Doctor and patient

Credit: NIH

The US Food and Drug Administration and the European Commission have granted volasertib orphan designation for the treatment of acute myeloid leukemia (AML).

Volasertib, an investigational inhibitor of polo-like kinase 1 (Plk1), works by arresting the cell cycle and inducing apoptosis.

The drug is under evaluation as a potential treatment for patients aged 65 or older with previously untreated AML who are ineligible for intensive remission induction therapy.

In both the US and the European Union, orphan designation is awarded for drugs intended to treat rare conditions for which no authorized treatment exists. The designation gives the company developing volasertib, Boehringer Ingelheim, regulatory support and incentives to help the development and authorization process.

Volasertib has already been tested in a phase 1/2 trial of patients with newly diagnosed AML who were considered ineligible for intensive remission induction therapy. The results were presented at the 2012 ASH Annual Meeting as abstract 411.

In this study, volasertib in combination with low-dose cytarabine (LDAC) elicited higher rates of objective response and an improvement in event-free survival, when compared to LDAC alone.

Eighty-seven AML patients were assigned to receive volasertib + LDAC (n=42) or LDAC alone (n=45). Patient characteristics were similar between the 2 groups.

The objective response rate was 31% among patients who received volasertib + LDAC and 11.1% in those who received LDAC alone. The complete response rates were 16.7% and 6.7%, respectively.

The median event-free survival was 169 days for patients who received volasertib + LDAC and 69 days for patients who received LDAC alone.

Grade 3 or higher adverse events were more common in the volasertib + LDAC arm than the LDAC-alone arm—95.2% vs 68.9%.

The most frequent adverse events of any grade occurring in the volasertib + LDAC arm were febrile neutropenia (50%), constipation (45.2%), nausea (40.5%), and anemia (40.5%).

In the LDAC-alone arm, the most common adverse events were nausea (33.3%), anemia (28.9%), pyrexia (28.9%), constipation (26.7%), asthenia (26.7%), and diarrhea (26.7%).

Based on these results, researchers initiated a phase 3 study, called POLO-AML-2, comparing volasertib plus LDAC to LDAC plus placebo in older AML patients.

Doctor and patient

Credit: NIH

The US Food and Drug Administration and the European Commission have granted volasertib orphan designation for the treatment of acute myeloid leukemia (AML).

Volasertib, an investigational inhibitor of polo-like kinase 1 (Plk1), works by arresting the cell cycle and inducing apoptosis.

The drug is under evaluation as a potential treatment for patients aged 65 or older with previously untreated AML who are ineligible for intensive remission induction therapy.

In both the US and the European Union, orphan designation is awarded for drugs intended to treat rare conditions for which no authorized treatment exists. The designation gives the company developing volasertib, Boehringer Ingelheim, regulatory support and incentives to help the development and authorization process.

Volasertib has already been tested in a phase 1/2 trial of patients with newly diagnosed AML who were considered ineligible for intensive remission induction therapy. The results were presented at the 2012 ASH Annual Meeting as abstract 411.

In this study, volasertib in combination with low-dose cytarabine (LDAC) elicited higher rates of objective response and an improvement in event-free survival, when compared to LDAC alone.

Eighty-seven AML patients were assigned to receive volasertib + LDAC (n=42) or LDAC alone (n=45). Patient characteristics were similar between the 2 groups.

The objective response rate was 31% among patients who received volasertib + LDAC and 11.1% in those who received LDAC alone. The complete response rates were 16.7% and 6.7%, respectively.

The median event-free survival was 169 days for patients who received volasertib + LDAC and 69 days for patients who received LDAC alone.

Grade 3 or higher adverse events were more common in the volasertib + LDAC arm than the LDAC-alone arm—95.2% vs 68.9%.

The most frequent adverse events of any grade occurring in the volasertib + LDAC arm were febrile neutropenia (50%), constipation (45.2%), nausea (40.5%), and anemia (40.5%).

In the LDAC-alone arm, the most common adverse events were nausea (33.3%), anemia (28.9%), pyrexia (28.9%), constipation (26.7%), asthenia (26.7%), and diarrhea (26.7%).

Based on these results, researchers initiated a phase 3 study, called POLO-AML-2, comparing volasertib plus LDAC to LDAC plus placebo in older AML patients.

Doctor and patient

Credit: NIH

The US Food and Drug Administration and the European Commission have granted volasertib orphan designation for the treatment of acute myeloid leukemia (AML).

Volasertib, an investigational inhibitor of polo-like kinase 1 (Plk1), works by arresting the cell cycle and inducing apoptosis.

The drug is under evaluation as a potential treatment for patients aged 65 or older with previously untreated AML who are ineligible for intensive remission induction therapy.

In both the US and the European Union, orphan designation is awarded for drugs intended to treat rare conditions for which no authorized treatment exists. The designation gives the company developing volasertib, Boehringer Ingelheim, regulatory support and incentives to help the development and authorization process.

Volasertib has already been tested in a phase 1/2 trial of patients with newly diagnosed AML who were considered ineligible for intensive remission induction therapy. The results were presented at the 2012 ASH Annual Meeting as abstract 411.

In this study, volasertib in combination with low-dose cytarabine (LDAC) elicited higher rates of objective response and an improvement in event-free survival, when compared to LDAC alone.

Eighty-seven AML patients were assigned to receive volasertib + LDAC (n=42) or LDAC alone (n=45). Patient characteristics were similar between the 2 groups.

The objective response rate was 31% among patients who received volasertib + LDAC and 11.1% in those who received LDAC alone. The complete response rates were 16.7% and 6.7%, respectively.

The median event-free survival was 169 days for patients who received volasertib + LDAC and 69 days for patients who received LDAC alone.

Grade 3 or higher adverse events were more common in the volasertib + LDAC arm than the LDAC-alone arm—95.2% vs 68.9%.

The most frequent adverse events of any grade occurring in the volasertib + LDAC arm were febrile neutropenia (50%), constipation (45.2%), nausea (40.5%), and anemia (40.5%).

In the LDAC-alone arm, the most common adverse events were nausea (33.3%), anemia (28.9%), pyrexia (28.9%), constipation (26.7%), asthenia (26.7%), and diarrhea (26.7%).

Based on these results, researchers initiated a phase 3 study, called POLO-AML-2, comparing volasertib plus LDAC to LDAC plus placebo in older AML patients.

Plasmodium parasite

infecting a red blood cell

Credit: St Jude Hospital

High-resolution technology has revealed the structure of actin proteins in the malaria parasite Plasmodium falciparum.

Researchers found the 2 versions of the protein differ from each other more than actin proteins in any other organism.

And they were able to identify areas within these proteins that cause their different behaviors.

The team believes this discovery, published in PLOS Pathogens, may contribute to the development of tailor-made drugs against malaria.

Malaria parasites use actin to enter human cells and leave them again. Inside cells, actin confers stability, allows for cell division, and makes the movement of single cells possible.

The dynamic behavior needed for these processes is enabled by individual globular actin molecules assembling together to form thread-like structures called filaments.

