to bind to them and get rid of them. It’s a brand new immunotherapy target.”

Dr Kwak and his colleagues began this research by applying a peptide phage library to MDSCs, which allowed for a mass screening of candidate peptides that bind to the surface of MDSCs. This revealed 2 peptides, labeled G3 and H6, that bound only to MDSCs.

The researchers fused the 2 peptides to a portion of mouse immune globulin to generate experimental peptibodies called pep-G3 and pep-H6. Both peptibodies bound to both types of MDSCs—monocytic and granulocytic cells.

Dr Kwak and his colleagues then tested the peptibodies in 2 mouse models of thymic tumors, as well as models of melanoma and lymphoma. The team compared pep-G3 and pep-H6 to a control peptibody and an antibody against Gr-1.

Both pep-G3 and pep-H6 depleted monocytic and granulocytic MDSCs in the blood and spleens of all mice. But the Gr-1 antibody only worked against granulocytic MDSCs.

To see whether MDSC depletion would impede tumor growth, the researchers administered the peptibodies to mice with thymic tumors every other day for 2 weeks.

Mice treated with either pep-G3 or pep-H6 had tumors that were about half the size and weight of those in mice treated with the control peptibody or the Gr-1 antibody.

Lastly, the researchers analyzed surface proteins on the MDSCs and found that S100A9 and S100A8 are the likely binding targets for pep-G3 and pep-H6.

Dr Kwak and his colleagues said they are now working to extend these findings to human MDSCs.

Lab mouse

Researchers say they’ve found a way to target myeloid-derived suppressor cells (MDSCs) while sparing other immune cells.

In preclinical experiments, the team showed they could deplete MDSCs—and shrink tumors—using peptide antibodies.

These “peptibodies” wiped out MDSCs in the blood, spleen, and tumor cells of mice without binding to other white blood cells or dendritic cells.

The researchers described this work in Nature Medicine.

“We’ve known about [MDSCs] blocking immune response for a decade but haven’t been able to shut them down for lack of an identified target,” said the paper’s senior author, Larry Kwak, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston.

“This is the first demonstration of a molecule on these cells that allows us to make an antibody—in this case, a peptide—to bind to them and get rid of them. It’s a brand new immunotherapy target.”

Dr Kwak and his colleagues began this research by applying a peptide phage library to MDSCs, which allowed for a mass screening of candidate peptides that bind to the surface of MDSCs. This revealed 2 peptides, labeled G3 and H6, that bound only to MDSCs.

The researchers fused the 2 peptides to a portion of mouse immune globulin to generate experimental peptibodies called pep-G3 and pep-H6. Both peptibodies bound to both types of MDSCs—monocytic and granulocytic cells.

Dr Kwak and his colleagues then tested the peptibodies in 2 mouse models of thymic tumors, as well as models of melanoma and lymphoma. The team compared pep-G3 and pep-H6 to a control peptibody and an antibody against Gr-1.

Both pep-G3 and pep-H6 depleted monocytic and granulocytic MDSCs in the blood and spleens of all mice. But the Gr-1 antibody only worked against granulocytic MDSCs.

To see whether MDSC depletion would impede tumor growth, the researchers administered the peptibodies to mice with thymic tumors every other day for 2 weeks.

Mice treated with either pep-G3 or pep-H6 had tumors that were about half the size and weight of those in mice treated with the control peptibody or the Gr-1 antibody.

Lastly, the researchers analyzed surface proteins on the MDSCs and found that S100A9 and S100A8 are the likely binding targets for pep-G3 and pep-H6.

Dr Kwak and his colleagues said they are now working to extend these findings to human MDSCs.

Lab mouse

Researchers say they’ve found a way to target myeloid-derived suppressor cells (MDSCs) while sparing other immune cells.

In preclinical experiments, the team showed they could deplete MDSCs—and shrink tumors—using peptide antibodies.

These “peptibodies” wiped out MDSCs in the blood, spleen, and tumor cells of mice without binding to other white blood cells or dendritic cells.

The researchers described this work in Nature Medicine.

“We’ve known about [MDSCs] blocking immune response for a decade but haven’t been able to shut them down for lack of an identified target,” said the paper’s senior author, Larry Kwak, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston.

“This is the first demonstration of a molecule on these cells that allows us to make an antibody—in this case, a peptide—to bind to them and get rid of them. It’s a brand new immunotherapy target.”

Dr Kwak and his colleagues began this research by applying a peptide phage library to MDSCs, which allowed for a mass screening of candidate peptides that bind to the surface of MDSCs. This revealed 2 peptides, labeled G3 and H6, that bound only to MDSCs.

