Drug release in a cancer cell

Credit: PNAS

Researchers have discovered how a molecule called CUL5 helps HSP90 inhibitors kill cancer cells, according to a study published in Proceedings of the National Academy of Sciences.

The team found that CUL5 is required for the degradation of proteins that promote cancer cell proliferation, and CUL5 works in opposition to HSP90.

When cancer cells are treated with HSP90 inhibitors, CUL5 immediately steps in to help dispose of the proliferation-promoting proteins.

Based on these findings, the researchers speculate that some patients may be resistant to HSP90 inhibitors if their cancer cells have lower amounts of CUL5. And conversely, the drugs may work better in patients with higher CUL5 levels.

Paul Workman, PhD, of The Institute of Cancer Research in London, UK, and his colleagues conducted this research in cell lines of melanoma, as well as colon, breast, and lung cancers.

They first tested the HSP90 inhibitor 17-AAG in HT29 cells and found that CUL5 is involved in the drug-induced degradation of several protein kinase clients of HSP90.

Then, the researchers assessed the effects of silencing CUL5 and discovered that it delays the abrogation of protein signaling caused by an HSP90 inhibitor.

Furthermore, silencing CUL5 reduced cellular sensitivity to 3 different HSP90 inhibitors across the 4 different cancer types studied, which, as the researchers pointed out, are driven by different protein kinases.

So the team believes this research could apply to a number of different cancers. HSP90 inhibitors have proven effective against a range of malignancies, including leukemias, lymphomas, and multiple myeloma.

“We’ve known for some time that drugs that block HSP90 have great potential as treatments for cancers . . . , and we had an initial clue that the protein CUL5 may be involved in some way in how these drugs work,” Dr Workman said.

“Our new research shows that CUL5 is not only vital in the response of cancer cells to HSP90 inhibitors but also reveals surprising insights into precisely how it works by acting at several different levels. What also surprised us was that CUL5 gets rid of many more of the cancer-causing proteins than we’d previously imagined and that it’s effective across several types of tumor.”

“This suggests that a test for CUL5 in patients could help us tell whether they might respond to HSP90-blocking drugs, as well as pointing to new targets to develop more effective drugs.”

Drug release in a cancer cell

Credit: PNAS

Researchers have discovered how a molecule called CUL5 helps HSP90 inhibitors kill cancer cells, according to a study published in Proceedings of the National Academy of Sciences.

The team found that CUL5 is required for the degradation of proteins that promote cancer cell proliferation, and CUL5 works in opposition to HSP90.

When cancer cells are treated with HSP90 inhibitors, CUL5 immediately steps in to help dispose of the proliferation-promoting proteins.

Based on these findings, the researchers speculate that some patients may be resistant to HSP90 inhibitors if their cancer cells have lower amounts of CUL5. And conversely, the drugs may work better in patients with higher CUL5 levels.

Paul Workman, PhD, of The Institute of Cancer Research in London, UK, and his colleagues conducted this research in cell lines of melanoma, as well as colon, breast, and lung cancers.

They first tested the HSP90 inhibitor 17-AAG in HT29 cells and found that CUL5 is involved in the drug-induced degradation of several protein kinase clients of HSP90.

Then, the researchers assessed the effects of silencing CUL5 and discovered that it delays the abrogation of protein signaling caused by an HSP90 inhibitor.

Furthermore, silencing CUL5 reduced cellular sensitivity to 3 different HSP90 inhibitors across the 4 different cancer types studied, which, as the researchers pointed out, are driven by different protein kinases.

So the team believes this research could apply to a number of different cancers. HSP90 inhibitors have proven effective against a range of malignancies, including leukemias, lymphomas, and multiple myeloma.

“We’ve known for some time that drugs that block HSP90 have great potential as treatments for cancers . . . , and we had an initial clue that the protein CUL5 may be involved in some way in how these drugs work,” Dr Workman said.

“Our new research shows that CUL5 is not only vital in the response of cancer cells to HSP90 inhibitors but also reveals surprising insights into precisely how it works by acting at several different levels. What also surprised us was that CUL5 gets rid of many more of the cancer-causing proteins than we’d previously imagined and that it’s effective across several types of tumor.”

“This suggests that a test for CUL5 in patients could help us tell whether they might respond to HSP90-blocking drugs, as well as pointing to new targets to develop more effective drugs.”

Drug release in a cancer cell

Credit: PNAS

Researchers have discovered how a molecule called CUL5 helps HSP90 inhibitors kill cancer cells, according to a study published in Proceedings of the National Academy of Sciences.

The team found that CUL5 is required for the degradation of proteins that promote cancer cell proliferation, and CUL5 works in opposition to HSP90.

When cancer cells are treated with HSP90 inhibitors, CUL5 immediately steps in to help dispose of the proliferation-promoting proteins.

Based on these findings, the researchers speculate that some patients may be resistant to HSP90 inhibitors if their cancer cells have lower amounts of CUL5. And conversely, the drugs may work better in patients with higher CUL5 levels.

Paul Workman, PhD, of The Institute of Cancer Research in London, UK, and his colleagues conducted this research in cell lines of melanoma, as well as colon, breast, and lung cancers.

They first tested the HSP90 inhibitor 17-AAG in HT29 cells and found that CUL5 is involved in the drug-induced degradation of several protein kinase clients of HSP90.

Then, the researchers assessed the effects of silencing CUL5 and discovered that it delays the abrogation of protein signaling caused by an HSP90 inhibitor.