The malaria parasite has 2 versions of actin, actin I and actin II, which differ substantially from each other. These structural proteins are crucial for the pathogen’s infectivity, but researchers have not been able to demonstrate filament formation in the parasite, until now.

Inari Kursula, PhD, of the University of Oulu in Finland, and her colleagues have succeeded in detecting filament assembly of the parasite actin II proteins. For this, they used electron microscopy, which overcomes the resolution limit of classical light microscopy.

Male malaria parasites from which the researchers had deleted actin II were not able to form mature germ cells and, consequently, could not reproduce and propagate.

The researchers therefore speculated that having only 1 actin variant is not sufficient for this process, but they wondered why the 2 proteins show such different behavior. To answer this question, the team deciphered the structure of the globular actin proteins using X-radiation.

“We were able to determine the structures of actin I and actin II at very high resolutions–down to 1.3 and 2.2 Ångström, respectively,” Dr Kursula said.

“With this, we are in the range of single atoms. The structures show us that the 2 variants differ more from each other than actins in any other known living organism do.”

The high resolution enabled the researchers to identify areas within the proteins that cause the different behavior.

“We now understand that Plasmodium actin filaments are very different from other actin filaments—like, for example, from those found in humans—and that they are assembled in a very different manner,” Dr Kursula said.

“Now that we know the structural basis for this, we can look for ways to specifically interfere with the parasite cytoskeleton.”

This knowledge might, in the future, aid the design of tailor-made antimalarial drugs.

Plasmodium parasite

infecting a red blood cell

Credit: St Jude Hospital

High-resolution technology has revealed the structure of actin proteins in the malaria parasite Plasmodium falciparum.

Researchers found the 2 versions of the protein differ from each other more than actin proteins in any other organism.

And they were able to identify areas within these proteins that cause their different behaviors.

The team believes this discovery, published in PLOS Pathogens, may contribute to the development of tailor-made drugs against malaria.

Malaria parasites use actin to enter human cells and leave them again. Inside cells, actin confers stability, allows for cell division, and makes the movement of single cells possible.

The dynamic behavior needed for these processes is enabled by individual globular actin molecules assembling together to form thread-like structures called filaments.

The malaria parasite has 2 versions of actin, actin I and actin II, which differ substantially from each other. These structural proteins are crucial for the pathogen’s infectivity, but researchers have not been able to demonstrate filament formation in the parasite, until now.

Inari Kursula, PhD, of the University of Oulu in Finland, and her colleagues have succeeded in detecting filament assembly of the parasite actin II proteins. For this, they used electron microscopy, which overcomes the resolution limit of classical light microscopy.

Male malaria parasites from which the researchers had deleted actin II were not able to form mature germ cells and, consequently, could not reproduce and propagate.

The researchers therefore speculated that having only 1 actin variant is not sufficient for this process, but they wondered why the 2 proteins show such different behavior. To answer this question, the team deciphered the structure of the globular actin proteins using X-radiation.

“We were able to determine the structures of actin I and actin II at very high resolutions–down to 1.3 and 2.2 Ångström, respectively,” Dr Kursula said.

“With this, we are in the range of single atoms. The structures show us that the 2 variants differ more from each other than actins in any other known living organism do.”

The high resolution enabled the researchers to identify areas within the proteins that cause the different behavior.

“We now understand that Plasmodium actin filaments are very different from other actin filaments—like, for example, from those found in humans—and that they are assembled in a very different manner,” Dr Kursula said.

“Now that we know the structural basis for this, we can look for ways to specifically interfere with the parasite cytoskeleton.”

This knowledge might, in the future, aid the design of tailor-made antimalarial drugs.

Plasmodium parasite

infecting a red blood cell

Credit: St Jude Hospital

High-resolution technology has revealed the structure of actin proteins in the malaria parasite Plasmodium falciparum.

Researchers found the 2 versions of the protein differ from each other more than actin proteins in any other organism.

And they were able to identify areas within these proteins that cause their different behaviors.

The team believes this discovery, published in PLOS Pathogens, may contribute to the development of tailor-made drugs against malaria.

Malaria parasites use actin to enter human cells and leave them again. Inside cells, actin confers stability, allows for cell division, and makes the movement of single cells possible.

The dynamic behavior needed for these processes is enabled by individual globular actin molecules assembling together to form thread-like structures called filaments.

The malaria parasite has 2 versions of actin, actin I and actin II, which differ substantially from each other. These structural proteins are crucial for the pathogen’s infectivity, but researchers have not been able to demonstrate filament formation in the parasite, until now.

Inari Kursula, PhD, of the University of Oulu in Finland, and her colleagues have succeeded in detecting filament assembly of the parasite actin II proteins. For this, they used electron microscopy, which overcomes the resolution limit of classical light microscopy.

Male malaria parasites from which the researchers had deleted actin II were not able to form mature germ cells and, consequently, could not reproduce and propagate.

The researchers therefore speculated that having only 1 actin variant is not sufficient for this process, but they wondered why the 2 proteins show such different behavior. To answer this question, the team deciphered the structure of the globular actin proteins using X-radiation.

“We were able to determine the structures of actin I and actin II at very high resolutions–down to 1.3 and 2.2 Ångström, respectively,” Dr Kursula said.

“With this, we are in the range of single atoms. The structures show us that the 2 variants differ more from each other than actins in any other known living organism do.”

The high resolution enabled the researchers to identify areas within the proteins that cause the different behavior.

“We now understand that Plasmodium actin filaments are very different from other actin filaments—like, for example, from those found in humans—and that they are assembled in a very different manner,” Dr Kursula said.

“Now that we know the structural basis for this, we can look for ways to specifically interfere with the parasite cytoskeleton.”

This knowledge might, in the future, aid the design of tailor-made antimalarial drugs.

Michel Sadelain, MD, PhD

Credit: MSKCC

The US Food and Drug Administration (FDA) has lifted a clinical hold placed on a trial of chimeric antigen receptor (CAR) T-cell therapy, according to one of the study’s investigators.

The study is an evaluation of 19-28z CAR T cells in patients with B-cell acute lymphoblastic leukemia.

Trial enrollment was halted after 2 patients died from complications related to cytokine release syndrome, within 2 weeks of receiving CAR T-cell therapy.

Investigator Michel Sadelain, MD, PhD, of Memorial Sloan-Kettering Cancer Center (MSKCC) in New York, said these deaths have been reviewed, trial enrollment criteria have been changed, and the clinical hold has been lifted.

The FDA put the trial on hold last month, after researchers at MSKCC notified the agency of the deaths and had decided to halt trial enrollment themselves.

Though several other patients have died on this study, only 2 of the deaths had unexpected causes and prompted additional investigation. One of these patients died of cardiovascular disease, and the other died following “persistent seizure activity.”

So MSKCC conducted a review of these cases. And the results prompted them to amend trial enrollment criteria and dosing recommendations. Now, patients with cardiac disease are ineligible to receive 19-28z CAR T cells.