The researchers fused the 2 peptides to a portion of mouse immune globulin to generate experimental peptibodies called pep-G3 and pep-H6. Both peptibodies bound to both types of MDSCs—monocytic and granulocytic cells.

Dr Kwak and his colleagues then tested the peptibodies in 2 mouse models of thymic tumors, as well as models of melanoma and lymphoma. The team compared pep-G3 and pep-H6 to a control peptibody and an antibody against Gr-1.

Both pep-G3 and pep-H6 depleted monocytic and granulocytic MDSCs in the blood and spleens of all mice. But the Gr-1 antibody only worked against granulocytic MDSCs.

To see whether MDSC depletion would impede tumor growth, the researchers administered the peptibodies to mice with thymic tumors every other day for 2 weeks.

Mice treated with either pep-G3 or pep-H6 had tumors that were about half the size and weight of those in mice treated with the control peptibody or the Gr-1 antibody.

Lastly, the researchers analyzed surface proteins on the MDSCs and found that S100A9 and S100A8 are the likely binding targets for pep-G3 and pep-H6.

Dr Kwak and his colleagues said they are now working to extend these findings to human MDSCs.

Worker prepares capsules

to be used in a clinical trial

Credit: Esther Dyson

Many in the research community have lauded the European Medicines Agency’s (EMA’s) plans to make clinical trial data available to the public.

But the agency has also drawn criticism for the way it plans to go about increasing transparency.

The EMA has said it plans to make trial data available online in a “read-only” mode. So readers will not be able to save or transfer the data, making scientific analysis difficult, if not impossible.

The EMA also plans to allow drug manufacturers to omit some trial data from its public posts.

In response to this news, the European Ombudsman, Emily O’Reilly, wrote a letter to the EMA expressing concern about their seemingly significant change in policy.

“We were pleased when EMA announced, in 2012, a new pro-active transparency policy, giving the broadest possible public access to clinical trial data,” O’Reilly said.

“I am now concerned about what appears to be a significant change in EMA’s policy, which could undermine the fundamental right of public access to documents established by EU law. European citizens, doctors, and researchers need maximum information about the medicines they take, prescribe, and analyze.”

Beate Wieseler, PhD, and her colleagues from the German Institute for Quality and Efficiency in Health Care, echoed this sentiment in a “rapid response” published in the British Medical Journal.

The authors said the proposed read-only mode of accessing data makes scientific analyses, such as risk-benefit assessments of drugs, impossible.

For these assessments, an enormous amount of data must be viewed, annotated and saved, pooled from different studies, analyzed statistically, and shared among researchers. But the read-only mode would not allow for that.

Dr Wieseler and other critics also take issue with EMA’s decision to allow drug manufacturers to omit some trial data from its public posts.

The EMA has said that, within the context of market approval, drug manufacturers will be able to submit 2 versions of a clinical study report to the EMA: a complete one, by means of which the agency will decide on approval, and an incomplete one for the public.

The EMA previously decided that individual patient data, which could allow patients to be identified, would be deleted from the study reports. Now, this step has been extended to cover study results.

For example, the EMA believes deleting information is acceptable in cases of results on exploratory outcomes that are not supportive for the approval decision. However, Dr Weiseler and her colleagues noted that such study results often contain analyses of patient-relevant outcomes such as health-related quality of life.

“We are talking about studies in people who participated in a clinical study because they hoped that, with the information gained, better treatments would be developed,” Dr Wieseler said. “This information can only be used to improve patient care if it is publicly available to all.”

About the policy change

In June 2013, the EMA released for public consultation a draft policy on “publication and access to clinical trial data.” In that draft, the agency proposed publishing data submitted in support of marketing-authorization applications (only for centrally approved medicines from 2014 onward).

The idea was that interested parties would no longer need to invoke the European Freedom of Information Regulation (Regulation [EC] N°1049/2001), when exercising their right to access documents held by the EMA.

However, according to documents the EMA shared during a stakeholder consultation earlier this month, the EMA now plans to allow systematic censorship by pharmaceutical companies and impose both strict confidentiality requirements and restrictions on the use of data.

For more information on the policy, see the EMA website.

Worker prepares capsules

to be used in a clinical trial

Credit: Esther Dyson

Many in the research community have lauded the European Medicines Agency’s (EMA’s) plans to make clinical trial data available to the public.

But the agency has also drawn criticism for the way it plans to go about increasing transparency.