Furthermore, silencing CUL5 reduced cellular sensitivity to 3 different HSP90 inhibitors across the 4 different cancer types studied, which, as the researchers pointed out, are driven by different protein kinases.

So the team believes this research could apply to a number of different cancers. HSP90 inhibitors have proven effective against a range of malignancies, including leukemias, lymphomas, and multiple myeloma.

“We’ve known for some time that drugs that block HSP90 have great potential as treatments for cancers . . . , and we had an initial clue that the protein CUL5 may be involved in some way in how these drugs work,” Dr Workman said.

“Our new research shows that CUL5 is not only vital in the response of cancer cells to HSP90 inhibitors but also reveals surprising insights into precisely how it works by acting at several different levels. What also surprised us was that CUL5 gets rid of many more of the cancer-causing proteins than we’d previously imagined and that it’s effective across several types of tumor.”

“This suggests that a test for CUL5 in patients could help us tell whether they might respond to HSP90-blocking drugs, as well as pointing to new targets to develop more effective drugs.”

My wife and I recently (and successfully) had our kitchen and bathrooms remodeled. It wouldn’t have been possible without Pinterest.

For the uninitiated, Pinterest is a wildly popular social media site that allows users to find, share, and organize images called "pins." Pinterest launched in September 2010, and today it has more than 70 million active users. It’s one of the fastest-growing social media sites in history, and it ranks as one of the Top 50 most-visited websites in the United States.

In a previous column about Pinterest, I mentioned several reasons why it’s important for your medical practice. More than 80% of Pinterest users are female, and, according to the U.S. Department of Labor, women make 80% of health care decisions for their families. Therefore, Pinterest could be a persuasive marketing tool for physicians looking to expand their practices. Pinterest also can be an effective platform to share patient stories, to introduce your practice and staff to the public, and to show before and after images of medical procedures.

New research from Vision Critical, the world’s leading provider of Insight Communities, discovered a surprising new finding about Pinterest (published in the July-August 2013 issue of Harvard Business Review).

The researchers examined "showrooming," a phenomenon whereby shoppers visit actual stores to examine merchandise before purchasing it online. They say the threat is so intense to brick-and-mortar stores that at least one merchant has begun charging people to browse in his store! Their research, however, shows much less of a threat. Of the 3,000 social media users they surveyed, only 26% reported "regularly engaging in showrooming."

What they found more surprising was that 41% of respondents said that practice "reverse showrooming;" that is, they browse online first then purchase the product in a store. That’s exactly what my wife did when choosing and purchasing our new furniture, lighting fixtures, wallpaper, paint, and more.

This led me to contemplate how "reverse showrooming" might help a physician market his or her medical practice. First, understand that Pinterest relies on aspirational messaging. Marketers use images that tap into our desires, wants, and dreams. Pinterest typically represents our idealized selves – the fashion-forward woman, the perfect garden wedding, the sublime oceanfront hotel room. Pinterest is about the version of you that you want to become. The you with flawless skin, lustrous hair, and smooth thighs.

Pinterest can be a powerful marketing tool for dermatologists, particularly cosmetic dermatologists. Consider the Pinterest customer base: Data show that 83% of Pinterest users are female and 45% are aged 35-54 years. Consumers turn to Pinterest largely for fashion and beauty, DIY projects, home design, inspiration, education, humor, and product recommendations. In fact, Pinterest has become the No. 1 traffic driver to websites of women’s lifestyle magazines.

You can use Pinterest to drive traffic to your office website, where people can book appointments or buy products online. Although no formal data exist for physician referrals from Pinterest, the study showed that the social-to-sale purchasing power was 17% for hair and beauty products and women’s and men’s apparel.

How can Pinterest help you market your practice and encourage "pinners" to "reverse showroom" into your office? Let’s use the example of a cosmetic surgeon who is seeking to expand her patient base and promote her organic skincare product line.

Pinterest users are more likely to purchase items that are easy to find. So, if they’re looking for an organic sunscreen, and they click through the Pinterest image the doctor posted and land on her website where they can buy it, then they’ll be more apt to do so. Research shows that the likelihood of a purchase increases by an additional 34% when there are existing reviews and recommendations for the product, and 30% when there are product details provided.

Pins don’t have to be strictly medical; consider more purely social boards that relate to your specialty, such as the following examples:

Family practice doctors could use Pinterest for wellness promotion, with boards for spreading happiness, healthy recipes, and habits of healthy families. Oncologists could use Pinterest to share inspirational patient testimonials, best foods for chemotherapy patients, and support for caregivers. Ob.gyns could use Pinterest as an outreach tool for expectant and new moms with boards for breast-feeding tutorials, fashionable maternity clothing, and cool baby gear.

Pinterest has proven to deliver value to businesses. With the above recommendations, you can quickly and cost-effectively add this platform to your marketing and patient relationship efforts.

Dr. Jeffrey Benabio is a partner physician in the department of dermatology of the Southern California Permanente Group in San Diego and a volunteer clinical assistant professor at the University of California, San Diego. Dr. Benabio is @Dermdoc on Twitter.

My wife and I recently (and successfully) had our kitchen and bathrooms remodeled. It wouldn’t have been possible without Pinterest.

For the uninitiated, Pinterest is a wildly popular social media site that allows users to find, share, and organize images called "pins." Pinterest launched in September 2010, and today it has more than 70 million active users. It’s one of the fastest-growing social media sites in history, and it ranks as one of the Top 50 most-visited websites in the United States.

