Only 21% of liver transplantation patients who received ursodeoxycholic acid (UDCA) after surgery developed recurrent primary biliary cirrhosis, compared with 62% of patients who did not receive the bile acid, researchers reported in the Journal of Hepatology.

The results provide strong evidence that routinely giving liver transplant patients UDCA can prevent or delay recurrent primary biliary cirrhosis, said Alexie Bosch at Hôpital Edouard Herriot in Lyon, France, and his associates.

©pixologicstudio/thinkstockphotos.com

Primary biliary cirrhosis can recur after liver transplantation and increases the chances of graft dysfunction, the researchers noted. UDCA is the only approved medical treatment for primary biliary cirrhosis in the United States or Europe, but no research team has studied its potential to prevent recurrent primary biliary cirrhosis after liver transplantation, they added. Therefore, they retrospectively studied 90 patients with primary biliary cirrhosis who underwent liver transplantation at five centers in France and Switzerland between 1988 and 2010. In all, 21% of patients received oral UDCA (10-15 mg/kg per day in two divided doses) within 2 weeks after their operation, while the rest received it only if they developed biopsy-confirmed recurrent primary biliary cirrhosis. Biopsies were taken at posttransplant year 1 and every 5 years after that, or when clinically indicated, the investigators noted (J Hepatol. 2015 Aug. 14. doi: 10.1016/j.jhep.2015.07.038).

Patients who received preventive UDCA had a lower cumulative rate of recurrence throughout 15 years of postsurgical follow-up (P = .014), the researchers reported. The chances of recurrent primary biliary cirrhosis at 5, 10, and 15 years after transplantation were 11%, 21%, and 40% in the UDCA group, compared with 32%, 53%, and 70% for patients who did not receive prophylactic UDCA, they added. A multivariable analysis showed that recurrent primary biliary cirrhosis was associated with not receiving prophylactic UDCA (hazard ratio, 0.32; 95% confidence interval, 0.11, 0.91), but was not linked to donor age, Model For End-Stage Liver Disease (MELD) score, or sex mismatch between donor and recipient, the investigators said. Preventive UDCA also was tied to a 1.6-year longer median time to recurrence, although the trend did not reach statistical significance.

Although the study was retrospective and most patients who received UDCA were treated at one transplant center, all centers had similar histologic findings for recurrent primary biliary cirrhosis, said the researchers. Biopsies also were histologically similar regardless of whether they were event driven or obtained based on the study protocol, and time to recurrence did not vary based on biopsy type, they added. “In our multivariate analysis, we took care to account for all risk factors and confounders, as well as to test multilevel models in order to exclude potential misleading results and center effects,” they emphasized. “Given the extremely limited feasibility of prospective studies and the good tolerance and acceptability of long-term UDCA therapy, these results support the extended use of UDCA as prophylaxis for primary biliary cirrhosis recurrence after liver transplantation.”

The researchers declared no funding sources and reported having no conflicts of interest.

[email protected]

Only 21% of liver transplantation patients who received ursodeoxycholic acid (UDCA) after surgery developed recurrent primary biliary cirrhosis, compared with 62% of patients who did not receive the bile acid, researchers reported in the Journal of Hepatology.

The results provide strong evidence that routinely giving liver transplant patients UDCA can prevent or delay recurrent primary biliary cirrhosis, said Alexie Bosch at Hôpital Edouard Herriot in Lyon, France, and his associates.

©pixologicstudio/thinkstockphotos.com

Primary biliary cirrhosis can recur after liver transplantation and increases the chances of graft dysfunction, the researchers noted. UDCA is the only approved medical treatment for primary biliary cirrhosis in the United States or Europe, but no research team has studied its potential to prevent recurrent primary biliary cirrhosis after liver transplantation, they added. Therefore, they retrospectively studied 90 patients with primary biliary cirrhosis who underwent liver transplantation at five centers in France and Switzerland between 1988 and 2010. In all, 21% of patients received oral UDCA (10-15 mg/kg per day in two divided doses) within 2 weeks after their operation, while the rest received it only if they developed biopsy-confirmed recurrent primary biliary cirrhosis. Biopsies were taken at posttransplant year 1 and every 5 years after that, or when clinically indicated, the investigators noted (J Hepatol. 2015 Aug. 14. doi: 10.1016/j.jhep.2015.07.038).

Patients who received preventive UDCA had a lower cumulative rate of recurrence throughout 15 years of postsurgical follow-up (P = .014), the researchers reported. The chances of recurrent primary biliary cirrhosis at 5, 10, and 15 years after transplantation were 11%, 21%, and 40% in the UDCA group, compared with 32%, 53%, and 70% for patients who did not receive prophylactic UDCA, they added. A multivariable analysis showed that recurrent primary biliary cirrhosis was associated with not receiving prophylactic UDCA (hazard ratio, 0.32; 95% confidence interval, 0.11, 0.91), but was not linked to donor age, Model For End-Stage Liver Disease (MELD) score, or sex mismatch between donor and recipient, the investigators said. Preventive UDCA also was tied to a 1.6-year longer median time to recurrence, although the trend did not reach statistical significance.

Although the study was retrospective and most patients who received UDCA were treated at one transplant center, all centers had similar histologic findings for recurrent primary biliary cirrhosis, said the researchers. Biopsies also were histologically similar regardless of whether they were event driven or obtained based on the study protocol, and time to recurrence did not vary based on biopsy type, they added. “In our multivariate analysis, we took care to account for all risk factors and confounders, as well as to test multilevel models in order to exclude potential misleading results and center effects,” they emphasized. “Given the extremely limited feasibility of prospective studies and the good tolerance and acceptability of long-term UDCA therapy, these results support the extended use of UDCA as prophylaxis for primary biliary cirrhosis recurrence after liver transplantation.”

The researchers declared no funding sources and reported having no conflicts of interest.

[email protected]

Only 21% of liver transplantation patients who received ursodeoxycholic acid (UDCA) after surgery developed recurrent primary biliary cirrhosis, compared with 62% of patients who did not receive the bile acid, researchers reported in the Journal of Hepatology.

The results provide strong evidence that routinely giving liver transplant patients UDCA can prevent or delay recurrent primary biliary cirrhosis, said Alexie Bosch at Hôpital Edouard Herriot in Lyon, France, and his associates.

©pixologicstudio/thinkstockphotos.com

Primary biliary cirrhosis can recur after liver transplantation and increases the chances of graft dysfunction, the researchers noted. UDCA is the only approved medical treatment for primary biliary cirrhosis in the United States or Europe, but no research team has studied its potential to prevent recurrent primary biliary cirrhosis after liver transplantation, they added. Therefore, they retrospectively studied 90 patients with primary biliary cirrhosis who underwent liver transplantation at five centers in France and Switzerland between 1988 and 2010. In all, 21% of patients received oral UDCA (10-15 mg/kg per day in two divided doses) within 2 weeks after their operation, while the rest received it only if they developed biopsy-confirmed recurrent primary biliary cirrhosis. Biopsies were taken at posttransplant year 1 and every 5 years after that, or when clinically indicated, the investigators noted (J Hepatol. 2015 Aug. 14. doi: 10.1016/j.jhep.2015.07.038).

Patients who received preventive UDCA had a lower cumulative rate of recurrence throughout 15 years of postsurgical follow-up (P = .014), the researchers reported. The chances of recurrent primary biliary cirrhosis at 5, 10, and 15 years after transplantation were 11%, 21%, and 40% in the UDCA group, compared with 32%, 53%, and 70% for patients who did not receive prophylactic UDCA, they added. A multivariable analysis showed that recurrent primary biliary cirrhosis was associated with not receiving prophylactic UDCA (hazard ratio, 0.32; 95% confidence interval, 0.11, 0.91), but was not linked to donor age, Model For End-Stage Liver Disease (MELD) score, or sex mismatch between donor and recipient, the investigators said. Preventive UDCA also was tied to a 1.6-year longer median time to recurrence, although the trend did not reach statistical significance.

Although the study was retrospective and most patients who received UDCA were treated at one transplant center, all centers had similar histologic findings for recurrent primary biliary cirrhosis, said the researchers. Biopsies also were histologically similar regardless of whether they were event driven or obtained based on the study protocol, and time to recurrence did not vary based on biopsy type, they added. “In our multivariate analysis, we took care to account for all risk factors and confounders, as well as to test multilevel models in order to exclude potential misleading results and center effects,” they emphasized. “Given the extremely limited feasibility of prospective studies and the good tolerance and acceptability of long-term UDCA therapy, these results support the extended use of UDCA as prophylaxis for primary biliary cirrhosis recurrence after liver transplantation.”

The researchers declared no funding sources and reported having no conflicts of interest.

[email protected]

Pelvic ultrasonography remains the preferred imaging method to evaluate most adnexal cysts given its ability to characterize such cysts with high resolution and accuracy. Most cystic adnexal masses have characteristic findings that can guide counseling and management decisions. For instance, mature cystic teratomas have hyperechoic lines/dots and acoustic shadowing; hydrosalpinx are tubular or s shaped and show a “waist sign.”