The EMA has said it plans to make trial data available online in a “read-only” mode. So readers will not be able to save or transfer the data, making scientific analysis difficult, if not impossible.

The EMA also plans to allow drug manufacturers to omit some trial data from its public posts.

In response to this news, the European Ombudsman, Emily O’Reilly, wrote a letter to the EMA expressing concern about their seemingly significant change in policy.

“We were pleased when EMA announced, in 2012, a new pro-active transparency policy, giving the broadest possible public access to clinical trial data,” O’Reilly said.

“I am now concerned about what appears to be a significant change in EMA’s policy, which could undermine the fundamental right of public access to documents established by EU law. European citizens, doctors, and researchers need maximum information about the medicines they take, prescribe, and analyze.”

Beate Wieseler, PhD, and her colleagues from the German Institute for Quality and Efficiency in Health Care, echoed this sentiment in a “rapid response” published in the British Medical Journal.

The authors said the proposed read-only mode of accessing data makes scientific analyses, such as risk-benefit assessments of drugs, impossible.

For these assessments, an enormous amount of data must be viewed, annotated and saved, pooled from different studies, analyzed statistically, and shared among researchers. But the read-only mode would not allow for that.

Dr Wieseler and other critics also take issue with EMA’s decision to allow drug manufacturers to omit some trial data from its public posts.

The EMA has said that, within the context of market approval, drug manufacturers will be able to submit 2 versions of a clinical study report to the EMA: a complete one, by means of which the agency will decide on approval, and an incomplete one for the public.

The EMA previously decided that individual patient data, which could allow patients to be identified, would be deleted from the study reports. Now, this step has been extended to cover study results.

For example, the EMA believes deleting information is acceptable in cases of results on exploratory outcomes that are not supportive for the approval decision. However, Dr Weiseler and her colleagues noted that such study results often contain analyses of patient-relevant outcomes such as health-related quality of life.

“We are talking about studies in people who participated in a clinical study because they hoped that, with the information gained, better treatments would be developed,” Dr Wieseler said. “This information can only be used to improve patient care if it is publicly available to all.”

About the policy change

In June 2013, the EMA released for public consultation a draft policy on “publication and access to clinical trial data.” In that draft, the agency proposed publishing data submitted in support of marketing-authorization applications (only for centrally approved medicines from 2014 onward).

The idea was that interested parties would no longer need to invoke the European Freedom of Information Regulation (Regulation [EC] N°1049/2001), when exercising their right to access documents held by the EMA.

However, according to documents the EMA shared during a stakeholder consultation earlier this month, the EMA now plans to allow systematic censorship by pharmaceutical companies and impose both strict confidentiality requirements and restrictions on the use of data.

For more information on the policy, see the EMA website.

Worker prepares capsules

to be used in a clinical trial

Credit: Esther Dyson

Many in the research community have lauded the European Medicines Agency’s (EMA’s) plans to make clinical trial data available to the public.

But the agency has also drawn criticism for the way it plans to go about increasing transparency.

The EMA has said it plans to make trial data available online in a “read-only” mode. So readers will not be able to save or transfer the data, making scientific analysis difficult, if not impossible.

The EMA also plans to allow drug manufacturers to omit some trial data from its public posts.

In response to this news, the European Ombudsman, Emily O’Reilly, wrote a letter to the EMA expressing concern about their seemingly significant change in policy.

“We were pleased when EMA announced, in 2012, a new pro-active transparency policy, giving the broadest possible public access to clinical trial data,” O’Reilly said.

“I am now concerned about what appears to be a significant change in EMA’s policy, which could undermine the fundamental right of public access to documents established by EU law. European citizens, doctors, and researchers need maximum information about the medicines they take, prescribe, and analyze.”

Beate Wieseler, PhD, and her colleagues from the German Institute for Quality and Efficiency in Health Care, echoed this sentiment in a “rapid response” published in the British Medical Journal.

The authors said the proposed read-only mode of accessing data makes scientific analyses, such as risk-benefit assessments of drugs, impossible.

For these assessments, an enormous amount of data must be viewed, annotated and saved, pooled from different studies, analyzed statistically, and shared among researchers. But the read-only mode would not allow for that.

Dr Wieseler and other critics also take issue with EMA’s decision to allow drug manufacturers to omit some trial data from its public posts.

The EMA has said that, within the context of market approval, drug manufacturers will be able to submit 2 versions of a clinical study report to the EMA: a complete one, by means of which the agency will decide on approval, and an incomplete one for the public.