In a previous column about Pinterest, I mentioned several reasons why it’s important for your medical practice. More than 80% of Pinterest users are female, and, according to the U.S. Department of Labor, women make 80% of health care decisions for their families. Therefore, Pinterest could be a persuasive marketing tool for physicians looking to expand their practices. Pinterest also can be an effective platform to share patient stories, to introduce your practice and staff to the public, and to show before and after images of medical procedures.

New research from Vision Critical, the world’s leading provider of Insight Communities, discovered a surprising new finding about Pinterest (published in the July-August 2013 issue of Harvard Business Review).

The researchers examined "showrooming," a phenomenon whereby shoppers visit actual stores to examine merchandise before purchasing it online. They say the threat is so intense to brick-and-mortar stores that at least one merchant has begun charging people to browse in his store! Their research, however, shows much less of a threat. Of the 3,000 social media users they surveyed, only 26% reported "regularly engaging in showrooming."

What they found more surprising was that 41% of respondents said that practice "reverse showrooming;" that is, they browse online first then purchase the product in a store. That’s exactly what my wife did when choosing and purchasing our new furniture, lighting fixtures, wallpaper, paint, and more.

This led me to contemplate how "reverse showrooming" might help a physician market his or her medical practice. First, understand that Pinterest relies on aspirational messaging. Marketers use images that tap into our desires, wants, and dreams. Pinterest typically represents our idealized selves – the fashion-forward woman, the perfect garden wedding, the sublime oceanfront hotel room. Pinterest is about the version of you that you want to become. The you with flawless skin, lustrous hair, and smooth thighs.

Pinterest can be a powerful marketing tool for dermatologists, particularly cosmetic dermatologists. Consider the Pinterest customer base: Data show that 83% of Pinterest users are female and 45% are aged 35-54 years. Consumers turn to Pinterest largely for fashion and beauty, DIY projects, home design, inspiration, education, humor, and product recommendations. In fact, Pinterest has become the No. 1 traffic driver to websites of women’s lifestyle magazines.

You can use Pinterest to drive traffic to your office website, where people can book appointments or buy products online. Although no formal data exist for physician referrals from Pinterest, the study showed that the social-to-sale purchasing power was 17% for hair and beauty products and women’s and men’s apparel.

How can Pinterest help you market your practice and encourage "pinners" to "reverse showroom" into your office? Let’s use the example of a cosmetic surgeon who is seeking to expand her patient base and promote her organic skincare product line.

Pinterest users are more likely to purchase items that are easy to find. So, if they’re looking for an organic sunscreen, and they click through the Pinterest image the doctor posted and land on her website where they can buy it, then they’ll be more apt to do so. Research shows that the likelihood of a purchase increases by an additional 34% when there are existing reviews and recommendations for the product, and 30% when there are product details provided.

Pins don’t have to be strictly medical; consider more purely social boards that relate to your specialty, such as the following examples:

Family practice doctors could use Pinterest for wellness promotion, with boards for spreading happiness, healthy recipes, and habits of healthy families. Oncologists could use Pinterest to share inspirational patient testimonials, best foods for chemotherapy patients, and support for caregivers. Ob.gyns could use Pinterest as an outreach tool for expectant and new moms with boards for breast-feeding tutorials, fashionable maternity clothing, and cool baby gear.

Pinterest has proven to deliver value to businesses. With the above recommendations, you can quickly and cost-effectively add this platform to your marketing and patient relationship efforts.

Dr. Jeffrey Benabio is a partner physician in the department of dermatology of the Southern California Permanente Group in San Diego and a volunteer clinical assistant professor at the University of California, San Diego. Dr. Benabio is @Dermdoc on Twitter.

My wife and I recently (and successfully) had our kitchen and bathrooms remodeled. It wouldn’t have been possible without Pinterest.

For the uninitiated, Pinterest is a wildly popular social media site that allows users to find, share, and organize images called "pins." Pinterest launched in September 2010, and today it has more than 70 million active users. It’s one of the fastest-growing social media sites in history, and it ranks as one of the Top 50 most-visited websites in the United States.

In a previous column about Pinterest, I mentioned several reasons why it’s important for your medical practice. More than 80% of Pinterest users are female, and, according to the U.S. Department of Labor, women make 80% of health care decisions for their families. Therefore, Pinterest could be a persuasive marketing tool for physicians looking to expand their practices. Pinterest also can be an effective platform to share patient stories, to introduce your practice and staff to the public, and to show before and after images of medical procedures.

New research from Vision Critical, the world’s leading provider of Insight Communities, discovered a surprising new finding about Pinterest (published in the July-August 2013 issue of Harvard Business Review).

The researchers examined "showrooming," a phenomenon whereby shoppers visit actual stores to examine merchandise before purchasing it online. They say the threat is so intense to brick-and-mortar stores that at least one merchant has begun charging people to browse in his store! Their research, however, shows much less of a threat. Of the 3,000 social media users they surveyed, only 26% reported "regularly engaging in showrooming."

What they found more surprising was that 41% of respondents said that practice "reverse showrooming;" that is, they browse online first then purchase the product in a store. That’s exactly what my wife did when choosing and purchasing our new furniture, lighting fixtures, wallpaper, paint, and more.