In parts 1 through 3 of this 4-part series on adnexal pathology, we presented images detailing common benign adnexal cysts, including:

• simple and hemorrhagic cysts (Part 1:Telltale sonographic features of simple and hemorrhagic cysts)
• mature cystic teratomas (dermoid cysts) and endometriomas (Part 2: Imaging the endometrioma and mature cystic teratoma)
• hydrosalpinx and pelvic inclusion cysts (Part 3: “Cogwheel” and other signs of hydrosalpinx and pelvic inclusion cysts)

In this conclusion to the series, we detail imaging for ovarian neoplasias (including cystadenoma and cystadenocarcinoma).

OVARIAN NEOPLASIA

A woman’s lifetime risk of undergoing surgery for suspected ovarian malignancy is 5% to 10% in the United States, and only about 13% to 21% of those undergoing surgery will actually be diagnosed with ovarian cancer.¹ Therefore, the goal of diagnostic evaluation is to exclude malignancy.

Diagnostic evaluation includes:

• imaging
• lab work
• history
• physical findings.

The preferred imaging modality for a pelvic mass in asymptomatic premenopausal and postmenopausal women is transvaginal ultrasonography according to the American College of Obstetricians and Gynecologists (ACOG) practice bulletin, which was reaffirmed in 2013.¹ “No alternative imaging modality has demonstrated sufficient superiority to transvaginal ultrasonography to justify its routine use.”¹

Transvaginal ultrasonography with color Doppler interrogation has demonstrated a sensitivity of 0.86% and a specificity of 0.91% for discriminating between malignant and benign ovarian masses.

Sonographic features that are worrisome for malignancy include:

• Multiple thin septations (if indeterminate, the mass may possibly be benign)
• Thick (> 3 mm), irregular septations
• Focal areas of wall thickening (> 3 mm)
• Mural nodules or papillary projections
  • Levine and colleagues note that a cyst with a mural nodule with internal blood flow on color Doppler has the highest likelihood of being malignant²
• Moderate or large amount of ascitic fluid in pelvis (in conjunction with ovarian mass showing the above characteristics)

Various morphology indices have been developed that combine these criteria with ovarian mass volume to determine the preoperative predictive value for malignancy.

In the images that follow, we present 14 cases that demonstrate cystadenoma, low malignant potential tumors, and ovarian neoplasia.

CASE 1. Right ovarian mucinous cystadenoma in 68-year-old woman with uterine prolapse and history of ovarian cyst

CASE 2. Borderline serous cystadenoma in 56-year-old woman with right lower quadrant pain, nausea, and loss of appetite

CASE 3. Mucinous cystadenoma in 38-year-old woman undergoing sonography for spontaneous abortion

CASE 4. Mucinous cystadenoma in 54-year-old woman undergoing follow-up ultrasound for persistent ovarian cyst

CASE 7. Mature cystic teratoma in 31-year-old woman with progressively heavier bleeding and pelvic pain

CASE 11. Sex-cord stromal tumor in 61-year-old woman with postmenopausal bleeding

CASE 12. Juvenile granulosa cell tumor in 19-year-old patient with secondary amenorrhea

CASE 14. Mucinous borderline tumor in 55-year-old woman with pelvic discomfort

Pelvic ultrasonography remains the preferred imaging method to evaluate most adnexal cysts given its ability to characterize such cysts with high resolution and accuracy. Most cystic adnexal masses have characteristic findings that can guide counseling and management decisions. For instance, mature cystic teratomas have hyperechoic lines/dots and acoustic shadowing; hydrosalpinx are tubular or s shaped and show a “waist sign.”

In parts 1 through 3 of this 4-part series on adnexal pathology, we presented images detailing common benign adnexal cysts, including:

• simple and hemorrhagic cysts (Part 1:Telltale sonographic features of simple and hemorrhagic cysts)
• mature cystic teratomas (dermoid cysts) and endometriomas (Part 2: Imaging the endometrioma and mature cystic teratoma)
• hydrosalpinx and pelvic inclusion cysts (Part 3: “Cogwheel” and other signs of hydrosalpinx and pelvic inclusion cysts)

In this conclusion to the series, we detail imaging for ovarian neoplasias (including cystadenoma and cystadenocarcinoma).

OVARIAN NEOPLASIA

A woman’s lifetime risk of undergoing surgery for suspected ovarian malignancy is 5% to 10% in the United States, and only about 13% to 21% of those undergoing surgery will actually be diagnosed with ovarian cancer.¹ Therefore, the goal of diagnostic evaluation is to exclude malignancy.

Diagnostic evaluation includes:

• imaging
• lab work
• history
• physical findings.

The preferred imaging modality for a pelvic mass in asymptomatic premenopausal and postmenopausal women is transvaginal ultrasonography according to the American College of Obstetricians and Gynecologists (ACOG) practice bulletin, which was reaffirmed in 2013.¹ “No alternative imaging modality has demonstrated sufficient superiority to transvaginal ultrasonography to justify its routine use.”¹

Transvaginal ultrasonography with color Doppler interrogation has demonstrated a sensitivity of 0.86% and a specificity of 0.91% for discriminating between malignant and benign ovarian masses.

Sonographic features that are worrisome for malignancy include:

• Multiple thin septations (if indeterminate, the mass may possibly be benign)
• Thick (> 3 mm), irregular septations
• Focal areas of wall thickening (> 3 mm)
• Mural nodules or papillary projections
  • Levine and colleagues note that a cyst with a mural nodule with internal blood flow on color Doppler has the highest likelihood of being malignant²
• Moderate or large amount of ascitic fluid in pelvis (in conjunction with ovarian mass showing the above characteristics)

Various morphology indices have been developed that combine these criteria with ovarian mass volume to determine the preoperative predictive value for malignancy.

In the images that follow, we present 14 cases that demonstrate cystadenoma, low malignant potential tumors, and ovarian neoplasia.

CASE 1. Right ovarian mucinous cystadenoma in 68-year-old woman with uterine prolapse and history of ovarian cyst

CASE 2. Borderline serous cystadenoma in 56-year-old woman with right lower quadrant pain, nausea, and loss of appetite

CASE 3. Mucinous cystadenoma in 38-year-old woman undergoing sonography for spontaneous abortion

CASE 4. Mucinous cystadenoma in 54-year-old woman undergoing follow-up ultrasound for persistent ovarian cyst

CASE 7. Mature cystic teratoma in 31-year-old woman with progressively heavier bleeding and pelvic pain

CASE 11. Sex-cord stromal tumor in 61-year-old woman with postmenopausal bleeding

CASE 12. Juvenile granulosa cell tumor in 19-year-old patient with secondary amenorrhea

CASE 14. Mucinous borderline tumor in 55-year-old woman with pelvic discomfort

Pelvic ultrasonography remains the preferred imaging method to evaluate most adnexal cysts given its ability to characterize such cysts with high resolution and accuracy. Most cystic adnexal masses have characteristic findings that can guide counseling and management decisions. For instance, mature cystic teratomas have hyperechoic lines/dots and acoustic shadowing; hydrosalpinx are tubular or s shaped and show a “waist sign.”

In parts 1 through 3 of this 4-part series on adnexal pathology, we presented images detailing common benign adnexal cysts, including:

• simple and hemorrhagic cysts (Part 1:Telltale sonographic features of simple and hemorrhagic cysts)
• mature cystic teratomas (dermoid cysts) and endometriomas (Part 2: Imaging the endometrioma and mature cystic teratoma)
• hydrosalpinx and pelvic inclusion cysts (Part 3: “Cogwheel” and other signs of hydrosalpinx and pelvic inclusion cysts)

In this conclusion to the series, we detail imaging for ovarian neoplasias (including cystadenoma and cystadenocarcinoma).

OVARIAN NEOPLASIA

A woman’s lifetime risk of undergoing surgery for suspected ovarian malignancy is 5% to 10% in the United States, and only about 13% to 21% of those undergoing surgery will actually be diagnosed with ovarian cancer.¹ Therefore, the goal of diagnostic evaluation is to exclude malignancy.

Diagnostic evaluation includes:

• imaging
• lab work
• history
• physical findings.

The preferred imaging modality for a pelvic mass in asymptomatic premenopausal and postmenopausal women is transvaginal ultrasonography according to the American College of Obstetricians and Gynecologists (ACOG) practice bulletin, which was reaffirmed in 2013.¹ “No alternative imaging modality has demonstrated sufficient superiority to transvaginal ultrasonography to justify its routine use.”¹

Transvaginal ultrasonography with color Doppler interrogation has demonstrated a sensitivity of 0.86% and a specificity of 0.91% for discriminating between malignant and benign ovarian masses.

Sonographic features that are worrisome for malignancy include:

• Multiple thin septations (if indeterminate, the mass may possibly be benign)
• Thick (> 3 mm), irregular septations
• Focal areas of wall thickening (> 3 mm)
• Mural nodules or papillary projections
  • Levine and colleagues note that a cyst with a mural nodule with internal blood flow on color Doppler has the highest likelihood of being malignant²
• Moderate or large amount of ascitic fluid in pelvis (in conjunction with ovarian mass showing the above characteristics)

Various morphology indices have been developed that combine these criteria with ovarian mass volume to determine the preoperative predictive value for malignancy.