The EMA previously decided that individual patient data, which could allow patients to be identified, would be deleted from the study reports. Now, this step has been extended to cover study results.

For example, the EMA believes deleting information is acceptable in cases of results on exploratory outcomes that are not supportive for the approval decision. However, Dr Weiseler and her colleagues noted that such study results often contain analyses of patient-relevant outcomes such as health-related quality of life.

“We are talking about studies in people who participated in a clinical study because they hoped that, with the information gained, better treatments would be developed,” Dr Wieseler said. “This information can only be used to improve patient care if it is publicly available to all.”

About the policy change

In June 2013, the EMA released for public consultation a draft policy on “publication and access to clinical trial data.” In that draft, the agency proposed publishing data submitted in support of marketing-authorization applications (only for centrally approved medicines from 2014 onward).

The idea was that interested parties would no longer need to invoke the European Freedom of Information Regulation (Regulation [EC] N°1049/2001), when exercising their right to access documents held by the EMA.

However, according to documents the EMA shared during a stakeholder consultation earlier this month, the EMA now plans to allow systematic censorship by pharmaceutical companies and impose both strict confidentiality requirements and restrictions on the use of data.

For more information on the policy, see the EMA website.

Researchers in the lab

Credit: Rhoda Baer

Researchers say they have identified a source of drug resistance in chronic lymphocytic leukemia (CLL).

In a letter to The New England Journal of Medicine, the team described how a mutation in Bruton’s tyrosine kinase (BTK) triggers resistance to ibrutinib, a drug that treats CLL by inhibiting BTK.

The researchers discovered this point mutation in a CLL patient enrolled in a clinical trial. The patient initially responded well to ibrutinib but stopped responding after almost 20 months.

“In a way, we are repeating, at a faster pace, the story of Gleevec [imatinib],” said study author Y. Lynn Wang, MD, PhD, of the University of Chicago in Illinois.

“That story began with development of an effective drug with few side effects, but, in many patients, the leukemia eventually found a way around it after long-term use. So researchers developed second-line drugs to overcome resistance.”

The ibrutinib study began in 2010 at Weill Cornell Medical College in New York, one of several sites for a phase 1 trial of ibrutinib. The researchers recruited 16 patients with CLL whose disease had progressed or relapsed despite multiple treatments.

Dr Wang arranged to track the progress of each patient’s leukemic cells before and during treatment and to correlate any cellular or molecular changes with each patient’s disease activity.

One of the 16 patients in the trial seemed to be unusual. This 61-year-old woman was diagnosed in 2000 at age 49. She had unsuccessfully received several different treatments before entering the study.

Within 18 months of starting ibrutinib, she showed significant improvement. At about 20 months, however, she started to decline, developing a respiratory infection that did not improve with treatment. By 21 months, it was clear she was having a relapse. The clinical team increased her dose, with no discernable effect.

Dr Wang’s team quickly began analyzing her blood samples, looking for changes that occurred between the period when she was responding well to ibrutinib and after she began to relapse.

Because complete gene sequencing would be time consuming, Dr Wang asked a graduate student working on the project, Menu Setty from Memorial Sloan-Kettering in New York, to first focus on 3 proteins that were likely candidates. One of the candidates was BTK.

And sure enough, Setty discovered a tiny but consistent change in BTK in about 90% of post-relapse cells. It was a thymidine-to-adenine mutation at nucleotide 1634 of the BTK complementary DNA, leading to a substitution of serine for cysteine at residue 481 (C481S).

When the researchers later analyzed the entire set of the patient’s genes, they found no other genetic changes that correlated with the patient’s clinical course. BTK made perfect sense as the cause for drug resistance, the researchers noted, as it’s the primary target of ibrutinib binding, and it plays a central role in rapid cell proliferation.

Dr Wang and her colleagues used structural and biochemical measures to confirm that the C481S mutation made CLL cells resistant to ibrutinib. The studies indicated that ibrutinib was 500 times less likely to bind to mutant BTK.

In an attempt to save the patient, the researchers tested alternative kinase inhibitors against the patient’s leukemic cells in the lab.

They found some kinase inhibitors remained effective against ibrutinib-resistant cells. (These studies are described in a separate manuscript that has been submitted for publication.) Unfortunately, despite this effort, the patient passed away a few weeks later, due to sepsis.

The researchers noted that the C481S mutation is one of several mechanisms that underlie resistance to ibrutinib, but this research highlights the mutation’s role in disease development and drug resistance.

Understanding the molecular and cellular mechanisms of resistance is the first step toward monitoring, early detection, and development of novel strategies to overcome drug resistance.