This led me to contemplate how "reverse showrooming" might help a physician market his or her medical practice. First, understand that Pinterest relies on aspirational messaging. Marketers use images that tap into our desires, wants, and dreams. Pinterest typically represents our idealized selves – the fashion-forward woman, the perfect garden wedding, the sublime oceanfront hotel room. Pinterest is about the version of you that you want to become. The you with flawless skin, lustrous hair, and smooth thighs.

Pinterest can be a powerful marketing tool for dermatologists, particularly cosmetic dermatologists. Consider the Pinterest customer base: Data show that 83% of Pinterest users are female and 45% are aged 35-54 years. Consumers turn to Pinterest largely for fashion and beauty, DIY projects, home design, inspiration, education, humor, and product recommendations. In fact, Pinterest has become the No. 1 traffic driver to websites of women’s lifestyle magazines.

You can use Pinterest to drive traffic to your office website, where people can book appointments or buy products online. Although no formal data exist for physician referrals from Pinterest, the study showed that the social-to-sale purchasing power was 17% for hair and beauty products and women’s and men’s apparel.

How can Pinterest help you market your practice and encourage "pinners" to "reverse showroom" into your office? Let’s use the example of a cosmetic surgeon who is seeking to expand her patient base and promote her organic skincare product line.

Pinterest users are more likely to purchase items that are easy to find. So, if they’re looking for an organic sunscreen, and they click through the Pinterest image the doctor posted and land on her website where they can buy it, then they’ll be more apt to do so. Research shows that the likelihood of a purchase increases by an additional 34% when there are existing reviews and recommendations for the product, and 30% when there are product details provided.

Pins don’t have to be strictly medical; consider more purely social boards that relate to your specialty, such as the following examples:

Family practice doctors could use Pinterest for wellness promotion, with boards for spreading happiness, healthy recipes, and habits of healthy families. Oncologists could use Pinterest to share inspirational patient testimonials, best foods for chemotherapy patients, and support for caregivers. Ob.gyns could use Pinterest as an outreach tool for expectant and new moms with boards for breast-feeding tutorials, fashionable maternity clothing, and cool baby gear.

Pinterest has proven to deliver value to businesses. With the above recommendations, you can quickly and cost-effectively add this platform to your marketing and patient relationship efforts.

Dr. Jeffrey Benabio is a partner physician in the department of dermatology of the Southern California Permanente Group in San Diego and a volunteer clinical assistant professor at the University of California, San Diego. Dr. Benabio is @Dermdoc on Twitter.

Obstetrician-gynecologists play a unique role in screening women for various malignancies, including breast, colon, and cervical carcinoma. Although less common, genetic syndromes also can affect the female reproductive tract; therefore, knowledge of the screening guidelines for the most common genetic syndromes – hereditary breast and ovarian cancer syndrome, hereditary nonpolyposis colorectal cancer syndrome, and Cowden syndrome – is important.

Hereditary breast and ovarian cancer syndrome

Caused by autosomal-dominant deletions in the BRCA1/2 genes, the lifetime risk of ovarian cancer in patients with a BRCA1 and BRCA2 mutation is 39%-46% and 12%-20%, respectively. Although not proven to improve detection or survival, the American College of Obstetricians and Gynecologists (ACOG) and National Comprehensive Cancer Network (NCCN) guidelines recommend that women with BRCA1/2 mutations should undergo screening with transvaginal ultrasonography and CA125 every 6 months beginning between ages 30-35 years or 5-10 years prior to the age of the youngest affected family member. For patients who have not completed childbearing, a recent meta-analysis showed that use of oral contraceptives was associated with a decreased risk of ovarian cancer in patients with BRCA1/2 (J. Clin. Oncol. 2013;31:4188-98). Once childbearing has been completed or at the age of 40 years, a risk-reducing bilateral salpingo-oophorectomy (BSO) should be strongly considered (Gynecol. Oncol. 2009;113:6-11; Obstet. Gynecol. 2011;117:742-6).

In addition, patients with BRCA 1/2 mutations carry a 65%-74% lifetime risk of developing breast cancer (Gynecol. Oncol. 2009;113:6-11).ACOG recommends that these women begin screening for breast cancer at the age of 25 years through semiannual self-breast exams as well as annual mammography and breast MRI or sooner if a family member’s cancer was diagnosed prior to this age. Chemoprevention with tamoxifen also has been shown to reduce the risk of breast cancer in patients with BRCA2 disease, but is less effective for BRCA1 patients. Prophylactic mastectomy has the ability to reduce a woman’s risk of developing breast cancer by 90%-95%.

Hereditary nonpolyposis colorectal cancer syndrome

Another autosomal-dominant disorder, hereditary nonpolyposis colorectal cancer (HNPCC) syndrome arises as a result of a genetic defect in DNA mismatch repair mechanisms. Colon cancer is the most common malignancy associated with this syndrome, with a 70% risk by the age of 70 years (JAMA 2006;296:1507-17). Other associated cancers include those of the urinary tract, hepatobiliary tract, small intestine, skin, and brain, but strong supportive data are lacking. Beginning at age 20-25 years (or 10 years before the age of the youngest family member to develop colon cancer), a colonoscopy is recommended every 1-2 years. Annual urinalysis with cytology is advocated by some as a screening test for urinary tract cancers.