In the images that follow, we present 14 cases that demonstrate cystadenoma, low malignant potential tumors, and ovarian neoplasia.

CASE 1. Right ovarian mucinous cystadenoma in 68-year-old woman with uterine prolapse and history of ovarian cyst

CASE 2. Borderline serous cystadenoma in 56-year-old woman with right lower quadrant pain, nausea, and loss of appetite

CASE 3. Mucinous cystadenoma in 38-year-old woman undergoing sonography for spontaneous abortion

CASE 4. Mucinous cystadenoma in 54-year-old woman undergoing follow-up ultrasound for persistent ovarian cyst

CASE 7. Mature cystic teratoma in 31-year-old woman with progressively heavier bleeding and pelvic pain

CASE 11. Sex-cord stromal tumor in 61-year-old woman with postmenopausal bleeding

CASE 12. Juvenile granulosa cell tumor in 19-year-old patient with secondary amenorrhea

CASE 14. Mucinous borderline tumor in 55-year-old woman with pelvic discomfort

KHSV-infected cells (yellow)

Image courtesy of the

University of North Carolina

Researchers say they have uncovered a viral protein that inhibits cGAS, the principal cytosolic DNA sensor that detects invading viral DNA and triggers antiviral responses.

The protein, Kaposi’s sarcoma-associated herpesvirus (KSHV) ORF52, subverts cytosolic DNA sensing by directly inhibiting cGAS enzymatic activity.

The team believes this finding could have a range of therapeutic implications.

“We can manipulate the protein and/or the sensor to boost or tune down the immune response in order to fight infectious and autoimmune diseases, as well as cancers,” said Fanxiu Zhu, PhD, of Florida State University in Tallahassee.

Dr Zhu and his colleagues described this research in Cell Host and Microbe.

The authors noted that, although cGAS senses several DNA viruses, viral strategies targeting cGAS are “virtually unknown.”

To uncover a cGAS inhibitor, the researchers screened every protein in a KSHV cell—90 in total. This revealed KSHV ORF52, which the team renamed “KicGas,” an abbreviation for “KSHV inhibitor of cGAS.”

Further investigation revealed how KicGas inhibits cGAS activity: it must bind to both DNA and cGAS.

The researchers then found that ORF52 homologs in other gammaherpesviruses also inhibit cGAS activity and similarly bind cGAS and DNA.

Finally, the team infected human cell lines with KSHV to mimic natural infection. They found that KSHV triggers a cGAS-dependent immune response that can be partially mitigated by KicGas.

When the researchers eliminated KicGas from infected cells, the cells produced a much stronger immune response.

For the next phase of research, the team is building a 3-dimensional model to help them better understand how KicGas functions. They hope this will help them utilize KicGas to fight disease.

KHSV-infected cells (yellow)

Image courtesy of the

University of North Carolina

Researchers say they have uncovered a viral protein that inhibits cGAS, the principal cytosolic DNA sensor that detects invading viral DNA and triggers antiviral responses.

The protein, Kaposi’s sarcoma-associated herpesvirus (KSHV) ORF52, subverts cytosolic DNA sensing by directly inhibiting cGAS enzymatic activity.

The team believes this finding could have a range of therapeutic implications.

“We can manipulate the protein and/or the sensor to boost or tune down the immune response in order to fight infectious and autoimmune diseases, as well as cancers,” said Fanxiu Zhu, PhD, of Florida State University in Tallahassee.

Dr Zhu and his colleagues described this research in Cell Host and Microbe.

The authors noted that, although cGAS senses several DNA viruses, viral strategies targeting cGAS are “virtually unknown.”

To uncover a cGAS inhibitor, the researchers screened every protein in a KSHV cell—90 in total. This revealed KSHV ORF52, which the team renamed “KicGas,” an abbreviation for “KSHV inhibitor of cGAS.”

Further investigation revealed how KicGas inhibits cGAS activity: it must bind to both DNA and cGAS.

The researchers then found that ORF52 homologs in other gammaherpesviruses also inhibit cGAS activity and similarly bind cGAS and DNA.

Finally, the team infected human cell lines with KSHV to mimic natural infection. They found that KSHV triggers a cGAS-dependent immune response that can be partially mitigated by KicGas.

When the researchers eliminated KicGas from infected cells, the cells produced a much stronger immune response.

For the next phase of research, the team is building a 3-dimensional model to help them better understand how KicGas functions. They hope this will help them utilize KicGas to fight disease.

KHSV-infected cells (yellow)

Image courtesy of the

University of North Carolina

Researchers say they have uncovered a viral protein that inhibits cGAS, the principal cytosolic DNA sensor that detects invading viral DNA and triggers antiviral responses.

The protein, Kaposi’s sarcoma-associated herpesvirus (KSHV) ORF52, subverts cytosolic DNA sensing by directly inhibiting cGAS enzymatic activity.

The team believes this finding could have a range of therapeutic implications.

“We can manipulate the protein and/or the sensor to boost or tune down the immune response in order to fight infectious and autoimmune diseases, as well as cancers,” said Fanxiu Zhu, PhD, of Florida State University in Tallahassee.

Dr Zhu and his colleagues described this research in Cell Host and Microbe.

The authors noted that, although cGAS senses several DNA viruses, viral strategies targeting cGAS are “virtually unknown.”

To uncover a cGAS inhibitor, the researchers screened every protein in a KSHV cell—90 in total. This revealed KSHV ORF52, which the team renamed “KicGas,” an abbreviation for “KSHV inhibitor of cGAS.”

Further investigation revealed how KicGas inhibits cGAS activity: it must bind to both DNA and cGAS.

The researchers then found that ORF52 homologs in other gammaherpesviruses also inhibit cGAS activity and similarly bind cGAS and DNA.

Finally, the team infected human cell lines with KSHV to mimic natural infection. They found that KSHV triggers a cGAS-dependent immune response that can be partially mitigated by KicGas.

When the researchers eliminated KicGas from infected cells, the cells produced a much stronger immune response.

For the next phase of research, the team is building a 3-dimensional model to help them better understand how KicGas functions. They hope this will help them utilize KicGas to fight disease.

Multiple reports of severe and disabling joint pain in some patients taking dipeptidyl peptidase-4 (DPP-4) inhibitors for type 2 diabetes have prompted the Food and Drug Administration to add a new warning and precaution for this class of drugs. Some cases were severe enough to require hospitalization, though symptoms eventually resolved after patients stopped taking the medication.

In a MedWatch Bulletin, the FDA advises that physicians should be alert for DPP-4 inhibitors as a causative factor for patients who present with severe, persistent joint pain, even for those who have been on the medication for some time.

Courtesy Wikimedia Commons/FitzColinGerald/Creative Commons License

Most patients developed symptoms within a month of beginning treatment; however, some patients had been on a DPP-4 inhibitor for as long as a year before the onset of joint pain. When the medication was stopped, arthralgia resolved within a month in all reported cases.

Of the 33 cases of severe arthralgia found in the FDA adverse events reporting database, 28 were associated with the use of sitagliptin (Januvia), with some cases also reported with saxagliptin (Onglyza), linagliptin (Tradjenta), alogliptin (Nesina), and vildagliptin (Galvus). Ten patients’ symptoms were severe enough to require hospitalization; eight experienced recurrent arthralgia when rechallenged.

A literature search conducted by FDA officials revealed seven reports of DPP-4 inhibitor–associated arthralgia, two of which also were in their reporting database.

Patients taking DPP-4 inhibitors should continue taking their medication but consult their health care providers if they experience severe, persistent joint pain, according to the FDA advisory.

[email protected]

On Twitter @karioakes

Multiple reports of severe and disabling joint pain in some patients taking dipeptidyl peptidase-4 (DPP-4) inhibitors for type 2 diabetes have prompted the Food and Drug Administration to add a new warning and precaution for this class of drugs. Some cases were severe enough to require hospitalization, though symptoms eventually resolved after patients stopped taking the medication.

In a MedWatch Bulletin, the FDA advises that physicians should be alert for DPP-4 inhibitors as a causative factor for patients who present with severe, persistent joint pain, even for those who have been on the medication for some time.

Courtesy Wikimedia Commons/FitzColinGerald/Creative Commons License

Most patients developed symptoms within a month of beginning treatment; however, some patients had been on a DPP-4 inhibitor for as long as a year before the onset of joint pain. When the medication was stopped, arthralgia resolved within a month in all reported cases.

Of the 33 cases of severe arthralgia found in the FDA adverse events reporting database, 28 were associated with the use of sitagliptin (Januvia), with some cases also reported with saxagliptin (Onglyza), linagliptin (Tradjenta), alogliptin (Nesina), and vildagliptin (Galvus). Ten patients’ symptoms were severe enough to require hospitalization; eight experienced recurrent arthralgia when rechallenged.