And the T-cell dose a patient receives will depend on the extent of his or her disease. The hope is that this will reduce the risk of cytokine release syndrome and any resulting seizures.

The researchers also noted that the monoclonal antibody tocilizumab has proven effective in treating cytokine release syndrome.

Michel Sadelain, MD, PhD

Credit: MSKCC

The US Food and Drug Administration (FDA) has lifted a clinical hold placed on a trial of chimeric antigen receptor (CAR) T-cell therapy, according to one of the study’s investigators.

The study is an evaluation of 19-28z CAR T cells in patients with B-cell acute lymphoblastic leukemia.

Trial enrollment was halted after 2 patients died from complications related to cytokine release syndrome, within 2 weeks of receiving CAR T-cell therapy.

Investigator Michel Sadelain, MD, PhD, of Memorial Sloan-Kettering Cancer Center (MSKCC) in New York, said these deaths have been reviewed, trial enrollment criteria have been changed, and the clinical hold has been lifted.

The FDA put the trial on hold last month, after researchers at MSKCC notified the agency of the deaths and had decided to halt trial enrollment themselves.

Though several other patients have died on this study, only 2 of the deaths had unexpected causes and prompted additional investigation. One of these patients died of cardiovascular disease, and the other died following “persistent seizure activity.”

So MSKCC conducted a review of these cases. And the results prompted them to amend trial enrollment criteria and dosing recommendations. Now, patients with cardiac disease are ineligible to receive 19-28z CAR T cells.

And the T-cell dose a patient receives will depend on the extent of his or her disease. The hope is that this will reduce the risk of cytokine release syndrome and any resulting seizures.

The researchers also noted that the monoclonal antibody tocilizumab has proven effective in treating cytokine release syndrome.

Michel Sadelain, MD, PhD

Credit: MSKCC

The US Food and Drug Administration (FDA) has lifted a clinical hold placed on a trial of chimeric antigen receptor (CAR) T-cell therapy, according to one of the study’s investigators.

The study is an evaluation of 19-28z CAR T cells in patients with B-cell acute lymphoblastic leukemia.

Trial enrollment was halted after 2 patients died from complications related to cytokine release syndrome, within 2 weeks of receiving CAR T-cell therapy.

Investigator Michel Sadelain, MD, PhD, of Memorial Sloan-Kettering Cancer Center (MSKCC) in New York, said these deaths have been reviewed, trial enrollment criteria have been changed, and the clinical hold has been lifted.

The FDA put the trial on hold last month, after researchers at MSKCC notified the agency of the deaths and had decided to halt trial enrollment themselves.

Though several other patients have died on this study, only 2 of the deaths had unexpected causes and prompted additional investigation. One of these patients died of cardiovascular disease, and the other died following “persistent seizure activity.”

So MSKCC conducted a review of these cases. And the results prompted them to amend trial enrollment criteria and dosing recommendations. Now, patients with cardiac disease are ineligible to receive 19-28z CAR T cells.

And the T-cell dose a patient receives will depend on the extent of his or her disease. The hope is that this will reduce the risk of cytokine release syndrome and any resulting seizures.

The researchers also noted that the monoclonal antibody tocilizumab has proven effective in treating cytokine release syndrome.

In this episode of our monthly dermatology podcast, we bring you an expert update on vitiligo research, a dose of humor from our columnist, Dr. Alan Rockoff, and the top news on edermatologynews.com.

In this episode of our monthly dermatology podcast, we bring you an expert update on vitiligo research, a dose of humor from our columnist, Dr. Alan Rockoff, and the top news on edermatologynews.com.

In this episode of our monthly dermatology podcast, we bring you an expert update on vitiligo research, a dose of humor from our columnist, Dr. Alan Rockoff, and the top news on edermatologynews.com.

PHOENIX – A fractional carbon dioxide laser at 10,600 nm was the only one of three laser treatments for hypertrophic scars that produced significant overall improvements in a comparison of data on 141 scars in 66 patients.

Less successful were treatments using a vascular KTP laser at 532 nm or a 1,550-nm nonablative fractional erbium glass laser.

"The only one that showed significant improvement compared with the control scar, adjusted for the baseline scar, was the fractional CO2 laser," Dr. Sigrid Blome-Eberwein said at the annual meeting of the American Society for Laser Medicine and Surgery.

The data came from three prospective controlled studies at one institution. The patients were burn survivors who had at least two scars of similar appearance and physiologic function in the same body area that were at least 6 months from wound healing. Patients underwent a series of at least three treatments at 4-week intervals on one or more scars, with a similar scar left untreated as the control scar.

Subjective assessments of the scars showed statistically significant improvements in scores on the Vancouver Scar Scale with all three treatments compared with control scars, but fewer changes were seen in objective measurements of scar qualities. "Measurements of these improvements are really difficult to tackle. We tried to add some objective measurement instruments to our evaluations," reported Dr. Blome-Eberwein of Lehigh Valley Regional Burn Center, Allentown, Pa.

None of the treatments produced significant changes in elasticity as measured by the Cutometer device. "It’s really a complete mix of results in this value," she said.

Courtesy Dr. Sigrid Blome-Eberwein

The fractional erbium laser produced one statistically significant improvement, compared with control scars, in thickness as measured by high-resolution ultrasound used to assess scar thickness (so that patients could avoid biopsies). The KTP laser also produced one statistically significant improvement, compared with control scars: improved sensation as assessed by Semmes Weinstein monofilaments.

The CO₂ laser, however, produced greater improvements in scar thickness and sensation, as well as significant improvements in erythema and pigment (both measured by spectrometry), compared with control scars. Measurements of pain and pruritus did not differ significantly between treated and control scars in any of the studies; pain levels tended to improve in both the treated and control areas and pruritus tended to remain steady.

The KTP laser caused blisters in some patients. The fractional CO₂ and fractional erbium lasers produced minimal damage. Increased power was more likely to produce collateral damage and blisters, Dr. Blome-Eberwein said.

Any results were persistent and additive. Because penetration of these lasers is limited, multiple treatments are needed for thick scars, she noted.

Courtesy Dr. Sigrid Blome-Eberwein

Based on these findings and her experience at the burn center, Dr. Blome-Eberwein recommended treating scars that seem to turn hypertrophic early (within 4 weeks of wound healing) and frequently (every 3 weeks) with a nonablative fractional erbium glass laser or pulsed dye laser. The erbium glass laser does seem to prevent "some degree of hypertrophy early on," she said. Either of these early treatments may decrease hypertrophic activity and prevent hypertrophy with no dermal damage.

Dr. Blome-Eberwein said she treats hypertrophic scars 3-12 months after healing with fractional CO₂ laser. Treating scar pigment remains a challenge, she added.

"In the future, there will be handheld devices" to treat scars at home "because a lot of people are affected by this problem," she said.

Most of the scars in the studies were from burns, with a few from trauma.

Dr. Blome-Eberwein reported having no financial disclosures.

[email protected]

On Twitter @sherryboschert

PHOENIX – A fractional carbon dioxide laser at 10,600 nm was the only one of three laser treatments for hypertrophic scars that produced significant overall improvements in a comparison of data on 141 scars in 66 patients.