Patients with HNPCC have up to a 60% lifetime risk of endometrial cancer and a 10% risk of ovarian cancer (Int. J. Cancer 1999;81:214-8; Hum. Mol. Gene. 1997;6:105-10). The American Cancer Society recommends an endometrial biopsy and transvaginal ultrasonography annually between 30-35 years of age (JAMA 2006;296:1507-17). Schmeler et al. compared outcomes among 315 women with mismatch repair defects, 61 of whom underwent risk-reducing hysterectomy and BSO. With an average follow-up of greater than 7 years, none of the patients who underwent surgery developed cancer, while 33% of those who did not have surgery developed endometrial cancer and 5.5% developed ovarian cancer (N. Engl. J. Med. 2006;354:261-9). Because of these data, risk-reducing surgery at the age of 35 should be considered.

Cowden Syndrome

Cowden Syndrome, caused by an autosomal-dominant mutation in the PTEN gene, is associated with an up to 10% lifetime risk of endometrial cancer and a 50% risk of breast cancer (Obstet. Gynecol. Clin. N. Am. 2010;37:109-33). The NCCN notes that data are limited, but discussion of endometrial cancer symptoms should be encouraged (NCCN Guidelines Version 4, 2013). Annual endometrial sampling and ultrasound should be considered in woman aged 35-40 years or 10 years earlier than the youngest affected family member (Obstet. Gynecol. Clin. N. Am. 2010;37:109-33). Screening for breast cancer should include annual mammography and breast MRI starting between age 30-35 years or earlier depending on family history, per the NCCN guidelines.

It is important to note that additional genetic syndromes can have repercussions on the female genital tract, including the Li-Fraumeni (ovarian cancer), the Peutz-Jeghers (sex cord–stromal tumors of the ovary, granulosa cell tumors), and the Ollier (granulosa cell tumors) syndromes; unfortunately, screening guidelines for these rare syndromes have not been well studied (JAMA 2006;296:1507-17).

Dr. Schuler is a gynecologic oncologist at Good Samaritan Hospital in Cincinnati. Dr. Gehrig is professor and director of gynecologic oncology at the University of North Carolina at Chapel Hill. Dr. Gehrig and Dr. Schuler said they had no relevant financial disclosures.

Obstetrician-gynecologists play a unique role in screening women for various malignancies, including breast, colon, and cervical carcinoma. Although less common, genetic syndromes also can affect the female reproductive tract; therefore, knowledge of the screening guidelines for the most common genetic syndromes – hereditary breast and ovarian cancer syndrome, hereditary nonpolyposis colorectal cancer syndrome, and Cowden syndrome – is important.

Hereditary breast and ovarian cancer syndrome

Caused by autosomal-dominant deletions in the BRCA1/2 genes, the lifetime risk of ovarian cancer in patients with a BRCA1 and BRCA2 mutation is 39%-46% and 12%-20%, respectively. Although not proven to improve detection or survival, the American College of Obstetricians and Gynecologists (ACOG) and National Comprehensive Cancer Network (NCCN) guidelines recommend that women with BRCA1/2 mutations should undergo screening with transvaginal ultrasonography and CA125 every 6 months beginning between ages 30-35 years or 5-10 years prior to the age of the youngest affected family member. For patients who have not completed childbearing, a recent meta-analysis showed that use of oral contraceptives was associated with a decreased risk of ovarian cancer in patients with BRCA1/2 (J. Clin. Oncol. 2013;31:4188-98). Once childbearing has been completed or at the age of 40 years, a risk-reducing bilateral salpingo-oophorectomy (BSO) should be strongly considered (Gynecol. Oncol. 2009;113:6-11; Obstet. Gynecol. 2011;117:742-6).

In addition, patients with BRCA 1/2 mutations carry a 65%-74% lifetime risk of developing breast cancer (Gynecol. Oncol. 2009;113:6-11).ACOG recommends that these women begin screening for breast cancer at the age of 25 years through semiannual self-breast exams as well as annual mammography and breast MRI or sooner if a family member’s cancer was diagnosed prior to this age. Chemoprevention with tamoxifen also has been shown to reduce the risk of breast cancer in patients with BRCA2 disease, but is less effective for BRCA1 patients. Prophylactic mastectomy has the ability to reduce a woman’s risk of developing breast cancer by 90%-95%.

Hereditary nonpolyposis colorectal cancer syndrome

Another autosomal-dominant disorder, hereditary nonpolyposis colorectal cancer (HNPCC) syndrome arises as a result of a genetic defect in DNA mismatch repair mechanisms. Colon cancer is the most common malignancy associated with this syndrome, with a 70% risk by the age of 70 years (JAMA 2006;296:1507-17). Other associated cancers include those of the urinary tract, hepatobiliary tract, small intestine, skin, and brain, but strong supportive data are lacking. Beginning at age 20-25 years (or 10 years before the age of the youngest family member to develop colon cancer), a colonoscopy is recommended every 1-2 years. Annual urinalysis with cytology is advocated by some as a screening test for urinary tract cancers.

Patients with HNPCC have up to a 60% lifetime risk of endometrial cancer and a 10% risk of ovarian cancer (Int. J. Cancer 1999;81:214-8; Hum. Mol. Gene. 1997;6:105-10). The American Cancer Society recommends an endometrial biopsy and transvaginal ultrasonography annually between 30-35 years of age (JAMA 2006;296:1507-17). Schmeler et al. compared outcomes among 315 women with mismatch repair defects, 61 of whom underwent risk-reducing hysterectomy and BSO. With an average follow-up of greater than 7 years, none of the patients who underwent surgery developed cancer, while 33% of those who did not have surgery developed endometrial cancer and 5.5% developed ovarian cancer (N. Engl. J. Med. 2006;354:261-9). Because of these data, risk-reducing surgery at the age of 35 should be considered.