A literature search conducted by FDA officials revealed seven reports of DPP-4 inhibitor–associated arthralgia, two of which also were in their reporting database.

Patients taking DPP-4 inhibitors should continue taking their medication but consult their health care providers if they experience severe, persistent joint pain, according to the FDA advisory.

[email protected]

On Twitter @karioakes

Multiple reports of severe and disabling joint pain in some patients taking dipeptidyl peptidase-4 (DPP-4) inhibitors for type 2 diabetes have prompted the Food and Drug Administration to add a new warning and precaution for this class of drugs. Some cases were severe enough to require hospitalization, though symptoms eventually resolved after patients stopped taking the medication.

In a MedWatch Bulletin, the FDA advises that physicians should be alert for DPP-4 inhibitors as a causative factor for patients who present with severe, persistent joint pain, even for those who have been on the medication for some time.

Courtesy Wikimedia Commons/FitzColinGerald/Creative Commons License

Most patients developed symptoms within a month of beginning treatment; however, some patients had been on a DPP-4 inhibitor for as long as a year before the onset of joint pain. When the medication was stopped, arthralgia resolved within a month in all reported cases.

Of the 33 cases of severe arthralgia found in the FDA adverse events reporting database, 28 were associated with the use of sitagliptin (Januvia), with some cases also reported with saxagliptin (Onglyza), linagliptin (Tradjenta), alogliptin (Nesina), and vildagliptin (Galvus). Ten patients’ symptoms were severe enough to require hospitalization; eight experienced recurrent arthralgia when rechallenged.

A literature search conducted by FDA officials revealed seven reports of DPP-4 inhibitor–associated arthralgia, two of which also were in their reporting database.

Patients taking DPP-4 inhibitors should continue taking their medication but consult their health care providers if they experience severe, persistent joint pain, according to the FDA advisory.

[email protected]

On Twitter @karioakes

Drs Michelle Churchman

and Charles Mullighan

Photo courtesy of St. Jude

Children’s Research Hospital

and Peter Barta

Retinoids and FAK inhibitors may override resistance to tyrosine kinase inhibitors (TKIs) in IKZF1-mutated, Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), according to preclinical research published in Cancer Cell.

Experiments showed that, in Ph+ ALL, IKZF1 mutations prompt changes that reduce responsiveness to TKIs. But combining a TKI with a retinoid or FAK inhibitor can overcome this problem.

“The research shows why, in this era of targeted therapies, Ph+ ALL patients who also have IKZF1 mutations fare so poorly,” said study author Charles Mullighan, MD, MBBS, of St. Jude Children’s Research Hospital in Memphis, Tennessee. “The insight also led us to a promising new treatment strategy.”

To conduct this research, Dr Mullighan and his colleagues began with mouse models of IKZF1-mutated Ph+ ALL, with and without mutations in the ARF gene. ARF encodes a tumor suppressor protein and is altered in about half of Ph+ ALL cases.

With these models, the researchers showed that the addition of IKZF1 mutations, particularly in combination with ARF mutations, was a central event in driving ALL.

In pre-B cells with BCR-ABL1, IKZF1 mutations induced a stem cell-like phenotype, increased stromal bone marrow adhesion, and reduced responsiveness to the TKI dasatinib.

When the researchers investigated the increased adhesion of mutated cells, they found overexpression of FAK and other molecules implicated in leukemic and stem cell adherence. This led the researchers to speculate that FAK inhibitors might prove useful against IKZF1-mutated Ph+ ALL.

But the team also found, through a screen of 483 compounds, that retinoids can reverse the effects of IKZF1 mutations. The antineoplastic agent bexarotene and 4 nuclear hormone receptor effectors—carbacyclin, all-trans retinoic acid (ATRA), 9-cis RA, and 13-cis RA—proved particularly effective.

The drugs worked, in part, by inducing expression of wild-type IKZF1. But they also worked in other ways to reverse the stem-cell phenotype, halt cell proliferation, and promote differentiation of altered cells.

The researchers then tested bexarotene and dasatinib, alone and in combination, in mice transplanted with ARF^-/- BCR-ABL1 pre-B cells, with or without IK6 expression. Bexarotene alone produced “significant benefit without detectable toxicity.”

Dasatinib alone increased survival, but dasatinib and bexarotene in combination resulted in a greater survival advantage. The combination nearly doubled the survival time of mice with IK6 tumors, when compared to dasatinib alone.

The researchers also established xenografts of Ph+ ALL that recapitulate a range of IKZF1 genotypes. They administered dasatinib plus bexarotene, ATRA, or the FAK inhibitors PF-562271, NVPTAE226, or PF-573228 ex vivo and observed “significant potentiation of cell killing.”

The team is currently investigating how to incorporate retinoids or FAK inhibitors into the existing treatment of IKZF1-mutated Ph+ ALL.

Drs Michelle Churchman

and Charles Mullighan

Photo courtesy of St. Jude

Children’s Research Hospital

and Peter Barta

Retinoids and FAK inhibitors may override resistance to tyrosine kinase inhibitors (TKIs) in IKZF1-mutated, Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), according to preclinical research published in Cancer Cell.

Experiments showed that, in Ph+ ALL, IKZF1 mutations prompt changes that reduce responsiveness to TKIs. But combining a TKI with a retinoid or FAK inhibitor can overcome this problem.

“The research shows why, in this era of targeted therapies, Ph+ ALL patients who also have IKZF1 mutations fare so poorly,” said study author Charles Mullighan, MD, MBBS, of St. Jude Children’s Research Hospital in Memphis, Tennessee. “The insight also led us to a promising new treatment strategy.”

To conduct this research, Dr Mullighan and his colleagues began with mouse models of IKZF1-mutated Ph+ ALL, with and without mutations in the ARF gene. ARF encodes a tumor suppressor protein and is altered in about half of Ph+ ALL cases.

With these models, the researchers showed that the addition of IKZF1 mutations, particularly in combination with ARF mutations, was a central event in driving ALL.

In pre-B cells with BCR-ABL1, IKZF1 mutations induced a stem cell-like phenotype, increased stromal bone marrow adhesion, and reduced responsiveness to the TKI dasatinib.

When the researchers investigated the increased adhesion of mutated cells, they found overexpression of FAK and other molecules implicated in leukemic and stem cell adherence. This led the researchers to speculate that FAK inhibitors might prove useful against IKZF1-mutated Ph+ ALL.

But the team also found, through a screen of 483 compounds, that retinoids can reverse the effects of IKZF1 mutations. The antineoplastic agent bexarotene and 4 nuclear hormone receptor effectors—carbacyclin, all-trans retinoic acid (ATRA), 9-cis RA, and 13-cis RA—proved particularly effective.

The drugs worked, in part, by inducing expression of wild-type IKZF1. But they also worked in other ways to reverse the stem-cell phenotype, halt cell proliferation, and promote differentiation of altered cells.

The researchers then tested bexarotene and dasatinib, alone and in combination, in mice transplanted with ARF^-/- BCR-ABL1 pre-B cells, with or without IK6 expression. Bexarotene alone produced “significant benefit without detectable toxicity.”

Dasatinib alone increased survival, but dasatinib and bexarotene in combination resulted in a greater survival advantage. The combination nearly doubled the survival time of mice with IK6 tumors, when compared to dasatinib alone.

The researchers also established xenografts of Ph+ ALL that recapitulate a range of IKZF1 genotypes. They administered dasatinib plus bexarotene, ATRA, or the FAK inhibitors PF-562271, NVPTAE226, or PF-573228 ex vivo and observed “significant potentiation of cell killing.”

The team is currently investigating how to incorporate retinoids or FAK inhibitors into the existing treatment of IKZF1-mutated Ph+ ALL.

Drs Michelle Churchman

and Charles Mullighan

Photo courtesy of St. Jude

Children’s Research Hospital

and Peter Barta

Retinoids and FAK inhibitors may override resistance to tyrosine kinase inhibitors (TKIs) in IKZF1-mutated, Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), according to preclinical research published in Cancer Cell.

Experiments showed that, in Ph+ ALL, IKZF1 mutations prompt changes that reduce responsiveness to TKIs. But combining a TKI with a retinoid or FAK inhibitor can overcome this problem.

“The research shows why, in this era of targeted therapies, Ph+ ALL patients who also have IKZF1 mutations fare so poorly,” said study author Charles Mullighan, MD, MBBS, of St. Jude Children’s Research Hospital in Memphis, Tennessee. “The insight also led us to a promising new treatment strategy.”

To conduct this research, Dr Mullighan and his colleagues began with mouse models of IKZF1-mutated Ph+ ALL, with and without mutations in the ARF gene. ARF encodes a tumor suppressor protein and is altered in about half of Ph+ ALL cases.

With these models, the researchers showed that the addition of IKZF1 mutations, particularly in combination with ARF mutations, was a central event in driving ALL.

In pre-B cells with BCR-ABL1, IKZF1 mutations induced a stem cell-like phenotype, increased stromal bone marrow adhesion, and reduced responsiveness to the TKI dasatinib.