Less successful were treatments using a vascular KTP laser at 532 nm or a 1,550-nm nonablative fractional erbium glass laser.

"The only one that showed significant improvement compared with the control scar, adjusted for the baseline scar, was the fractional CO2 laser," Dr. Sigrid Blome-Eberwein said at the annual meeting of the American Society for Laser Medicine and Surgery.

The data came from three prospective controlled studies at one institution. The patients were burn survivors who had at least two scars of similar appearance and physiologic function in the same body area that were at least 6 months from wound healing. Patients underwent a series of at least three treatments at 4-week intervals on one or more scars, with a similar scar left untreated as the control scar.

Subjective assessments of the scars showed statistically significant improvements in scores on the Vancouver Scar Scale with all three treatments compared with control scars, but fewer changes were seen in objective measurements of scar qualities. "Measurements of these improvements are really difficult to tackle. We tried to add some objective measurement instruments to our evaluations," reported Dr. Blome-Eberwein of Lehigh Valley Regional Burn Center, Allentown, Pa.

None of the treatments produced significant changes in elasticity as measured by the Cutometer device. "It’s really a complete mix of results in this value," she said.

Courtesy Dr. Sigrid Blome-Eberwein

The fractional erbium laser produced one statistically significant improvement, compared with control scars, in thickness as measured by high-resolution ultrasound used to assess scar thickness (so that patients could avoid biopsies). The KTP laser also produced one statistically significant improvement, compared with control scars: improved sensation as assessed by Semmes Weinstein monofilaments.

The CO₂ laser, however, produced greater improvements in scar thickness and sensation, as well as significant improvements in erythema and pigment (both measured by spectrometry), compared with control scars. Measurements of pain and pruritus did not differ significantly between treated and control scars in any of the studies; pain levels tended to improve in both the treated and control areas and pruritus tended to remain steady.

The KTP laser caused blisters in some patients. The fractional CO₂ and fractional erbium lasers produced minimal damage. Increased power was more likely to produce collateral damage and blisters, Dr. Blome-Eberwein said.

Any results were persistent and additive. Because penetration of these lasers is limited, multiple treatments are needed for thick scars, she noted.

Courtesy Dr. Sigrid Blome-Eberwein

Based on these findings and her experience at the burn center, Dr. Blome-Eberwein recommended treating scars that seem to turn hypertrophic early (within 4 weeks of wound healing) and frequently (every 3 weeks) with a nonablative fractional erbium glass laser or pulsed dye laser. The erbium glass laser does seem to prevent "some degree of hypertrophy early on," she said. Either of these early treatments may decrease hypertrophic activity and prevent hypertrophy with no dermal damage.

Dr. Blome-Eberwein said she treats hypertrophic scars 3-12 months after healing with fractional CO₂ laser. Treating scar pigment remains a challenge, she added.

"In the future, there will be handheld devices" to treat scars at home "because a lot of people are affected by this problem," she said.

Most of the scars in the studies were from burns, with a few from trauma.

Dr. Blome-Eberwein reported having no financial disclosures.

[email protected]

On Twitter @sherryboschert

PHOENIX – A fractional carbon dioxide laser at 10,600 nm was the only one of three laser treatments for hypertrophic scars that produced significant overall improvements in a comparison of data on 141 scars in 66 patients.

Less successful were treatments using a vascular KTP laser at 532 nm or a 1,550-nm nonablative fractional erbium glass laser.

"The only one that showed significant improvement compared with the control scar, adjusted for the baseline scar, was the fractional CO2 laser," Dr. Sigrid Blome-Eberwein said at the annual meeting of the American Society for Laser Medicine and Surgery.

The data came from three prospective controlled studies at one institution. The patients were burn survivors who had at least two scars of similar appearance and physiologic function in the same body area that were at least 6 months from wound healing. Patients underwent a series of at least three treatments at 4-week intervals on one or more scars, with a similar scar left untreated as the control scar.

Subjective assessments of the scars showed statistically significant improvements in scores on the Vancouver Scar Scale with all three treatments compared with control scars, but fewer changes were seen in objective measurements of scar qualities. "Measurements of these improvements are really difficult to tackle. We tried to add some objective measurement instruments to our evaluations," reported Dr. Blome-Eberwein of Lehigh Valley Regional Burn Center, Allentown, Pa.

None of the treatments produced significant changes in elasticity as measured by the Cutometer device. "It’s really a complete mix of results in this value," she said.

Courtesy Dr. Sigrid Blome-Eberwein

The fractional erbium laser produced one statistically significant improvement, compared with control scars, in thickness as measured by high-resolution ultrasound used to assess scar thickness (so that patients could avoid biopsies). The KTP laser also produced one statistically significant improvement, compared with control scars: improved sensation as assessed by Semmes Weinstein monofilaments.

The CO₂ laser, however, produced greater improvements in scar thickness and sensation, as well as significant improvements in erythema and pigment (both measured by spectrometry), compared with control scars. Measurements of pain and pruritus did not differ significantly between treated and control scars in any of the studies; pain levels tended to improve in both the treated and control areas and pruritus tended to remain steady.

The KTP laser caused blisters in some patients. The fractional CO₂ and fractional erbium lasers produced minimal damage. Increased power was more likely to produce collateral damage and blisters, Dr. Blome-Eberwein said.

Any results were persistent and additive. Because penetration of these lasers is limited, multiple treatments are needed for thick scars, she noted.

Courtesy Dr. Sigrid Blome-Eberwein

Based on these findings and her experience at the burn center, Dr. Blome-Eberwein recommended treating scars that seem to turn hypertrophic early (within 4 weeks of wound healing) and frequently (every 3 weeks) with a nonablative fractional erbium glass laser or pulsed dye laser. The erbium glass laser does seem to prevent "some degree of hypertrophy early on," she said. Either of these early treatments may decrease hypertrophic activity and prevent hypertrophy with no dermal damage.

Dr. Blome-Eberwein said she treats hypertrophic scars 3-12 months after healing with fractional CO₂ laser. Treating scar pigment remains a challenge, she added.

"In the future, there will be handheld devices" to treat scars at home "because a lot of people are affected by this problem," she said.

Most of the scars in the studies were from burns, with a few from trauma.

Dr. Blome-Eberwein reported having no financial disclosures.

[email protected]

On Twitter @sherryboschert

Lab mice

Credit: Aaron Logan

Investigators believe they’ve uncovered information that explains the connection between Down syndrome and B-cell acute lymphoblastic leukemia (B-ALL).

In a letter to Nature Genetics, the team described how they tracked the chain of events that links a chromosomal abnormality in Down syndrome to the cellular havoc that occurs in B-cell ALL.

Experiments in mice and patient samples revealed that the gene HMGN1 turns off the function of PRC2, which prompts B-cell proliferation.

“For 80 years, it hasn’t been clear why children with Down syndrome face a sharply elevated risk of ALL,” said the study’s lead author, Andrew Lane, MD, PhD, of Dana-Farber Cancer Institute in Boston.