Cowden Syndrome

Cowden Syndrome, caused by an autosomal-dominant mutation in the PTEN gene, is associated with an up to 10% lifetime risk of endometrial cancer and a 50% risk of breast cancer (Obstet. Gynecol. Clin. N. Am. 2010;37:109-33). The NCCN notes that data are limited, but discussion of endometrial cancer symptoms should be encouraged (NCCN Guidelines Version 4, 2013). Annual endometrial sampling and ultrasound should be considered in woman aged 35-40 years or 10 years earlier than the youngest affected family member (Obstet. Gynecol. Clin. N. Am. 2010;37:109-33). Screening for breast cancer should include annual mammography and breast MRI starting between age 30-35 years or earlier depending on family history, per the NCCN guidelines.

It is important to note that additional genetic syndromes can have repercussions on the female genital tract, including the Li-Fraumeni (ovarian cancer), the Peutz-Jeghers (sex cord–stromal tumors of the ovary, granulosa cell tumors), and the Ollier (granulosa cell tumors) syndromes; unfortunately, screening guidelines for these rare syndromes have not been well studied (JAMA 2006;296:1507-17).

Dr. Schuler is a gynecologic oncologist at Good Samaritan Hospital in Cincinnati. Dr. Gehrig is professor and director of gynecologic oncology at the University of North Carolina at Chapel Hill. Dr. Gehrig and Dr. Schuler said they had no relevant financial disclosures.

Obstetrician-gynecologists play a unique role in screening women for various malignancies, including breast, colon, and cervical carcinoma. Although less common, genetic syndromes also can affect the female reproductive tract; therefore, knowledge of the screening guidelines for the most common genetic syndromes – hereditary breast and ovarian cancer syndrome, hereditary nonpolyposis colorectal cancer syndrome, and Cowden syndrome – is important.

Hereditary breast and ovarian cancer syndrome

Caused by autosomal-dominant deletions in the BRCA1/2 genes, the lifetime risk of ovarian cancer in patients with a BRCA1 and BRCA2 mutation is 39%-46% and 12%-20%, respectively. Although not proven to improve detection or survival, the American College of Obstetricians and Gynecologists (ACOG) and National Comprehensive Cancer Network (NCCN) guidelines recommend that women with BRCA1/2 mutations should undergo screening with transvaginal ultrasonography and CA125 every 6 months beginning between ages 30-35 years or 5-10 years prior to the age of the youngest affected family member. For patients who have not completed childbearing, a recent meta-analysis showed that use of oral contraceptives was associated with a decreased risk of ovarian cancer in patients with BRCA1/2 (J. Clin. Oncol. 2013;31:4188-98). Once childbearing has been completed or at the age of 40 years, a risk-reducing bilateral salpingo-oophorectomy (BSO) should be strongly considered (Gynecol. Oncol. 2009;113:6-11; Obstet. Gynecol. 2011;117:742-6).

In addition, patients with BRCA 1/2 mutations carry a 65%-74% lifetime risk of developing breast cancer (Gynecol. Oncol. 2009;113:6-11).ACOG recommends that these women begin screening for breast cancer at the age of 25 years through semiannual self-breast exams as well as annual mammography and breast MRI or sooner if a family member’s cancer was diagnosed prior to this age. Chemoprevention with tamoxifen also has been shown to reduce the risk of breast cancer in patients with BRCA2 disease, but is less effective for BRCA1 patients. Prophylactic mastectomy has the ability to reduce a woman’s risk of developing breast cancer by 90%-95%.

Hereditary nonpolyposis colorectal cancer syndrome

Another autosomal-dominant disorder, hereditary nonpolyposis colorectal cancer (HNPCC) syndrome arises as a result of a genetic defect in DNA mismatch repair mechanisms. Colon cancer is the most common malignancy associated with this syndrome, with a 70% risk by the age of 70 years (JAMA 2006;296:1507-17). Other associated cancers include those of the urinary tract, hepatobiliary tract, small intestine, skin, and brain, but strong supportive data are lacking. Beginning at age 20-25 years (or 10 years before the age of the youngest family member to develop colon cancer), a colonoscopy is recommended every 1-2 years. Annual urinalysis with cytology is advocated by some as a screening test for urinary tract cancers.

Patients with HNPCC have up to a 60% lifetime risk of endometrial cancer and a 10% risk of ovarian cancer (Int. J. Cancer 1999;81:214-8; Hum. Mol. Gene. 1997;6:105-10). The American Cancer Society recommends an endometrial biopsy and transvaginal ultrasonography annually between 30-35 years of age (JAMA 2006;296:1507-17). Schmeler et al. compared outcomes among 315 women with mismatch repair defects, 61 of whom underwent risk-reducing hysterectomy and BSO. With an average follow-up of greater than 7 years, none of the patients who underwent surgery developed cancer, while 33% of those who did not have surgery developed endometrial cancer and 5.5% developed ovarian cancer (N. Engl. J. Med. 2006;354:261-9). Because of these data, risk-reducing surgery at the age of 35 should be considered.