When the researchers investigated the increased adhesion of mutated cells, they found overexpression of FAK and other molecules implicated in leukemic and stem cell adherence. This led the researchers to speculate that FAK inhibitors might prove useful against IKZF1-mutated Ph+ ALL.

But the team also found, through a screen of 483 compounds, that retinoids can reverse the effects of IKZF1 mutations. The antineoplastic agent bexarotene and 4 nuclear hormone receptor effectors—carbacyclin, all-trans retinoic acid (ATRA), 9-cis RA, and 13-cis RA—proved particularly effective.

The drugs worked, in part, by inducing expression of wild-type IKZF1. But they also worked in other ways to reverse the stem-cell phenotype, halt cell proliferation, and promote differentiation of altered cells.

The researchers then tested bexarotene and dasatinib, alone and in combination, in mice transplanted with ARF^-/- BCR-ABL1 pre-B cells, with or without IK6 expression. Bexarotene alone produced “significant benefit without detectable toxicity.”

Dasatinib alone increased survival, but dasatinib and bexarotene in combination resulted in a greater survival advantage. The combination nearly doubled the survival time of mice with IK6 tumors, when compared to dasatinib alone.

The researchers also established xenografts of Ph+ ALL that recapitulate a range of IKZF1 genotypes. They administered dasatinib plus bexarotene, ATRA, or the FAK inhibitors PF-562271, NVPTAE226, or PF-573228 ex vivo and observed “significant potentiation of cell killing.”

The team is currently investigating how to incorporate retinoids or FAK inhibitors into the existing treatment of IKZF1-mutated Ph+ ALL.

Malaria rapid diagnostic test

Photo courtesy of USAID

A study conducted in Nigeria has shown that health providers continue to prescribe malaria medicines inappropriately, even after they learn to test for malaria and receive testing kits free of charge.

Health providers were given rapid diagnostic tests (RDT) for malaria and learned to use the tests via 3 different methods.

However, the use of RDTs was “critically low” in all 3 groups, as was the proportion of patients treated appropriately.

“This study confirms that treating malaria based on signs and symptoms alone remains an ingrained behavior that is difficult to change,” said Obinna Onwujekwe, MD, PhD, of the University of Nigeria in Enugu.

Dr Onwujekwe and his colleagues reported these findings in PLOS ONE.

Interventions

Their study included health workers and patients from 40 communities in the Nigerian state of Enugu. Health workers received free RDT kits and were taught to use the tests in 3 different ways.

The first group received comprehensive RDT training, which included instructions on how to use an RDT, guidelines on malaria diagnosis and treatment, information about other causes of fever, and help with communications skills, especially for patients whose test results were negative.

The second group received the same training plus a school-based intervention that involved training 2 teachers per school. The aim was to influence the attitudes of school children and their families as well as the wider community.

And health workers in the third group—the control arm—were invited to a demonstration and practical on how to safely use RDTs and supplied with written instructions on their use.

Results

The primary outcome was the proportion of patients who were treated according to guidelines. In other words, they presented with symptoms consistent with malaria, were tested for malaria, and received treatment consistent with the test result.

The researchers assessed the primary outcome in 4946 patients from 40 communities—12 in the control arm and 14 in each intervention arm.

There was no significant difference between the arms with regard to this outcome. The proportion of patients treated according to guidelines was 36% in the comprehensive training arm, 24% in the training-school arm, and 23% in the control arm (P=0.36).

Likewise, the use of testing was low in all arms—34% in the control arm, 48% in the training arm, and 37% in the training-school arm (P=0.47).

The use of testing was lower at private facilities than public ones. Cost may have been a factor here, as public facilities were asked to offer testing free of charge, but private facilities could charge 100 Naira (0.6 USD).

“We have shown that training alone is not enough to realize the full potential of an RDT,” said Virginia Wiseman, PhD, of the London School of Hygiene & Tropical Medicine in the UK.

“We must continue to explore alternative ways of encouraging providers to deliver appropriate treatment and avoid the misuse of valuable medicines, especially in the private sector, where we found levels of testing to be lowest.”

Malaria rapid diagnostic test

Photo courtesy of USAID

A study conducted in Nigeria has shown that health providers continue to prescribe malaria medicines inappropriately, even after they learn to test for malaria and receive testing kits free of charge.

Health providers were given rapid diagnostic tests (RDT) for malaria and learned to use the tests via 3 different methods.

However, the use of RDTs was “critically low” in all 3 groups, as was the proportion of patients treated appropriately.

“This study confirms that treating malaria based on signs and symptoms alone remains an ingrained behavior that is difficult to change,” said Obinna Onwujekwe, MD, PhD, of the University of Nigeria in Enugu.

Dr Onwujekwe and his colleagues reported these findings in PLOS ONE.

Interventions

Their study included health workers and patients from 40 communities in the Nigerian state of Enugu. Health workers received free RDT kits and were taught to use the tests in 3 different ways.

The first group received comprehensive RDT training, which included instructions on how to use an RDT, guidelines on malaria diagnosis and treatment, information about other causes of fever, and help with communications skills, especially for patients whose test results were negative.

The second group received the same training plus a school-based intervention that involved training 2 teachers per school. The aim was to influence the attitudes of school children and their families as well as the wider community.

And health workers in the third group—the control arm—were invited to a demonstration and practical on how to safely use RDTs and supplied with written instructions on their use.

Results

The primary outcome was the proportion of patients who were treated according to guidelines. In other words, they presented with symptoms consistent with malaria, were tested for malaria, and received treatment consistent with the test result.

The researchers assessed the primary outcome in 4946 patients from 40 communities—12 in the control arm and 14 in each intervention arm.

There was no significant difference between the arms with regard to this outcome. The proportion of patients treated according to guidelines was 36% in the comprehensive training arm, 24% in the training-school arm, and 23% in the control arm (P=0.36).

Likewise, the use of testing was low in all arms—34% in the control arm, 48% in the training arm, and 37% in the training-school arm (P=0.47).

The use of testing was lower at private facilities than public ones. Cost may have been a factor here, as public facilities were asked to offer testing free of charge, but private facilities could charge 100 Naira (0.6 USD).

“We have shown that training alone is not enough to realize the full potential of an RDT,” said Virginia Wiseman, PhD, of the London School of Hygiene & Tropical Medicine in the UK.

“We must continue to explore alternative ways of encouraging providers to deliver appropriate treatment and avoid the misuse of valuable medicines, especially in the private sector, where we found levels of testing to be lowest.”

Malaria rapid diagnostic test

Photo courtesy of USAID

A study conducted in Nigeria has shown that health providers continue to prescribe malaria medicines inappropriately, even after they learn to test for malaria and receive testing kits free of charge.

Health providers were given rapid diagnostic tests (RDT) for malaria and learned to use the tests via 3 different methods.

However, the use of RDTs was “critically low” in all 3 groups, as was the proportion of patients treated appropriately.

“This study confirms that treating malaria based on signs and symptoms alone remains an ingrained behavior that is difficult to change,” said Obinna Onwujekwe, MD, PhD, of the University of Nigeria in Enugu.

Dr Onwujekwe and his colleagues reported these findings in PLOS ONE.

Interventions

Their study included health workers and patients from 40 communities in the Nigerian state of Enugu. Health workers received free RDT kits and were taught to use the tests in 3 different ways.

The first group received comprehensive RDT training, which included instructions on how to use an RDT, guidelines on malaria diagnosis and treatment, information about other causes of fever, and help with communications skills, especially for patients whose test results were negative.

The second group received the same training plus a school-based intervention that involved training 2 teachers per school. The aim was to influence the attitudes of school children and their families as well as the wider community.

And health workers in the third group—the control arm—were invited to a demonstration and practical on how to safely use RDTs and supplied with written instructions on their use.

Results

The primary outcome was the proportion of patients who were treated according to guidelines. In other words, they presented with symptoms consistent with malaria, were tested for malaria, and received treatment consistent with the test result.

The researchers assessed the primary outcome in 4946 patients from 40 communities—12 in the control arm and 14 in each intervention arm.

There was no significant difference between the arms with regard to this outcome. The proportion of patients treated according to guidelines was 36% in the comprehensive training arm, 24% in the training-school arm, and 23% in the control arm (P=0.36).

Likewise, the use of testing was low in all arms—34% in the control arm, 48% in the training arm, and 37% in the training-school arm (P=0.47).

The use of testing was lower at private facilities than public ones. Cost may have been a factor here, as public facilities were asked to offer testing free of charge, but private facilities could charge 100 Naira (0.6 USD).

“We have shown that training alone is not enough to realize the full potential of an RDT,” said Virginia Wiseman, PhD, of the London School of Hygiene & Tropical Medicine in the UK.

“We must continue to explore alternative ways of encouraging providers to deliver appropriate treatment and avoid the misuse of valuable medicines, especially in the private sector, where we found levels of testing to be lowest.”