Researchers in the lab

Credit: Rhoda Baer

Researchers say they have identified a source of drug resistance in chronic lymphocytic leukemia (CLL).

In a letter to The New England Journal of Medicine, the team described how a mutation in Bruton’s tyrosine kinase (BTK) triggers resistance to ibrutinib, a drug that treats CLL by inhibiting BTK.

The researchers discovered this point mutation in a CLL patient enrolled in a clinical trial. The patient initially responded well to ibrutinib but stopped responding after almost 20 months.

“In a way, we are repeating, at a faster pace, the story of Gleevec [imatinib],” said study author Y. Lynn Wang, MD, PhD, of the University of Chicago in Illinois.

“That story began with development of an effective drug with few side effects, but, in many patients, the leukemia eventually found a way around it after long-term use. So researchers developed second-line drugs to overcome resistance.”

The ibrutinib study began in 2010 at Weill Cornell Medical College in New York, one of several sites for a phase 1 trial of ibrutinib. The researchers recruited 16 patients with CLL whose disease had progressed or relapsed despite multiple treatments.

Dr Wang arranged to track the progress of each patient’s leukemic cells before and during treatment and to correlate any cellular or molecular changes with each patient’s disease activity.

One of the 16 patients in the trial seemed to be unusual. This 61-year-old woman was diagnosed in 2000 at age 49. She had unsuccessfully received several different treatments before entering the study.

Within 18 months of starting ibrutinib, she showed significant improvement. At about 20 months, however, she started to decline, developing a respiratory infection that did not improve with treatment. By 21 months, it was clear she was having a relapse. The clinical team increased her dose, with no discernable effect.

Dr Wang’s team quickly began analyzing her blood samples, looking for changes that occurred between the period when she was responding well to ibrutinib and after she began to relapse.

Because complete gene sequencing would be time consuming, Dr Wang asked a graduate student working on the project, Menu Setty from Memorial Sloan-Kettering in New York, to first focus on 3 proteins that were likely candidates. One of the candidates was BTK.

And sure enough, Setty discovered a tiny but consistent change in BTK in about 90% of post-relapse cells. It was a thymidine-to-adenine mutation at nucleotide 1634 of the BTK complementary DNA, leading to a substitution of serine for cysteine at residue 481 (C481S).

When the researchers later analyzed the entire set of the patient’s genes, they found no other genetic changes that correlated with the patient’s clinical course. BTK made perfect sense as the cause for drug resistance, the researchers noted, as it’s the primary target of ibrutinib binding, and it plays a central role in rapid cell proliferation.

Dr Wang and her colleagues used structural and biochemical measures to confirm that the C481S mutation made CLL cells resistant to ibrutinib. The studies indicated that ibrutinib was 500 times less likely to bind to mutant BTK.

In an attempt to save the patient, the researchers tested alternative kinase inhibitors against the patient’s leukemic cells in the lab.

They found some kinase inhibitors remained effective against ibrutinib-resistant cells. (These studies are described in a separate manuscript that has been submitted for publication.) Unfortunately, despite this effort, the patient passed away a few weeks later, due to sepsis.

The researchers noted that the C481S mutation is one of several mechanisms that underlie resistance to ibrutinib, but this research highlights the mutation’s role in disease development and drug resistance.

Understanding the molecular and cellular mechanisms of resistance is the first step toward monitoring, early detection, and development of novel strategies to overcome drug resistance.

Researchers in the lab

Credit: Rhoda Baer

Researchers say they have identified a source of drug resistance in chronic lymphocytic leukemia (CLL).

In a letter to The New England Journal of Medicine, the team described how a mutation in Bruton’s tyrosine kinase (BTK) triggers resistance to ibrutinib, a drug that treats CLL by inhibiting BTK.

The researchers discovered this point mutation in a CLL patient enrolled in a clinical trial. The patient initially responded well to ibrutinib but stopped responding after almost 20 months.

“In a way, we are repeating, at a faster pace, the story of Gleevec [imatinib],” said study author Y. Lynn Wang, MD, PhD, of the University of Chicago in Illinois.

“That story began with development of an effective drug with few side effects, but, in many patients, the leukemia eventually found a way around it after long-term use. So researchers developed second-line drugs to overcome resistance.”

The ibrutinib study began in 2010 at Weill Cornell Medical College in New York, one of several sites for a phase 1 trial of ibrutinib. The researchers recruited 16 patients with CLL whose disease had progressed or relapsed despite multiple treatments.