“Advances in technology—which make it possible to study blood cells and leukemias that model Down syndrome in the laboratory—have enabled us to make that link.”

To trace the link between Down syndrome and B-ALL, the investigators acquired a strain of mice that carry an extra copy of 31 genes found on chromosome 21. B cells from these mice were abnormal and grew uncontrollably, just as they do in B-ALL patients.

The team set out to characterize the pattern of gene activity that distinguishes these abnormal B cells from normal B cells. They found the chief difference was that, in the abnormal cells, PRC2 proteins did not function. Somehow, the loss of PRC2 was spurring the B cells to divide and proliferate before they were fully mature.

To confirm that a shutdown of PRC2 is critical to the formation of B-ALL in Down syndrome patients, the investigators focused on the genes controlled by PRC2. Using 2 sets of B-ALL cell samples—1 from patients with Down syndrome and 1 from patients without it—they measured the activity of thousands of different genes, looking for differences between the 2 sets.

About 100 genes were much more active in the Down syndrome group, and all of them were under the control of PRC2. When PRC2 is silenced, those 100 genes respond with a burst of activity, driving cell growth and division.

The investigators then wondered what gene or group of genes was stifling PRC2 in Down syndrome patients’ B cells. Using cells from the mouse models, the team systematically switched off each of the 31 genes to determine its effect on the cells. When they turned off HMGN1, the cells stopped growing and died.

“We concluded that the extra copy of HMGN1 is important for turning off PRC2, and that, in turn, increases the cell proliferation,” Dr Lane said. “This provides the long-sought-after molecular link between Down syndrome and the development of B-cell ALL.”

Although there are currently no drugs that target HMGN1, the investigators suggest HDAC inhibitors that switch on PRC2 could have an antileukemic effect in patients with Down syndrome. Work is under way to improve these drugs so they can be tested in preclinical experiments.

As other forms of B-ALL also have the same 100-gene signature as the one discovered for B-ALL associated with Down syndrome, agents that target PRC2 might be effective in those cancers as well, Dr Lane noted.

Lab mice

Credit: Aaron Logan

Investigators believe they’ve uncovered information that explains the connection between Down syndrome and B-cell acute lymphoblastic leukemia (B-ALL).

In a letter to Nature Genetics, the team described how they tracked the chain of events that links a chromosomal abnormality in Down syndrome to the cellular havoc that occurs in B-cell ALL.

Experiments in mice and patient samples revealed that the gene HMGN1 turns off the function of PRC2, which prompts B-cell proliferation.

“For 80 years, it hasn’t been clear why children with Down syndrome face a sharply elevated risk of ALL,” said the study’s lead author, Andrew Lane, MD, PhD, of Dana-Farber Cancer Institute in Boston.

“Advances in technology—which make it possible to study blood cells and leukemias that model Down syndrome in the laboratory—have enabled us to make that link.”

To trace the link between Down syndrome and B-ALL, the investigators acquired a strain of mice that carry an extra copy of 31 genes found on chromosome 21. B cells from these mice were abnormal and grew uncontrollably, just as they do in B-ALL patients.

The team set out to characterize the pattern of gene activity that distinguishes these abnormal B cells from normal B cells. They found the chief difference was that, in the abnormal cells, PRC2 proteins did not function. Somehow, the loss of PRC2 was spurring the B cells to divide and proliferate before they were fully mature.

To confirm that a shutdown of PRC2 is critical to the formation of B-ALL in Down syndrome patients, the investigators focused on the genes controlled by PRC2. Using 2 sets of B-ALL cell samples—1 from patients with Down syndrome and 1 from patients without it—they measured the activity of thousands of different genes, looking for differences between the 2 sets.

About 100 genes were much more active in the Down syndrome group, and all of them were under the control of PRC2. When PRC2 is silenced, those 100 genes respond with a burst of activity, driving cell growth and division.

The investigators then wondered what gene or group of genes was stifling PRC2 in Down syndrome patients’ B cells. Using cells from the mouse models, the team systematically switched off each of the 31 genes to determine its effect on the cells. When they turned off HMGN1, the cells stopped growing and died.

“We concluded that the extra copy of HMGN1 is important for turning off PRC2, and that, in turn, increases the cell proliferation,” Dr Lane said. “This provides the long-sought-after molecular link between Down syndrome and the development of B-cell ALL.”

Although there are currently no drugs that target HMGN1, the investigators suggest HDAC inhibitors that switch on PRC2 could have an antileukemic effect in patients with Down syndrome. Work is under way to improve these drugs so they can be tested in preclinical experiments.

As other forms of B-ALL also have the same 100-gene signature as the one discovered for B-ALL associated with Down syndrome, agents that target PRC2 might be effective in those cancers as well, Dr Lane noted.

Lab mice

Credit: Aaron Logan

Investigators believe they’ve uncovered information that explains the connection between Down syndrome and B-cell acute lymphoblastic leukemia (B-ALL).

In a letter to Nature Genetics, the team described how they tracked the chain of events that links a chromosomal abnormality in Down syndrome to the cellular havoc that occurs in B-cell ALL.

Experiments in mice and patient samples revealed that the gene HMGN1 turns off the function of PRC2, which prompts B-cell proliferation.

“For 80 years, it hasn’t been clear why children with Down syndrome face a sharply elevated risk of ALL,” said the study’s lead author, Andrew Lane, MD, PhD, of Dana-Farber Cancer Institute in Boston.

“Advances in technology—which make it possible to study blood cells and leukemias that model Down syndrome in the laboratory—have enabled us to make that link.”

To trace the link between Down syndrome and B-ALL, the investigators acquired a strain of mice that carry an extra copy of 31 genes found on chromosome 21. B cells from these mice were abnormal and grew uncontrollably, just as they do in B-ALL patients.

The team set out to characterize the pattern of gene activity that distinguishes these abnormal B cells from normal B cells. They found the chief difference was that, in the abnormal cells, PRC2 proteins did not function. Somehow, the loss of PRC2 was spurring the B cells to divide and proliferate before they were fully mature.

To confirm that a shutdown of PRC2 is critical to the formation of B-ALL in Down syndrome patients, the investigators focused on the genes controlled by PRC2. Using 2 sets of B-ALL cell samples—1 from patients with Down syndrome and 1 from patients without it—they measured the activity of thousands of different genes, looking for differences between the 2 sets.

About 100 genes were much more active in the Down syndrome group, and all of them were under the control of PRC2. When PRC2 is silenced, those 100 genes respond with a burst of activity, driving cell growth and division.

The investigators then wondered what gene or group of genes was stifling PRC2 in Down syndrome patients’ B cells. Using cells from the mouse models, the team systematically switched off each of the 31 genes to determine its effect on the cells. When they turned off HMGN1, the cells stopped growing and died.

“We concluded that the extra copy of HMGN1 is important for turning off PRC2, and that, in turn, increases the cell proliferation,” Dr Lane said. “This provides the long-sought-after molecular link between Down syndrome and the development of B-cell ALL.”

