Brain organoid model shows molecular signs of Alzheimer’s before birth

In a model of human fetal brain development, Emory researchers can see perturbations of epigenetic markers in cells derived from people with familial early-onset Alzheimer’s disease, which takes decades to appear. This suggests that in people who inherit mutations linked to early-onset Alzheimer’s, it would be possible to detect molecular changes in their brains before birth. The results were published in the journal Cell Reports. “The beauty of using organoids is that they allow us to Read more

The earliest spot for Alzheimer's blues

How the most common genetic risk factor in AD interacts with the earliest site of neurodegeneration Read more

Make ‘em fight: redirecting neutrophils in CF

Why do people with cystic fibrosis (CF) have such trouble with lung infections? The conventional view is that people with CF are at greater risk for lung infections because thick, sticky mucus builds up in their lungs, allowing bacteria to thrive. CF is caused by a mutation that affects the composition of the mucus. Rabindra Tirouvanziam, an immunologist at Emory, says a better question is: what type of cell is supposed to be fighting the Read more

triple negative breast cancer

To fight cancer, mix harmless reovirus with ‘red devil’

A recent paper in Journal of Virology mixes tried-and-true cancer-fighting tactics with the exotic. Sort of a peanut-butter-and-chocolate story, but definitely not tasty!

The tried and true is doxorubicin (Adriamycin), the notorious ‘red devil’ chemotherapy drug, which has been around for decades. On the exotic side, we have oncolytic viruses – viruses retuned to attack cancer cells more than healthy cells. This idea finally made it to FDA approval in 2015 in the form of a re-engineered herpes virus directed against melanoma.

Bernardo Mainou’s lab in the Department of Pediatrics is combining both of these approaches together. He and his team are looking to supercharge reoviruses, a mostly harmless type of virus that has been adapted into an anticancer agent. A Canadian company has brought its reovirus forward into several cancer clinical trials, but its product has not gotten to the finish line.

In the JVI paper, graduate students Roxana Rodriguez-Stewart, Jameson Berry and their colleagues infected triple-negative breast cancer cells with a variety of reoviruses, in an effort to select for those that replicate better in those cells. They also looked for drugs that enhance viral infection of those cells, and landed on doxorubicin and related drugs. Doxorubicin is part of a class of anticancer drugs that inhibit topoisomerases, enzymes that unwind DNA as part of the process of replication.

Yesterday at the GDBBS graduate research symposium, Berry gave a talk about the next step: attaching the souped-up reovirus to doxorubicin.

Three varieties of reovirus were grown together in breast cancer cells to select for efficient replication. 





Posted on by Quinn Eastman in Cancer Leave a comment

CAPTCHA some cancer cells

Humans are good at deciphering complex images, compared to computers. Until recently, internet users often needed to verify that they were human by completing a CAPTCHA security check. A familiar variety asked the user to check all the boxes that contain a car, or a street sign.

If we asked random people off the street to look at pathology slides and “quick, check all the boxes that contain tumor cells,” what would happen? The accuracy, compared to a trained pathologist, wouldn’t be very good.

Not as easy as labeling which boxes contain street signs!

This challenge of expertise – crowdsourcing and pathology are not immediately compatible – is what Lee Cooper and colleagues sought to overcome in a recent paper published in Bioinformatics. So they put together something they called “structured crowdsourcing.”

“We are interested in describing how the immune system behaves in breast cancers, and so we built an artificial intelligence system to look at pathology slides and identify the tissue components,” Cooper says.

His group was particularly interested in the aggressive form of breast cancer: triple negative. They used pathology slide images from the Cancer Genome Atlas, a National Cancer Institute resource. The goal was to mark up the slides and label which sections contained tumor, stroma, white blood cells, dead cells etc.

They used social media to recruit 25 volunteers — medical students and pathologists from around the world (Egypt, Bangladesh, Saudi Arabia, United Arab Emirates, Syria, USA). Participants underwent training and used Slack to communicate and learn about how to classify images. They collaborated using the Digital Slide Archive, a tool developed at Emory. Read more

Posted on by Quinn Eastman in Cancer Leave a comment

Nox-ious link to cancer Warburg effect

At Emory, Kathy Griendling’s group is well known for studying NADPH oxidases (also known as Nox), enzymes which generate reactive oxygen species. In 2009, they published a paper on a regulator of Nox enzymes called Poldip2. Griendling’s former postdoc, now assistant professor, Alejandra San Martin has taken up Poldip2.

Griendling first came to Nox enzymes from a cardiology/vascular biology perspective, but they have links to cancer. Nox enzymes are multifarious and it appears that Poldip2 is too. As its full name suggests, Poldip2 (polymerase delta interacting protein 2) was first identified as interacting with DNA replication enzymes.  Poldip2 also appears in mitochondria, indirectly regulating the process of lipoylation — attachment of a fatty acid to proteins anchoring them in membranes. That’s where a recent PNAS paper from San Martin, Griendling and colleagues comes in. It identifies Poldip2 as playing a role in hypoxia and cancer cell metabolic adaptation.

Part of the PNAS paper focuses on Poldip2 in triple-negative breast cancer, more difficult to treat. In TNBC cells, Poldip2’s absence appears to be part of the warped cancer cell metabolism known as the Warburg effect. Lab Land has explored the Warburg effect with Winship’s Jing Chen.

Posted on by Quinn Eastman in Cancer, Heart Leave a comment

Immunotherapy for triple negative breast cancer

Treatments that unleash the immune system against cancer have been a hot topic for the last few years, but they do not appear in our recent feature on breast cancer for Winship Cancer Institute’s magazine.

Partly, that’s because decent avenues for treatment exist for most types of breast cancer, with improvements in survival since the 1980s. Immunotherapy’s successes have been more dramatic for types of cancer against which progress had been otherwise meager, such as lung cancers and metastatic melanoma.

Jane Meisel, MD with patient

Winship oncologist Jane Meisel, MD with patient

However, for “triple-negative” breast cancer (TNBC) in particular, immunotherapy could be a good match, because of the scarcity of targeted treatments and because TNBC’s genomic instability may be well-suited to immunotherapy.

Winship oncologists Jane Meisel and Keerthi Gogineni inform Lab Land that several early-phase clinical studies open to breast cancer patients, testing “checkpoint inhibitor” agents such as PD-1 inhibitors, are underway. More are pending.

Meisel’s presentation at Winship’s Sea Island retreat says that immunotherapy is “not yet ready for prime time, but a very promising experimental approach for a subset of patients for whom current therapies are not sufficient. We need to better understand which subsets of patients are most likely to benefit, and how we can use other therapies to enhance efficacy in patients who don’t initially respond.”

Read more

Posted on by Quinn Eastman in Cancer Leave a comment