Dr Wang arranged to track the progress of each patient’s leukemic cells before and during treatment and to correlate any cellular or molecular changes with each patient’s disease activity.

One of the 16 patients in the trial seemed to be unusual. This 61-year-old woman was diagnosed in 2000 at age 49. She had unsuccessfully received several different treatments before entering the study.

Within 18 months of starting ibrutinib, she showed significant improvement. At about 20 months, however, she started to decline, developing a respiratory infection that did not improve with treatment. By 21 months, it was clear she was having a relapse. The clinical team increased her dose, with no discernable effect.

Dr Wang’s team quickly began analyzing her blood samples, looking for changes that occurred between the period when she was responding well to ibrutinib and after she began to relapse.

Because complete gene sequencing would be time consuming, Dr Wang asked a graduate student working on the project, Menu Setty from Memorial Sloan-Kettering in New York, to first focus on 3 proteins that were likely candidates. One of the candidates was BTK.

And sure enough, Setty discovered a tiny but consistent change in BTK in about 90% of post-relapse cells. It was a thymidine-to-adenine mutation at nucleotide 1634 of the BTK complementary DNA, leading to a substitution of serine for cysteine at residue 481 (C481S).

When the researchers later analyzed the entire set of the patient’s genes, they found no other genetic changes that correlated with the patient’s clinical course. BTK made perfect sense as the cause for drug resistance, the researchers noted, as it’s the primary target of ibrutinib binding, and it plays a central role in rapid cell proliferation.

Dr Wang and her colleagues used structural and biochemical measures to confirm that the C481S mutation made CLL cells resistant to ibrutinib. The studies indicated that ibrutinib was 500 times less likely to bind to mutant BTK.

In an attempt to save the patient, the researchers tested alternative kinase inhibitors against the patient’s leukemic cells in the lab.

They found some kinase inhibitors remained effective against ibrutinib-resistant cells. (These studies are described in a separate manuscript that has been submitted for publication.) Unfortunately, despite this effort, the patient passed away a few weeks later, due to sepsis.

The researchers noted that the C481S mutation is one of several mechanisms that underlie resistance to ibrutinib, but this research highlights the mutation’s role in disease development and drug resistance.

Understanding the molecular and cellular mechanisms of resistance is the first step toward monitoring, early detection, and development of novel strategies to overcome drug resistance.

Thrombus

Credit: Andre E.X. Brown

The US Food and Drug Administration has cleared for marketing a device that facilitates the treatment of pulmonary embolism (PE).

The EkoSonic Endovascular System is intended for controlled and selective infusion of physician-specified fluids, including thrombolytics, into the peripheral vasculature.

The device is designed to gently accelerate the penetration of thrombolytic agents into thrombi, thereby providing high levels of lysis.

The EkoSonic Endovascular System is the only minimally invasive endovascular therapy that is FDA-cleared for the treatment of PE. The device is manufactured by EKOS Corporation.

“The EKOS clinical data established that patients stricken with a life-threatening pulmonary embolism can be successfully and safely treated with the EkoSonic system,” said Samuel Z. Goldhaber, MD, of Brigham and Woman’s Hospital in Boston, Massachusetts.

The system produced favorable results in the ULTIMA and SEATTLE II trials.

Results of the ULTIMA trial were published in Circulation. The trial showed that, for PE patients at intermediate risk of adverse events, EKOS treatment was clinically superior to anticoagulation with heparin alone in reversing right ventricular dilation at 24 hours, without an increase in bleeding complications.

The results of SEATTLE II, the prospective, single-arm, multicenter trial of 150 patients, were released at the American College of Cardiology’s 63rd Annual Scientific Session & Expo.

SEATTLE II showed that ultrasound-facilitated catheter-directed low-dose fibrinolysis for acute PE minimizes the risk of intracranial hemorrhage, improves right ventricle function, and decreases pulmonary hypertension.

Thrombus

Credit: Andre E.X. Brown

The US Food and Drug Administration has cleared for marketing a device that facilitates the treatment of pulmonary embolism (PE).

The EkoSonic Endovascular System is intended for controlled and selective infusion of physician-specified fluids, including thrombolytics, into the peripheral vasculature.

The device is designed to gently accelerate the penetration of thrombolytic agents into thrombi, thereby providing high levels of lysis.

The EkoSonic Endovascular System is the only minimally invasive endovascular therapy that is FDA-cleared for the treatment of PE. The device is manufactured by EKOS Corporation.

“The EKOS clinical data established that patients stricken with a life-threatening pulmonary embolism can be successfully and safely treated with the EkoSonic system,” said Samuel Z. Goldhaber, MD, of Brigham and Woman’s Hospital in Boston, Massachusetts.