Although there are currently no drugs that target HMGN1, the investigators suggest HDAC inhibitors that switch on PRC2 could have an antileukemic effect in patients with Down syndrome. Work is under way to improve these drugs so they can be tested in preclinical experiments.

As other forms of B-ALL also have the same 100-gene signature as the one discovered for B-ALL associated with Down syndrome, agents that target PRC2 might be effective in those cancers as well, Dr Lane noted.

Researcher in the lab

Credit: Darren Baker

Researchers say they’ve developed a computational method that dramatically speeds up estimates of gene activity from RNA sequencing (RNA-seq) data.

With the new method, called Sailfish, estimates of gene expression that previously took hours can be completed in a few minutes.

And the researchers say the accuracy of Sailfish equals or exceeds that of previous methods.

The team described the Sailfish method in Nature Biotechnology.

They noted that gigantic repositories of RNA-seq data now exist, making it possible to re-analyze experiments in light of new discoveries.

“But 15 hours a pop really starts to add up, particularly if you want to look at 100 experiments,” said study author Carl Kingsford, PhD, of Carnegie Mellon University in Pittsburg, Pennsylvania.

“With Sailfish, we can give researchers everything they got from previous methods, but faster.”

With previous methods, the RNA molecules from which read sequences originated could be identified and measured only by mapping the reads to their original positions in the larger molecules—a time-consuming process.

Dr Kingsford and his colleagues found this step can actually be eliminated. The team discovered they could allocate parts of the reads to different types of RNA molecules, much as if each read acted as several “votes” for one molecule or another.

Without the mapping step, Sailfish can complete its RNA analysis 20 to 30 times faster than previous methods.

Dr Kingsford also said the Sailfish method is more robust than previous methods. It’s better able to tolerate errors in the reads or differences between individuals’ genomes.

These errors can prevent some reads from being mapped, he explained. But the Sailfish method can make use of all the RNA read “votes,” which improves the method’s accuracy.

For more information and to download the Sailfish code, visit: http://www.cs.cmu.edu/~ckingsf/software/sailfish/.

Researcher in the lab

Credit: Darren Baker

Researchers say they’ve developed a computational method that dramatically speeds up estimates of gene activity from RNA sequencing (RNA-seq) data.

With the new method, called Sailfish, estimates of gene expression that previously took hours can be completed in a few minutes.

And the researchers say the accuracy of Sailfish equals or exceeds that of previous methods.

The team described the Sailfish method in Nature Biotechnology.

They noted that gigantic repositories of RNA-seq data now exist, making it possible to re-analyze experiments in light of new discoveries.

“But 15 hours a pop really starts to add up, particularly if you want to look at 100 experiments,” said study author Carl Kingsford, PhD, of Carnegie Mellon University in Pittsburg, Pennsylvania.

“With Sailfish, we can give researchers everything they got from previous methods, but faster.”

With previous methods, the RNA molecules from which read sequences originated could be identified and measured only by mapping the reads to their original positions in the larger molecules—a time-consuming process.

Dr Kingsford and his colleagues found this step can actually be eliminated. The team discovered they could allocate parts of the reads to different types of RNA molecules, much as if each read acted as several “votes” for one molecule or another.

Without the mapping step, Sailfish can complete its RNA analysis 20 to 30 times faster than previous methods.

Dr Kingsford also said the Sailfish method is more robust than previous methods. It’s better able to tolerate errors in the reads or differences between individuals’ genomes.

These errors can prevent some reads from being mapped, he explained. But the Sailfish method can make use of all the RNA read “votes,” which improves the method’s accuracy.

For more information and to download the Sailfish code, visit: http://www.cs.cmu.edu/~ckingsf/software/sailfish/.

Researcher in the lab

Credit: Darren Baker

Researchers say they’ve developed a computational method that dramatically speeds up estimates of gene activity from RNA sequencing (RNA-seq) data.

With the new method, called Sailfish, estimates of gene expression that previously took hours can be completed in a few minutes.

And the researchers say the accuracy of Sailfish equals or exceeds that of previous methods.

The team described the Sailfish method in Nature Biotechnology.

They noted that gigantic repositories of RNA-seq data now exist, making it possible to re-analyze experiments in light of new discoveries.

“But 15 hours a pop really starts to add up, particularly if you want to look at 100 experiments,” said study author Carl Kingsford, PhD, of Carnegie Mellon University in Pittsburg, Pennsylvania.

“With Sailfish, we can give researchers everything they got from previous methods, but faster.”

With previous methods, the RNA molecules from which read sequences originated could be identified and measured only by mapping the reads to their original positions in the larger molecules—a time-consuming process.

Dr Kingsford and his colleagues found this step can actually be eliminated. The team discovered they could allocate parts of the reads to different types of RNA molecules, much as if each read acted as several “votes” for one molecule or another.

Without the mapping step, Sailfish can complete its RNA analysis 20 to 30 times faster than previous methods.

Dr Kingsford also said the Sailfish method is more robust than previous methods. It’s better able to tolerate errors in the reads or differences between individuals’ genomes.

These errors can prevent some reads from being mapped, he explained. But the Sailfish method can make use of all the RNA read “votes,” which improves the method’s accuracy.

For more information and to download the Sailfish code, visit: http://www.cs.cmu.edu/~ckingsf/software/sailfish/.

AML cells in the bone marrow

SAN DIEGO—A small molecule that has previously proven effective against solid tumors exhibits activity against leukemias and lymphomas, preclinical research suggests.

The molecule, LOR-253, showed antiproliferative activity in a range of leukemia and lymphoma cell lines, induced apoptosis in acute myeloid leukemia (AML) in vitro, and demonstrated synergy with chemotherapeutic agents.

Ronnie Lum, PhD, and colleagues at Lorus Therapeutics, Inc., the Toronto, Canada-based company developing LOR-253, presented these results at the AACR Annual Meeting 2014 (abstract 4544).

LOR-253 acts through induction of the innate tumor suppressor KLF4. Recent research has suggested that upregulation of the transcription factor CDX2 drives the development or progression of leukemic disease. And CDX2 has been shown to silence KLF4, which is reported to be a critical oncogenic event in AML.

Wih this in mind, the researchers decided to test LOR-253’s activity against AML and other hematologic malignancies in vitro.

Experiments revealed that LOR-253 exerts antiproliferative activity against a range of leukemia and lymphoma cell lines, including Ramos, Raji, K-562, Jurkat, MOLT-4, CCRF-CEM, HEL92.1.7, MOLM-13, THP-1, MV411, NB4, HL-60, KG-1, NOMO-1, SKM-1, OCI-AML-2, EOL-1, and Kasumi-1.

IC50 values were substantially lower in these cell lines than in melanoma cell lines, as well as lines of lung, bladder, colon, prostate, and breast cancers.

The researchers also found that LOR-253 induces KLF4 mRNA expression in the AML cell lines HL60 and THP1. This prompts increased expression of p21, a cyclin-dependent kinase inhibitor that is transcriptionally regulated by KLF4.