Micrograph showing CML

Preclinical research has revealed nutrients that support the activity of chronic myelogenous leukemia (CML) stem cells and suggests these nutrients may be promising targets for CML therapy.

Investigators discovered that CML stem cells accumulate high levels of certain dipeptide species, and these dipeptides act as nutrients for the cells.

When the team inhibited dipeptide uptake, they observed decreased CML stem cell activity.

Combining agents that inhibit dipeptide uptake with tyrosine kinase inhibitors (TKIs) proved more effective against CML than TKI treatment alone, both in vitro and in vivo.

Kazuhito Naka, PhD, of Hiroshima University in Japan, and his colleagues conducted this research and disclosed the results in Nature Communications.

The team began by analyzing CML stem cells isolated from a mouse model of the disease. They found that CML stem cells accumulate significantly higher levels of certain dipeptide species—such as Ala-Leu, Asp-Leu, Ser-Tyr, and Thr-Val—than normal hematopoietic stem cells.

Additional investigation revealed that CML stem cells take up dipeptides via the Slc15A2 transporter. And once internalized, the dipeptides act as nutrients and play a role in CML stem cell maintenance.

The dipeptides activate amino-acid signaling via a pathway involving p38MAPK and Smad3, and this promotes CML stem cell maintenance.

To build upon these findings, the investigators assessed the effects of cefadroxil, which inhibits Slc15A2-mediated nutrient signaling, in combination with imatinib as CML treatment.

In murine CML stem cell cultures, the 2 drugs in combination reduced colony formation more effectively than imatinib alone.

In vivo, mice with CML responded to imatinib alone but eventually experienced disease recurrence. And cefadroxil alone promoted disease development. But when cefadroxil was given in combination with imatinib, disease recurrence was significantly lower than in mice that received imatinib alone.

The investigators then showed that cefadroxil decreases the number of CML stem cells in CML-affected mice. And cefadroxil combined with imatinib reduces CML stem cell numbers more effectively than imatinib alone.

In serial transplantation experiments, CML stem cells isolated from cefadroxil-treated mice completely lost their ability to drive BCR-ABL1+ disease in new recipients. These animals survived for more than 90 days, whereas mice that received CML stem cells from vehicle-treated mice developed BCR-ABL1+ disease and died before 80 days.

The investigators also tested cefadroxil in stem cells derived from humans with chronic CML. Cefadroxil suppressed the colony-forming capacity of all 3 samples tested. And combining cefadroxil with imatinib or dasatinib reduced colony formation more effectively than either TKI alone.

Lastly, the team decided to test 3 clinical-grade p38MAPK inhibitors that are already approved for use in the US—Ly2228820 (ralimetinib), VX-702, and BIRB796 (doramapimod). When cultured with CML stem cells, each of these drugs significantly decreased colony formation.

In addition, Ly2228820 combined with dasatinib delayed CML onset in mice and improved their survival when compared with dasatinib alone.

These results suggest p38MAPK inhibitors and cefadroxil may be useful additions to TKI therapy in CML, the investigators said.

“Our proposed approach of using inhibitors to shut down a key nutrient uptake process specific to CML stem cells, in combination with TKI therapy, may thus provide concrete therapeutic benefits to patients with CML,” Dr Naka said. “It will open up a novel avenue for curative CML therapy.”

Micrograph showing CML

Preclinical research has revealed nutrients that support the activity of chronic myelogenous leukemia (CML) stem cells and suggests these nutrients may be promising targets for CML therapy.

Investigators discovered that CML stem cells accumulate high levels of certain dipeptide species, and these dipeptides act as nutrients for the cells.

When the team inhibited dipeptide uptake, they observed decreased CML stem cell activity.

Combining agents that inhibit dipeptide uptake with tyrosine kinase inhibitors (TKIs) proved more effective against CML than TKI treatment alone, both in vitro and in vivo.

Kazuhito Naka, PhD, of Hiroshima University in Japan, and his colleagues conducted this research and disclosed the results in Nature Communications.

The team began by analyzing CML stem cells isolated from a mouse model of the disease. They found that CML stem cells accumulate significantly higher levels of certain dipeptide species—such as Ala-Leu, Asp-Leu, Ser-Tyr, and Thr-Val—than normal hematopoietic stem cells.

Additional investigation revealed that CML stem cells take up dipeptides via the Slc15A2 transporter. And once internalized, the dipeptides act as nutrients and play a role in CML stem cell maintenance.

The dipeptides activate amino-acid signaling via a pathway involving p38MAPK and Smad3, and this promotes CML stem cell maintenance.

To build upon these findings, the investigators assessed the effects of cefadroxil, which inhibits Slc15A2-mediated nutrient signaling, in combination with imatinib as CML treatment.

In murine CML stem cell cultures, the 2 drugs in combination reduced colony formation more effectively than imatinib alone.

In vivo, mice with CML responded to imatinib alone but eventually experienced disease recurrence. And cefadroxil alone promoted disease development. But when cefadroxil was given in combination with imatinib, disease recurrence was significantly lower than in mice that received imatinib alone.

The investigators then showed that cefadroxil decreases the number of CML stem cells in CML-affected mice. And cefadroxil combined with imatinib reduces CML stem cell numbers more effectively than imatinib alone.

In serial transplantation experiments, CML stem cells isolated from cefadroxil-treated mice completely lost their ability to drive BCR-ABL1+ disease in new recipients. These animals survived for more than 90 days, whereas mice that received CML stem cells from vehicle-treated mice developed BCR-ABL1+ disease and died before 80 days.

The investigators also tested cefadroxil in stem cells derived from humans with chronic CML. Cefadroxil suppressed the colony-forming capacity of all 3 samples tested. And combining cefadroxil with imatinib or dasatinib reduced colony formation more effectively than either TKI alone.

Lastly, the team decided to test 3 clinical-grade p38MAPK inhibitors that are already approved for use in the US—Ly2228820 (ralimetinib), VX-702, and BIRB796 (doramapimod). When cultured with CML stem cells, each of these drugs significantly decreased colony formation.

In addition, Ly2228820 combined with dasatinib delayed CML onset in mice and improved their survival when compared with dasatinib alone.

These results suggest p38MAPK inhibitors and cefadroxil may be useful additions to TKI therapy in CML, the investigators said.

“Our proposed approach of using inhibitors to shut down a key nutrient uptake process specific to CML stem cells, in combination with TKI therapy, may thus provide concrete therapeutic benefits to patients with CML,” Dr Naka said. “It will open up a novel avenue for curative CML therapy.”

Micrograph showing CML

Preclinical research has revealed nutrients that support the activity of chronic myelogenous leukemia (CML) stem cells and suggests these nutrients may be promising targets for CML therapy.

Investigators discovered that CML stem cells accumulate high levels of certain dipeptide species, and these dipeptides act as nutrients for the cells.

When the team inhibited dipeptide uptake, they observed decreased CML stem cell activity.

Combining agents that inhibit dipeptide uptake with tyrosine kinase inhibitors (TKIs) proved more effective against CML than TKI treatment alone, both in vitro and in vivo.

Kazuhito Naka, PhD, of Hiroshima University in Japan, and his colleagues conducted this research and disclosed the results in Nature Communications.

The team began by analyzing CML stem cells isolated from a mouse model of the disease. They found that CML stem cells accumulate significantly higher levels of certain dipeptide species—such as Ala-Leu, Asp-Leu, Ser-Tyr, and Thr-Val—than normal hematopoietic stem cells.

Additional investigation revealed that CML stem cells take up dipeptides via the Slc15A2 transporter. And once internalized, the dipeptides act as nutrients and play a role in CML stem cell maintenance.

The dipeptides activate amino-acid signaling via a pathway involving p38MAPK and Smad3, and this promotes CML stem cell maintenance.

To build upon these findings, the investigators assessed the effects of cefadroxil, which inhibits Slc15A2-mediated nutrient signaling, in combination with imatinib as CML treatment.

In murine CML stem cell cultures, the 2 drugs in combination reduced colony formation more effectively than imatinib alone.

In vivo, mice with CML responded to imatinib alone but eventually experienced disease recurrence. And cefadroxil alone promoted disease development. But when cefadroxil was given in combination with imatinib, disease recurrence was significantly lower than in mice that received imatinib alone.

The investigators then showed that cefadroxil decreases the number of CML stem cells in CML-affected mice. And cefadroxil combined with imatinib reduces CML stem cell numbers more effectively than imatinib alone.

In serial transplantation experiments, CML stem cells isolated from cefadroxil-treated mice completely lost their ability to drive BCR-ABL1+ disease in new recipients. These animals survived for more than 90 days, whereas mice that received CML stem cells from vehicle-treated mice developed BCR-ABL1+ disease and died before 80 days.

The investigators also tested cefadroxil in stem cells derived from humans with chronic CML. Cefadroxil suppressed the colony-forming capacity of all 3 samples tested. And combining cefadroxil with imatinib or dasatinib reduced colony formation more effectively than either TKI alone.

Lastly, the team decided to test 3 clinical-grade p38MAPK inhibitors that are already approved for use in the US—Ly2228820 (ralimetinib), VX-702, and BIRB796 (doramapimod). When cultured with CML stem cells, each of these drugs significantly decreased colony formation.