The system produced favorable results in the ULTIMA and SEATTLE II trials.

Results of the ULTIMA trial were published in Circulation. The trial showed that, for PE patients at intermediate risk of adverse events, EKOS treatment was clinically superior to anticoagulation with heparin alone in reversing right ventricular dilation at 24 hours, without an increase in bleeding complications.

The results of SEATTLE II, the prospective, single-arm, multicenter trial of 150 patients, were released at the American College of Cardiology’s 63rd Annual Scientific Session & Expo.

SEATTLE II showed that ultrasound-facilitated catheter-directed low-dose fibrinolysis for acute PE minimizes the risk of intracranial hemorrhage, improves right ventricle function, and decreases pulmonary hypertension.

Thrombus

Credit: Andre E.X. Brown

The US Food and Drug Administration has cleared for marketing a device that facilitates the treatment of pulmonary embolism (PE).

The EkoSonic Endovascular System is intended for controlled and selective infusion of physician-specified fluids, including thrombolytics, into the peripheral vasculature.

The device is designed to gently accelerate the penetration of thrombolytic agents into thrombi, thereby providing high levels of lysis.

The EkoSonic Endovascular System is the only minimally invasive endovascular therapy that is FDA-cleared for the treatment of PE. The device is manufactured by EKOS Corporation.

“The EKOS clinical data established that patients stricken with a life-threatening pulmonary embolism can be successfully and safely treated with the EkoSonic system,” said Samuel Z. Goldhaber, MD, of Brigham and Woman’s Hospital in Boston, Massachusetts.

The system produced favorable results in the ULTIMA and SEATTLE II trials.

Results of the ULTIMA trial were published in Circulation. The trial showed that, for PE patients at intermediate risk of adverse events, EKOS treatment was clinically superior to anticoagulation with heparin alone in reversing right ventricular dilation at 24 hours, without an increase in bleeding complications.

The results of SEATTLE II, the prospective, single-arm, multicenter trial of 150 patients, were released at the American College of Cardiology’s 63rd Annual Scientific Session & Expo.

SEATTLE II showed that ultrasound-facilitated catheter-directed low-dose fibrinolysis for acute PE minimizes the risk of intracranial hemorrhage, improves right ventricle function, and decreases pulmonary hypertension.

Prescription medications

Credit: CDC

Patients who delay filling a prescription of clopidogrel after coronary stenting may increase their risk of recurrent myocardial infarction (MI) and death, according to a study published in the Journal of the American Heart Association. 

Researchers analyzed records of more than 15,000 patients who received drug-eluting or bare metal stents.

Roughly 30% of patients in each group failed to fill their prescription of the anticoagulant clopidogrel within 3 days of hospital discharge.

And this roughly doubled the patients’ risk of death and recurrent MI, regardless of their stent type.

“It is very important that patients take clopidogrel after having a coronary stent implanted to prevent blood clots forming within the stent,” said study author Nicholas Cruden, MBChB, PhD, of the Royal Infirmary of Edinburgh in the UK.

He and his colleagues analyzed hospital administrative, community pharmacy, and cardiac revascularization data from all patients who received a coronary stent in British Columbia between 2004 and 2006, with follow-up out to 2 years.

Of the 15,629 patients, 3599 had received at least 1 drug-eluting stent (DES), and 12,030 had received a bare metal stent (BMS). Thirty percent (n=1064) of patients in the DES group, and 31% (n=3758) of patients in the BMS group failed to fill their prescription for clopidogrel within 3 days of hospital discharge.

And a delay of more than 3 days was predictive of mortality and recurrent MI, regardless of the stent type. The hazard ratios (HRs) for mortality were 2.4 for the DES group and 2.2 for the BMS group. The HRs for recurrent MI were 2.0 and 1.8, respectively.

The excess risk associated with a delay in filling the prescription was greatest in the immediate period after hospital discharge—up to 30 days. In all patients, the HRs were 5.5 for mortality and 3.1 for recurrent MI.

Delaying filling the prescription for more than 3 days remained an independent predictor of death and MI beyond 30 days from hospital discharge. The HRs were 2.1 and 2.0, respectively, for patients in the DES group and 2.0 and 1.8, respectively, for patients in the BMS group.

“This study highlights the importance of ensuring patients have access to medications as soon as they leave the hospital,” Dr Cruden said. “Even a delay of a day or 2 was associated with worse outcomes.”