Cowden Syndrome

Cowden Syndrome, caused by an autosomal-dominant mutation in the PTEN gene, is associated with an up to 10% lifetime risk of endometrial cancer and a 50% risk of breast cancer (Obstet. Gynecol. Clin. N. Am. 2010;37:109-33). The NCCN notes that data are limited, but discussion of endometrial cancer symptoms should be encouraged (NCCN Guidelines Version 4, 2013). Annual endometrial sampling and ultrasound should be considered in woman aged 35-40 years or 10 years earlier than the youngest affected family member (Obstet. Gynecol. Clin. N. Am. 2010;37:109-33). Screening for breast cancer should include annual mammography and breast MRI starting between age 30-35 years or earlier depending on family history, per the NCCN guidelines.

It is important to note that additional genetic syndromes can have repercussions on the female genital tract, including the Li-Fraumeni (ovarian cancer), the Peutz-Jeghers (sex cord–stromal tumors of the ovary, granulosa cell tumors), and the Ollier (granulosa cell tumors) syndromes; unfortunately, screening guidelines for these rare syndromes have not been well studied (JAMA 2006;296:1507-17).

Dr. Schuler is a gynecologic oncologist at Good Samaritan Hospital in Cincinnati. Dr. Gehrig is professor and director of gynecologic oncology at the University of North Carolina at Chapel Hill. Dr. Gehrig and Dr. Schuler said they had no relevant financial disclosures.

DNA coiled around histones

Credit: Eric Smith

Researchers have presented evidence to support the use of a BET protein antagonist in FLT3-ITD-mutated acute myeloid leukemia (AML).

The group’s experiments showed the antagonist, JQ1, was active against FLT3-ITD-expressing AML cells in vitro and in vivo.

The agent also demonstrated synergy with the tyrosine kinase inhibitor (TKI) AC220 and the histone deacetylase (HDAC) inhibitor panobinostat.

In fact, JQ1 and panobinostat in combination induced apoptosis in a TKI-resistant cell line.

Melissa Rodriguez, MD, PhD, of the Houston Methodist Research Institute in Texas, and her colleagues presented these findings at the AACR Annual Meeting 2014 as abstract 1721.

The BET protein family members, including BRD4, bind to acetylated lysines on histone proteins, help assemble transcriptional regulators at the target gene promoters and enhancers, and regulate the expression of oncogenes such as MYC and BCL-2.

JQ1 interferes with BRD4 binding to acetylated lysines on histone proteins, resulting in the displacement of the BET proteins. This, in turn, disrupts transcription initiation and elongation factors situated on the chromatin, thereby inhibiting expressions of c-MYC and BCL-2 and their target genes. And this leads to growth arrest and the induction of apoptosis in AML cells.

Dr Rodriguez and her colleagues found that JQ1 alone induced apoptosis in cultured mouse lymphoid cells such as Ba/F3/FLT3-ITD but also Ba/F3/FLT3-ITD that expressed the FLT3-TKI-resistant mutations F691L and D835V.

JQ1 also attenuated the expression of c-MYC, BCL2, and CDK6 oncogenes; induced the expression of p21, p27, and BIM; and cleaved PARP levels.

Furthermore, JQ1 dose-dependently induced apoptosis in MOLM13 and MV4-11 cell lines, as well as in primary AML cells that all expressed FLT3-ITD but had not become resistant to TKIs.

In SCID mice that received non-TKI-treated MOLM13 xenografts, JQ1 alone significantly improved survival compared to vehicle controls. And the researchers observed no toxicity in the treated mice.

JQ1 plus AC220 or panobinostat synergistically induced apoptosis in MV4-11 cells, MOLM13 cells, and primary AML cells expressing FLT3-ITD.

In testing MOLM13/TKIR cells, which had a greater than 50-fold resistance to AC220 over the other cell lines tested, the researchers discovered these cells express higher levels of BRD4, c-MYC, and class I HDACs. They were also significantly more sensitive to JQ1-induced apoptosis.

In this AC220-resistant cell line, JQ1 and panobinostat synergistically induced apoptosis. But, as expected, the same effect did not occur when JQ1 was administered with AC220.

The synergistic apoptotic response of panobinostat and JQ1 was associated with the down-regulation of c-MYC and demonstrated JQ1’s ability to overcome AC220-induced TKI resistance in FLT3-ITD-expressing cells.

The researchers said these findings support future in vivo testing of BRD4 antagonists such as JQ1 in combination with TKIs such as AC220 or HDAC inhibitors such as panobinostat against FLT3-TKI-sensitive cell lines. The research also supports using BRD4 antagonists in combination with panobinostat against TKI-resistant, FLT3-ITD-mutated AML.

DNA coiled around histones

Credit: Eric Smith

Researchers have presented evidence to support the use of a BET protein antagonist in FLT3-ITD-mutated acute myeloid leukemia (AML).

The group’s experiments showed the antagonist, JQ1, was active against FLT3-ITD-expressing AML cells in vitro and in vivo.

The agent also demonstrated synergy with the tyrosine kinase inhibitor (TKI) AC220 and the histone deacetylase (HDAC) inhibitor panobinostat.

In fact, JQ1 and panobinostat in combination induced apoptosis in a TKI-resistant cell line.

Melissa Rodriguez, MD, PhD, of the Houston Methodist Research Institute in Texas, and her colleagues presented these findings at the AACR Annual Meeting 2014 as abstract 1721.

The BET protein family members, including BRD4, bind to acetylated lysines on histone proteins, help assemble transcriptional regulators at the target gene promoters and enhancers, and regulate the expression of oncogenes such as MYC and BCL-2.