Consistent with these results, LOR-253 induced cell-cycle arrest and apoptosis in the AML cell lines, which suggests the molecule acted through its intended mechanism of action.

LOR-253 also showed “strong anticancer synergy” in HL60 cells when delivered in combination with daunorubicin, azacitidine, decitabine, or cytarabine.

When LOR-253 was delivered concurrently with chemotherapy, cell viability decreased the most with cytarabine, followed by decitabine, azacitidine, and daunorubicin. With sequential treatment, cell viability decreased the most when LOR-253 was delivered with decitabine, followed by azacitidine, cytarabine, and daunorubicin.

The researchers said these results suggest LOR-253 could provide a new approach to treat AML and, possibly, other hematologic malignancies.

They are now conducting studies to further characterize the pathway that mediates KLF4 induction by LOR-253, to characterize the effects of LOR-253 in combination with approved chemotherapies for AML, and to assess the efficacy of LOR-253 in animal models of AML.

Lorus Therapeutics is also planning a dose-escalating, phase 1b trial of LOR-253 as monotherapy in AML, myelodysplastic syndromes, and other hematologic malignancies. The company expects to begin the trial this summer.

AML cells in the bone marrow

SAN DIEGO—A small molecule that has previously proven effective against solid tumors exhibits activity against leukemias and lymphomas, preclinical research suggests.

The molecule, LOR-253, showed antiproliferative activity in a range of leukemia and lymphoma cell lines, induced apoptosis in acute myeloid leukemia (AML) in vitro, and demonstrated synergy with chemotherapeutic agents.

Ronnie Lum, PhD, and colleagues at Lorus Therapeutics, Inc., the Toronto, Canada-based company developing LOR-253, presented these results at the AACR Annual Meeting 2014 (abstract 4544).

LOR-253 acts through induction of the innate tumor suppressor KLF4. Recent research has suggested that upregulation of the transcription factor CDX2 drives the development or progression of leukemic disease. And CDX2 has been shown to silence KLF4, which is reported to be a critical oncogenic event in AML.

Wih this in mind, the researchers decided to test LOR-253’s activity against AML and other hematologic malignancies in vitro.

Experiments revealed that LOR-253 exerts antiproliferative activity against a range of leukemia and lymphoma cell lines, including Ramos, Raji, K-562, Jurkat, MOLT-4, CCRF-CEM, HEL92.1.7, MOLM-13, THP-1, MV411, NB4, HL-60, KG-1, NOMO-1, SKM-1, OCI-AML-2, EOL-1, and Kasumi-1.

IC50 values were substantially lower in these cell lines than in melanoma cell lines, as well as lines of lung, bladder, colon, prostate, and breast cancers.

The researchers also found that LOR-253 induces KLF4 mRNA expression in the AML cell lines HL60 and THP1. This prompts increased expression of p21, a cyclin-dependent kinase inhibitor that is transcriptionally regulated by KLF4.

Consistent with these results, LOR-253 induced cell-cycle arrest and apoptosis in the AML cell lines, which suggests the molecule acted through its intended mechanism of action.

LOR-253 also showed “strong anticancer synergy” in HL60 cells when delivered in combination with daunorubicin, azacitidine, decitabine, or cytarabine.

When LOR-253 was delivered concurrently with chemotherapy, cell viability decreased the most with cytarabine, followed by decitabine, azacitidine, and daunorubicin. With sequential treatment, cell viability decreased the most when LOR-253 was delivered with decitabine, followed by azacitidine, cytarabine, and daunorubicin.

The researchers said these results suggest LOR-253 could provide a new approach to treat AML and, possibly, other hematologic malignancies.

They are now conducting studies to further characterize the pathway that mediates KLF4 induction by LOR-253, to characterize the effects of LOR-253 in combination with approved chemotherapies for AML, and to assess the efficacy of LOR-253 in animal models of AML.

Lorus Therapeutics is also planning a dose-escalating, phase 1b trial of LOR-253 as monotherapy in AML, myelodysplastic syndromes, and other hematologic malignancies. The company expects to begin the trial this summer.

AML cells in the bone marrow

SAN DIEGO—A small molecule that has previously proven effective against solid tumors exhibits activity against leukemias and lymphomas, preclinical research suggests.

The molecule, LOR-253, showed antiproliferative activity in a range of leukemia and lymphoma cell lines, induced apoptosis in acute myeloid leukemia (AML) in vitro, and demonstrated synergy with chemotherapeutic agents.

Ronnie Lum, PhD, and colleagues at Lorus Therapeutics, Inc., the Toronto, Canada-based company developing LOR-253, presented these results at the AACR Annual Meeting 2014 (abstract 4544).

LOR-253 acts through induction of the innate tumor suppressor KLF4. Recent research has suggested that upregulation of the transcription factor CDX2 drives the development or progression of leukemic disease. And CDX2 has been shown to silence KLF4, which is reported to be a critical oncogenic event in AML.

Wih this in mind, the researchers decided to test LOR-253’s activity against AML and other hematologic malignancies in vitro.

Experiments revealed that LOR-253 exerts antiproliferative activity against a range of leukemia and lymphoma cell lines, including Ramos, Raji, K-562, Jurkat, MOLT-4, CCRF-CEM, HEL92.1.7, MOLM-13, THP-1, MV411, NB4, HL-60, KG-1, NOMO-1, SKM-1, OCI-AML-2, EOL-1, and Kasumi-1.

IC50 values were substantially lower in these cell lines than in melanoma cell lines, as well as lines of lung, bladder, colon, prostate, and breast cancers.

The researchers also found that LOR-253 induces KLF4 mRNA expression in the AML cell lines HL60 and THP1. This prompts increased expression of p21, a cyclin-dependent kinase inhibitor that is transcriptionally regulated by KLF4.

Consistent with these results, LOR-253 induced cell-cycle arrest and apoptosis in the AML cell lines, which suggests the molecule acted through its intended mechanism of action.

LOR-253 also showed “strong anticancer synergy” in HL60 cells when delivered in combination with daunorubicin, azacitidine, decitabine, or cytarabine.

When LOR-253 was delivered concurrently with chemotherapy, cell viability decreased the most with cytarabine, followed by decitabine, azacitidine, and daunorubicin. With sequential treatment, cell viability decreased the most when LOR-253 was delivered with decitabine, followed by azacitidine, cytarabine, and daunorubicin.

The researchers said these results suggest LOR-253 could provide a new approach to treat AML and, possibly, other hematologic malignancies.

They are now conducting studies to further characterize the pathway that mediates KLF4 induction by LOR-253, to characterize the effects of LOR-253 in combination with approved chemotherapies for AML, and to assess the efficacy of LOR-253 in animal models of AML.

Lorus Therapeutics is also planning a dose-escalating, phase 1b trial of LOR-253 as monotherapy in AML, myelodysplastic syndromes, and other hematologic malignancies. The company expects to begin the trial this summer.

Drosophila melanogaster

Credit: Andre Karwath

Experiments conducted in fruit flies showed that when researchers eliminated a type of stem cell, a group of non-stem cells stepped in to replace them.