Discharging patients from the hospital with enough medicine for the highest-risk period (the first month or so) could help, he added.

Prescription medications

Credit: CDC

Patients who delay filling a prescription of clopidogrel after coronary stenting may increase their risk of recurrent myocardial infarction (MI) and death, according to a study published in the Journal of the American Heart Association. 

Researchers analyzed records of more than 15,000 patients who received drug-eluting or bare metal stents.

Roughly 30% of patients in each group failed to fill their prescription of the anticoagulant clopidogrel within 3 days of hospital discharge.

And this roughly doubled the patients’ risk of death and recurrent MI, regardless of their stent type.

“It is very important that patients take clopidogrel after having a coronary stent implanted to prevent blood clots forming within the stent,” said study author Nicholas Cruden, MBChB, PhD, of the Royal Infirmary of Edinburgh in the UK.

He and his colleagues analyzed hospital administrative, community pharmacy, and cardiac revascularization data from all patients who received a coronary stent in British Columbia between 2004 and 2006, with follow-up out to 2 years.

Of the 15,629 patients, 3599 had received at least 1 drug-eluting stent (DES), and 12,030 had received a bare metal stent (BMS). Thirty percent (n=1064) of patients in the DES group, and 31% (n=3758) of patients in the BMS group failed to fill their prescription for clopidogrel within 3 days of hospital discharge.

And a delay of more than 3 days was predictive of mortality and recurrent MI, regardless of the stent type. The hazard ratios (HRs) for mortality were 2.4 for the DES group and 2.2 for the BMS group. The HRs for recurrent MI were 2.0 and 1.8, respectively.

The excess risk associated with a delay in filling the prescription was greatest in the immediate period after hospital discharge—up to 30 days. In all patients, the HRs were 5.5 for mortality and 3.1 for recurrent MI.

Delaying filling the prescription for more than 3 days remained an independent predictor of death and MI beyond 30 days from hospital discharge. The HRs were 2.1 and 2.0, respectively, for patients in the DES group and 2.0 and 1.8, respectively, for patients in the BMS group.

“This study highlights the importance of ensuring patients have access to medications as soon as they leave the hospital,” Dr Cruden said. “Even a delay of a day or 2 was associated with worse outcomes.”

Discharging patients from the hospital with enough medicine for the highest-risk period (the first month or so) could help, he added.

Prescription medications

Credit: CDC

Patients who delay filling a prescription of clopidogrel after coronary stenting may increase their risk of recurrent myocardial infarction (MI) and death, according to a study published in the Journal of the American Heart Association. 

Researchers analyzed records of more than 15,000 patients who received drug-eluting or bare metal stents.

Roughly 30% of patients in each group failed to fill their prescription of the anticoagulant clopidogrel within 3 days of hospital discharge.

And this roughly doubled the patients’ risk of death and recurrent MI, regardless of their stent type.

“It is very important that patients take clopidogrel after having a coronary stent implanted to prevent blood clots forming within the stent,” said study author Nicholas Cruden, MBChB, PhD, of the Royal Infirmary of Edinburgh in the UK.

He and his colleagues analyzed hospital administrative, community pharmacy, and cardiac revascularization data from all patients who received a coronary stent in British Columbia between 2004 and 2006, with follow-up out to 2 years.

Of the 15,629 patients, 3599 had received at least 1 drug-eluting stent (DES), and 12,030 had received a bare metal stent (BMS). Thirty percent (n=1064) of patients in the DES group, and 31% (n=3758) of patients in the BMS group failed to fill their prescription for clopidogrel within 3 days of hospital discharge.

And a delay of more than 3 days was predictive of mortality and recurrent MI, regardless of the stent type. The hazard ratios (HRs) for mortality were 2.4 for the DES group and 2.2 for the BMS group. The HRs for recurrent MI were 2.0 and 1.8, respectively.

The excess risk associated with a delay in filling the prescription was greatest in the immediate period after hospital discharge—up to 30 days. In all patients, the HRs were 5.5 for mortality and 3.1 for recurrent MI.

Delaying filling the prescription for more than 3 days remained an independent predictor of death and MI beyond 30 days from hospital discharge. The HRs were 2.1 and 2.0, respectively, for patients in the DES group and 2.0 and 1.8, respectively, for patients in the BMS group.

“This study highlights the importance of ensuring patients have access to medications as soon as they leave the hospital,” Dr Cruden said. “Even a delay of a day or 2 was associated with worse outcomes.”

Discharging patients from the hospital with enough medicine for the highest-risk period (the first month or so) could help, he added.