In addition, Ly2228820 combined with dasatinib delayed CML onset in mice and improved their survival when compared with dasatinib alone.

These results suggest p38MAPK inhibitors and cefadroxil may be useful additions to TKI therapy in CML, the investigators said.

“Our proposed approach of using inhibitors to shut down a key nutrient uptake process specific to CML stem cells, in combination with TKI therapy, may thus provide concrete therapeutic benefits to patients with CML,” Dr Naka said. “It will open up a novel avenue for curative CML therapy.”

DNA coiled around histones

Image by Eric Smith

Researchers say they have discovered critical details that explain how a cellular response system tells the difference between damage to the body’s own DNA and the foreign DNA of an invading virus.

The team believes this discovery could aid the development of new cancer-selective viral therapies, and it may help explain why aging, cancers, and other diseases

seem to open the door to viral infections.

“Our study reveals fundamental mechanisms that distinguish DNA breaks at cellular and viral genomes to trigger different responses that protect the host,” said Clodagh O’Shea, of the Salk Institute for Biological Studies in La Jolla, California.

“The findings may also explain why certain conditions like aging, cancer chemotherapy, and inflammation make us more susceptible to viral infection.”

Dr O’Shea and Govind Shah, PhD, also of the Salk Institute, reported these findings in Cell.

The pair described how a cluster of proteins known as the MRN complex detects DNA breaks and amplifies its response through histones.

MRN starts a domino effect, activating histones on surrounding chromosomes, which summons a cascade of additional proteins and results in a cell-wide, all-hands-on-deck alarm to help mend the DNA.

If the cell can’t fix the DNA break, it will induce apoptosis—a self-destruct mechanism that helps to prevent mutated cells from replicating and therefore prevents tumor growth.

“What’s interesting is that even a single break transmits a global signal through the cell, halting cell division and growth,” Dr O’Shea said. “This response prevents replication so the cell doesn’t pass on a break.”

Drs O’Shea and Shah also found that, when it comes to defending against DNA viruses, the cell’s response system begins the same way—with MRN detecting breaks. But it never progresses to the global alarm signal in the case of the virus.

Typically, a common DNA virus enters the cell’s nucleus and turns on genes to replicate its own DNA. The cell detects the unauthorized replication, and the MRN complex grabs and selectively neutralizes viral DNA without triggering a global response that would arrest or kill the cell.

So the MRN response to the virus stays localized and only selectively prevents viral, but not cellular, replication.

When both threats to the genome are present, MRN will activate the massive response at the DNA break, and no MRN is left to respond to the virus. This means the virus is effectively ignored while the cell responds to the more massive alarm.

“The requirement of MRN for sensing both cellular and viral genome breaks has profound consequences,” Dr O’Shea said.

“When MRN is recruited to cellular DNA breaks, it can no longer sense and respond to incoming viral genomes. Thus, the act of responding to cellular genome breaks inactivates the host’s defenses to viral replication.”

Dr O’Shea said this may explain why people who have high levels of cellular DNA damage—such as cancer patients—are more susceptible to viral infections.

“Having damaged DNA compromises our cells’ ability to fight viral infection, while having healthy DNA boosts our cells’ ability to catch viral DNA,” Dr Shah said. “Our work implies that we may be able to engineer viruses that selectively kill cancer cells.”

The researchers aim to use this new knowledge to create viruses that are destroyed in normal cells but replicate specifically in cancer cells.

Unlike normal cells, cancer cells almost always have very high levels of DNA damage. In cancer cells, MRN is already so preoccupied with responding to DNA breaks that an engineered virus could sneak in undetected.

“Cancer cells, by definition, have high mutation rates and genomic instability even at the very earliest stages,” Dr O’Shea said. “So you could imagine building a virus that could destroy even the earliest lesions and be used as a prophylactic.”

DNA coiled around histones

Image by Eric Smith

Researchers say they have discovered critical details that explain how a cellular response system tells the difference between damage to the body’s own DNA and the foreign DNA of an invading virus.

The team believes this discovery could aid the development of new cancer-selective viral therapies, and it may help explain why aging, cancers, and other diseases

seem to open the door to viral infections.

“Our study reveals fundamental mechanisms that distinguish DNA breaks at cellular and viral genomes to trigger different responses that protect the host,” said Clodagh O’Shea, of the Salk Institute for Biological Studies in La Jolla, California.

“The findings may also explain why certain conditions like aging, cancer chemotherapy, and inflammation make us more susceptible to viral infection.”

Dr O’Shea and Govind Shah, PhD, also of the Salk Institute, reported these findings in Cell.

The pair described how a cluster of proteins known as the MRN complex detects DNA breaks and amplifies its response through histones.

MRN starts a domino effect, activating histones on surrounding chromosomes, which summons a cascade of additional proteins and results in a cell-wide, all-hands-on-deck alarm to help mend the DNA.

If the cell can’t fix the DNA break, it will induce apoptosis—a self-destruct mechanism that helps to prevent mutated cells from replicating and therefore prevents tumor growth.

“What’s interesting is that even a single break transmits a global signal through the cell, halting cell division and growth,” Dr O’Shea said. “This response prevents replication so the cell doesn’t pass on a break.”

Drs O’Shea and Shah also found that, when it comes to defending against DNA viruses, the cell’s response system begins the same way—with MRN detecting breaks. But it never progresses to the global alarm signal in the case of the virus.

Typically, a common DNA virus enters the cell’s nucleus and turns on genes to replicate its own DNA. The cell detects the unauthorized replication, and the MRN complex grabs and selectively neutralizes viral DNA without triggering a global response that would arrest or kill the cell.

So the MRN response to the virus stays localized and only selectively prevents viral, but not cellular, replication.

When both threats to the genome are present, MRN will activate the massive response at the DNA break, and no MRN is left to respond to the virus. This means the virus is effectively ignored while the cell responds to the more massive alarm.

“The requirement of MRN for sensing both cellular and viral genome breaks has profound consequences,” Dr O’Shea said.

“When MRN is recruited to cellular DNA breaks, it can no longer sense and respond to incoming viral genomes. Thus, the act of responding to cellular genome breaks inactivates the host’s defenses to viral replication.”

Dr O’Shea said this may explain why people who have high levels of cellular DNA damage—such as cancer patients—are more susceptible to viral infections.

“Having damaged DNA compromises our cells’ ability to fight viral infection, while having healthy DNA boosts our cells’ ability to catch viral DNA,” Dr Shah said. “Our work implies that we may be able to engineer viruses that selectively kill cancer cells.”

The researchers aim to use this new knowledge to create viruses that are destroyed in normal cells but replicate specifically in cancer cells.

Unlike normal cells, cancer cells almost always have very high levels of DNA damage. In cancer cells, MRN is already so preoccupied with responding to DNA breaks that an engineered virus could sneak in undetected.

“Cancer cells, by definition, have high mutation rates and genomic instability even at the very earliest stages,” Dr O’Shea said. “So you could imagine building a virus that could destroy even the earliest lesions and be used as a prophylactic.”

DNA coiled around histones

Image by Eric Smith

Researchers say they have discovered critical details that explain how a cellular response system tells the difference between damage to the body’s own DNA and the foreign DNA of an invading virus.

The team believes this discovery could aid the development of new cancer-selective viral therapies, and it may help explain why aging, cancers, and other diseases

seem to open the door to viral infections.

“Our study reveals fundamental mechanisms that distinguish DNA breaks at cellular and viral genomes to trigger different responses that protect the host,” said Clodagh O’Shea, of the Salk Institute for Biological Studies in La Jolla, California.

“The findings may also explain why certain conditions like aging, cancer chemotherapy, and inflammation make us more susceptible to viral infection.”

Dr O’Shea and Govind Shah, PhD, also of the Salk Institute, reported these findings in Cell.

The pair described how a cluster of proteins known as the MRN complex detects DNA breaks and amplifies its response through histones.

MRN starts a domino effect, activating histones on surrounding chromosomes, which summons a cascade of additional proteins and results in a cell-wide, all-hands-on-deck alarm to help mend the DNA.

If the cell can’t fix the DNA break, it will induce apoptosis—a self-destruct mechanism that helps to prevent mutated cells from replicating and therefore prevents tumor growth.

“What’s interesting is that even a single break transmits a global signal through the cell, halting cell division and growth,” Dr O’Shea said. “This response prevents replication so the cell doesn’t pass on a break.”

Drs O’Shea and Shah also found that, when it comes to defending against DNA viruses, the cell’s response system begins the same way—with MRN detecting breaks. But it never progresses to the global alarm signal in the case of the virus.

Typically, a common DNA virus enters the cell’s nucleus and turns on genes to replicate its own DNA. The cell detects the unauthorized replication, and the MRN complex grabs and selectively neutralizes viral DNA without triggering a global response that would arrest or kill the cell.

So the MRN response to the virus stays localized and only selectively prevents viral, but not cellular, replication.