The team said this discovery sheds new light on stem cell niches and may help explain how cancer stem cells (CSCs) replenish themselves after exposure to radiation and chemotherapy.

Erika Matunis, PhD, of the Johns Hopkins University School of Medicine in Baltimore, Maryland, and her colleagues detailed these findings in Cell Reports.

The researchers used the fruit fly as a model to examine stem cells in their natural state, studying stem cell niches in Drosophila testes.

In these niches are 3 kinds of cells: germ-line stem cells, which divide to produce sperm; somatic cyst stem cells, which make cyst cells; and hub cells, which produce signals that keep these 2 cell types going.

The hub cells have settled on their final form and are incapable of dividing further or changing their function—or so everyone thought.

In a bid to determine what happens when the somatic cyst stem cells are killed off, the researchers tried to figure out how to best do away with them. They thought the task would be straightforward, but it took many combinations of different genes working together to kill the somatic cyst cells.

“When we finally figured out a way to kill all of the somatic stem cells, we thought that the rest of the tissue would probably just empty out,” Dr Matunis said.

In 35% of testes, that’s just what happened. But in the rest, the somatic stem cells grew back.

This was a surprise, Dr Matunis said, and it raised the question of where these new stem cells originated.

The answer was another surprise: the hub cells. When the somatic stem cells were destroyed, the hub cells ramped up their machinery for cell division.

The team did several experiments to confirm the hub cells were involved, including one in which they genetically marked the hub cells and saw the mark appear in the newly formed somatic stem cells—a clear sign that hub cells had divided to make new stem cells.

Dr Matunis noted, however, that the new stem cells created by the hub cells weren’t exactly the same as the old ones. Sometimes, the new cells made molecules that only hub cells normally make.

As the researchers looked closer, they realized the damaged and recovered testes were making new niches. Instead of just one pocket of stem cells, a damaged testis might have 2 or 3.

The researchers have not determined how the new niches are formed, but they speculate that the original niche gets bigger as the new cells divide, then splits. The group is now conducting more experiments aimed at explaining the basics of how niches work, according to Dr Matunis.

She said this research may be useful for understanding CSCs. Knowing how tumor niches support the continued growth and division of CSCs might one day offer new targets for controlling such growth.

Drosophila melanogaster

Credit: Andre Karwath

Experiments conducted in fruit flies showed that when researchers eliminated a type of stem cell, a group of non-stem cells stepped in to replace them.

The team said this discovery sheds new light on stem cell niches and may help explain how cancer stem cells (CSCs) replenish themselves after exposure to radiation and chemotherapy.

Erika Matunis, PhD, of the Johns Hopkins University School of Medicine in Baltimore, Maryland, and her colleagues detailed these findings in Cell Reports.

The researchers used the fruit fly as a model to examine stem cells in their natural state, studying stem cell niches in Drosophila testes.

In these niches are 3 kinds of cells: germ-line stem cells, which divide to produce sperm; somatic cyst stem cells, which make cyst cells; and hub cells, which produce signals that keep these 2 cell types going.

The hub cells have settled on their final form and are incapable of dividing further or changing their function—or so everyone thought.

In a bid to determine what happens when the somatic cyst stem cells are killed off, the researchers tried to figure out how to best do away with them. They thought the task would be straightforward, but it took many combinations of different genes working together to kill the somatic cyst cells.

“When we finally figured out a way to kill all of the somatic stem cells, we thought that the rest of the tissue would probably just empty out,” Dr Matunis said.

In 35% of testes, that’s just what happened. But in the rest, the somatic stem cells grew back.

This was a surprise, Dr Matunis said, and it raised the question of where these new stem cells originated.

The answer was another surprise: the hub cells. When the somatic stem cells were destroyed, the hub cells ramped up their machinery for cell division.

The team did several experiments to confirm the hub cells were involved, including one in which they genetically marked the hub cells and saw the mark appear in the newly formed somatic stem cells—a clear sign that hub cells had divided to make new stem cells.

Dr Matunis noted, however, that the new stem cells created by the hub cells weren’t exactly the same as the old ones. Sometimes, the new cells made molecules that only hub cells normally make.

As the researchers looked closer, they realized the damaged and recovered testes were making new niches. Instead of just one pocket of stem cells, a damaged testis might have 2 or 3.

The researchers have not determined how the new niches are formed, but they speculate that the original niche gets bigger as the new cells divide, then splits. The group is now conducting more experiments aimed at explaining the basics of how niches work, according to Dr Matunis.

She said this research may be useful for understanding CSCs. Knowing how tumor niches support the continued growth and division of CSCs might one day offer new targets for controlling such growth.

Drosophila melanogaster

Credit: Andre Karwath

Experiments conducted in fruit flies showed that when researchers eliminated a type of stem cell, a group of non-stem cells stepped in to replace them.

The team said this discovery sheds new light on stem cell niches and may help explain how cancer stem cells (CSCs) replenish themselves after exposure to radiation and chemotherapy.

Erika Matunis, PhD, of the Johns Hopkins University School of Medicine in Baltimore, Maryland, and her colleagues detailed these findings in Cell Reports.

The researchers used the fruit fly as a model to examine stem cells in their natural state, studying stem cell niches in Drosophila testes.

In these niches are 3 kinds of cells: germ-line stem cells, which divide to produce sperm; somatic cyst stem cells, which make cyst cells; and hub cells, which produce signals that keep these 2 cell types going.

The hub cells have settled on their final form and are incapable of dividing further or changing their function—or so everyone thought.

In a bid to determine what happens when the somatic cyst stem cells are killed off, the researchers tried to figure out how to best do away with them. They thought the task would be straightforward, but it took many combinations of different genes working together to kill the somatic cyst cells.

“When we finally figured out a way to kill all of the somatic stem cells, we thought that the rest of the tissue would probably just empty out,” Dr Matunis said.

In 35% of testes, that’s just what happened. But in the rest, the somatic stem cells grew back.

This was a surprise, Dr Matunis said, and it raised the question of where these new stem cells originated.

The answer was another surprise: the hub cells. When the somatic stem cells were destroyed, the hub cells ramped up their machinery for cell division.

The team did several experiments to confirm the hub cells were involved, including one in which they genetically marked the hub cells and saw the mark appear in the newly formed somatic stem cells—a clear sign that hub cells had divided to make new stem cells.

Dr Matunis noted, however, that the new stem cells created by the hub cells weren’t exactly the same as the old ones. Sometimes, the new cells made molecules that only hub cells normally make.

As the researchers looked closer, they realized the damaged and recovered testes were making new niches. Instead of just one pocket of stem cells, a damaged testis might have 2 or 3.

The researchers have not determined how the new niches are formed, but they speculate that the original niche gets bigger as the new cells divide, then splits. The group is now conducting more experiments aimed at explaining the basics of how niches work, according to Dr Matunis.

She said this research may be useful for understanding CSCs. Knowing how tumor niches support the continued growth and division of CSCs might one day offer new targets for controlling such growth.