JQ1 interferes with BRD4 binding to acetylated lysines on histone proteins, resulting in the displacement of the BET proteins. This, in turn, disrupts transcription initiation and elongation factors situated on the chromatin, thereby inhibiting expressions of c-MYC and BCL-2 and their target genes. And this leads to growth arrest and the induction of apoptosis in AML cells.

Dr Rodriguez and her colleagues found that JQ1 alone induced apoptosis in cultured mouse lymphoid cells such as Ba/F3/FLT3-ITD but also Ba/F3/FLT3-ITD that expressed the FLT3-TKI-resistant mutations F691L and D835V.

JQ1 also attenuated the expression of c-MYC, BCL2, and CDK6 oncogenes; induced the expression of p21, p27, and BIM; and cleaved PARP levels.

Furthermore, JQ1 dose-dependently induced apoptosis in MOLM13 and MV4-11 cell lines, as well as in primary AML cells that all expressed FLT3-ITD but had not become resistant to TKIs.

In SCID mice that received non-TKI-treated MOLM13 xenografts, JQ1 alone significantly improved survival compared to vehicle controls. And the researchers observed no toxicity in the treated mice.

JQ1 plus AC220 or panobinostat synergistically induced apoptosis in MV4-11 cells, MOLM13 cells, and primary AML cells expressing FLT3-ITD.

In testing MOLM13/TKIR cells, which had a greater than 50-fold resistance to AC220 over the other cell lines tested, the researchers discovered these cells express higher levels of BRD4, c-MYC, and class I HDACs. They were also significantly more sensitive to JQ1-induced apoptosis.

In this AC220-resistant cell line, JQ1 and panobinostat synergistically induced apoptosis. But, as expected, the same effect did not occur when JQ1 was administered with AC220.

The synergistic apoptotic response of panobinostat and JQ1 was associated with the down-regulation of c-MYC and demonstrated JQ1’s ability to overcome AC220-induced TKI resistance in FLT3-ITD-expressing cells.

The researchers said these findings support future in vivo testing of BRD4 antagonists such as JQ1 in combination with TKIs such as AC220 or HDAC inhibitors such as panobinostat against FLT3-TKI-sensitive cell lines. The research also supports using BRD4 antagonists in combination with panobinostat against TKI-resistant, FLT3-ITD-mutated AML.

DNA coiled around histones

Credit: Eric Smith

Researchers have presented evidence to support the use of a BET protein antagonist in FLT3-ITD-mutated acute myeloid leukemia (AML).

The group’s experiments showed the antagonist, JQ1, was active against FLT3-ITD-expressing AML cells in vitro and in vivo.

The agent also demonstrated synergy with the tyrosine kinase inhibitor (TKI) AC220 and the histone deacetylase (HDAC) inhibitor panobinostat.

In fact, JQ1 and panobinostat in combination induced apoptosis in a TKI-resistant cell line.

Melissa Rodriguez, MD, PhD, of the Houston Methodist Research Institute in Texas, and her colleagues presented these findings at the AACR Annual Meeting 2014 as abstract 1721.

The BET protein family members, including BRD4, bind to acetylated lysines on histone proteins, help assemble transcriptional regulators at the target gene promoters and enhancers, and regulate the expression of oncogenes such as MYC and BCL-2.

JQ1 interferes with BRD4 binding to acetylated lysines on histone proteins, resulting in the displacement of the BET proteins. This, in turn, disrupts transcription initiation and elongation factors situated on the chromatin, thereby inhibiting expressions of c-MYC and BCL-2 and their target genes. And this leads to growth arrest and the induction of apoptosis in AML cells.

Dr Rodriguez and her colleagues found that JQ1 alone induced apoptosis in cultured mouse lymphoid cells such as Ba/F3/FLT3-ITD but also Ba/F3/FLT3-ITD that expressed the FLT3-TKI-resistant mutations F691L and D835V.

JQ1 also attenuated the expression of c-MYC, BCL2, and CDK6 oncogenes; induced the expression of p21, p27, and BIM; and cleaved PARP levels.

Furthermore, JQ1 dose-dependently induced apoptosis in MOLM13 and MV4-11 cell lines, as well as in primary AML cells that all expressed FLT3-ITD but had not become resistant to TKIs.

In SCID mice that received non-TKI-treated MOLM13 xenografts, JQ1 alone significantly improved survival compared to vehicle controls. And the researchers observed no toxicity in the treated mice.

JQ1 plus AC220 or panobinostat synergistically induced apoptosis in MV4-11 cells, MOLM13 cells, and primary AML cells expressing FLT3-ITD.

In testing MOLM13/TKIR cells, which had a greater than 50-fold resistance to AC220 over the other cell lines tested, the researchers discovered these cells express higher levels of BRD4, c-MYC, and class I HDACs. They were also significantly more sensitive to JQ1-induced apoptosis.

In this AC220-resistant cell line, JQ1 and panobinostat synergistically induced apoptosis. But, as expected, the same effect did not occur when JQ1 was administered with AC220.

The synergistic apoptotic response of panobinostat and JQ1 was associated with the down-regulation of c-MYC and demonstrated JQ1’s ability to overcome AC220-induced TKI resistance in FLT3-ITD-expressing cells.

The researchers said these findings support future in vivo testing of BRD4 antagonists such as JQ1 in combination with TKIs such as AC220 or HDAC inhibitors such as panobinostat against FLT3-TKI-sensitive cell lines. The research also supports using BRD4 antagonists in combination with panobinostat against TKI-resistant, FLT3-ITD-mutated AML.

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.