When both threats to the genome are present, MRN will activate the massive response at the DNA break, and no MRN is left to respond to the virus. This means the virus is effectively ignored while the cell responds to the more massive alarm.

“The requirement of MRN for sensing both cellular and viral genome breaks has profound consequences,” Dr O’Shea said.

“When MRN is recruited to cellular DNA breaks, it can no longer sense and respond to incoming viral genomes. Thus, the act of responding to cellular genome breaks inactivates the host’s defenses to viral replication.”

Dr O’Shea said this may explain why people who have high levels of cellular DNA damage—such as cancer patients—are more susceptible to viral infections.

“Having damaged DNA compromises our cells’ ability to fight viral infection, while having healthy DNA boosts our cells’ ability to catch viral DNA,” Dr Shah said. “Our work implies that we may be able to engineer viruses that selectively kill cancer cells.”

The researchers aim to use this new knowledge to create viruses that are destroyed in normal cells but replicate specifically in cancer cells.

Unlike normal cells, cancer cells almost always have very high levels of DNA damage. In cancer cells, MRN is already so preoccupied with responding to DNA breaks that an engineered virus could sneak in undetected.

“Cancer cells, by definition, have high mutation rates and genomic instability even at the very earliest stages,” Dr O’Shea said. “So you could imagine building a virus that could destroy even the earliest lesions and be used as a prophylactic.”

In late 2013, there were 45 cases of acute liver failure (ALF) in Hawaii, and 29 of those people reported taking OxyELITE Pro (an herbal dietary supplement marketed for weight reduction and “fat-burning”) 60 days before illness onset. Of 8 initial cases, 2 patients needed urgent liver transplants, one died, and 5 eventually recovered.¹ The manufacturer of OxyELITE Pro voluntarily recalled the product after receiving a warning letter from the US Food and Drug Administration (FDA).

One way to prevent situations like this from occurring might be to ban the sale of weight loss or sports enhancement supplements unless they are rigorously tested and approved by the FDA. Voluntary reporting to the FDA is time-consuming and it takes time for the FDA to follow up on these reports.

As primary care physicians, we need to consistently ask patients about their use of supplements, educate them about the potential dangers, and identify those who are experiencing adverse reactions. While we can’t put a stop to the harm that some herbal dietary supplements might inflict on a public eager to embrace quick fixes for weight loss and improved strength, we can be the best first responders.

Linda L. Wong, MD
Honolulu, Hawaii

In late 2013, there were 45 cases of acute liver failure (ALF) in Hawaii, and 29 of those people reported taking OxyELITE Pro (an herbal dietary supplement marketed for weight reduction and “fat-burning”) 60 days before illness onset. Of 8 initial cases, 2 patients needed urgent liver transplants, one died, and 5 eventually recovered.¹ The manufacturer of OxyELITE Pro voluntarily recalled the product after receiving a warning letter from the US Food and Drug Administration (FDA).

One way to prevent situations like this from occurring might be to ban the sale of weight loss or sports enhancement supplements unless they are rigorously tested and approved by the FDA. Voluntary reporting to the FDA is time-consuming and it takes time for the FDA to follow up on these reports.

As primary care physicians, we need to consistently ask patients about their use of supplements, educate them about the potential dangers, and identify those who are experiencing adverse reactions. While we can’t put a stop to the harm that some herbal dietary supplements might inflict on a public eager to embrace quick fixes for weight loss and improved strength, we can be the best first responders.

Linda L. Wong, MD
Honolulu, Hawaii

In late 2013, there were 45 cases of acute liver failure (ALF) in Hawaii, and 29 of those people reported taking OxyELITE Pro (an herbal dietary supplement marketed for weight reduction and “fat-burning”) 60 days before illness onset. Of 8 initial cases, 2 patients needed urgent liver transplants, one died, and 5 eventually recovered.¹ The manufacturer of OxyELITE Pro voluntarily recalled the product after receiving a warning letter from the US Food and Drug Administration (FDA).

One way to prevent situations like this from occurring might be to ban the sale of weight loss or sports enhancement supplements unless they are rigorously tested and approved by the FDA. Voluntary reporting to the FDA is time-consuming and it takes time for the FDA to follow up on these reports.

As primary care physicians, we need to consistently ask patients about their use of supplements, educate them about the potential dangers, and identify those who are experiencing adverse reactions. While we can’t put a stop to the harm that some herbal dietary supplements might inflict on a public eager to embrace quick fixes for weight loss and improved strength, we can be the best first responders.

Linda L. Wong, MD
Honolulu, Hawaii

A male immunodeficient patient excreted strains of a vaccine-derived poliovirus for 28 years, a study has found. This case suggests that there are new barriers to polio eradication, according to Glynis Dunn and coauthors of a research article published August 27 in PLoS Pathogens.

Poliovirus strains in the oral polio vaccine (OPV) can be transmitted from person to person in populations with low immunity and can cause outbreaks. The strains can also replicate for long periods of time in an immunodeficient individual. The patient in question received childhood OPV immunizations at 5, 7, and 12 months of age and a booster when he was about 7 years old. His case is the longest-known example of a vaccinated patient excreting the live poliovirus.

The researchers analyzed 185 stool samples that the patient provided between 1995 and 2015. All stools were positive for strain 2 polio virus; the virus titres shed in the stools were “comparable to virus titres shed by healthy vaccinees and paralytics cases infected with vaccine or wild poliovirus.”

The excreted virus began to diverge from the vaccine strain around the time of the individual’s last known OPV vaccination, acquiring various mutations that affected its antigenic structure.

The patient excreted “a highly virulent and antigenically modified type 2 poliovirus at high titres for a period estimated to be 28 years so far ... Provided antibody titres and immunizations coverage are maintained, it is likely that the population will be protected against paralytic disease, but it is also possible that this virus could circulate in populations only using [inactivated polio vaccine] as described in Israel for wild poliovirus, thus representing a possible source of polio reemergence,” according to the authors.

Read the full article in PLoS Pathogens (doi:10.1371/journal.ppat.1005114).

[email protected]

A male immunodeficient patient excreted strains of a vaccine-derived poliovirus for 28 years, a study has found. This case suggests that there are new barriers to polio eradication, according to Glynis Dunn and coauthors of a research article published August 27 in PLoS Pathogens.

Poliovirus strains in the oral polio vaccine (OPV) can be transmitted from person to person in populations with low immunity and can cause outbreaks. The strains can also replicate for long periods of time in an immunodeficient individual. The patient in question received childhood OPV immunizations at 5, 7, and 12 months of age and a booster when he was about 7 years old. His case is the longest-known example of a vaccinated patient excreting the live poliovirus.

The researchers analyzed 185 stool samples that the patient provided between 1995 and 2015. All stools were positive for strain 2 polio virus; the virus titres shed in the stools were “comparable to virus titres shed by healthy vaccinees and paralytics cases infected with vaccine or wild poliovirus.”

The excreted virus began to diverge from the vaccine strain around the time of the individual’s last known OPV vaccination, acquiring various mutations that affected its antigenic structure.

The patient excreted “a highly virulent and antigenically modified type 2 poliovirus at high titres for a period estimated to be 28 years so far ... Provided antibody titres and immunizations coverage are maintained, it is likely that the population will be protected against paralytic disease, but it is also possible that this virus could circulate in populations only using [inactivated polio vaccine] as described in Israel for wild poliovirus, thus representing a possible source of polio reemergence,” according to the authors.

Read the full article in PLoS Pathogens (doi:10.1371/journal.ppat.1005114).

[email protected]

A male immunodeficient patient excreted strains of a vaccine-derived poliovirus for 28 years, a study has found. This case suggests that there are new barriers to polio eradication, according to Glynis Dunn and coauthors of a research article published August 27 in PLoS Pathogens.

Poliovirus strains in the oral polio vaccine (OPV) can be transmitted from person to person in populations with low immunity and can cause outbreaks. The strains can also replicate for long periods of time in an immunodeficient individual. The patient in question received childhood OPV immunizations at 5, 7, and 12 months of age and a booster when he was about 7 years old. His case is the longest-known example of a vaccinated patient excreting the live poliovirus.

The researchers analyzed 185 stool samples that the patient provided between 1995 and 2015. All stools were positive for strain 2 polio virus; the virus titres shed in the stools were “comparable to virus titres shed by healthy vaccinees and paralytics cases infected with vaccine or wild poliovirus.”

The excreted virus began to diverge from the vaccine strain around the time of the individual’s last known OPV vaccination, acquiring various mutations that affected its antigenic structure.

The patient excreted “a highly virulent and antigenically modified type 2 poliovirus at high titres for a period estimated to be 28 years so far ... Provided antibody titres and immunizations coverage are maintained, it is likely that the population will be protected against paralytic disease, but it is also possible that this virus could circulate in populations only using [inactivated polio vaccine] as described in Israel for wild poliovirus, thus representing a possible source of polio reemergence,” according to the authors.

Read the full article in PLoS Pathogens (doi:10.1371/journal.ppat.1005114).

[email protected]