Plasma cells, antibody factories

Alterations in DNA methylation patterns when B cells turn into plasma cells. From Barwick Nature Immunology et al (2016) Read more

Are you experienced?

Part of a package on sepsis we've been working on for Emory Medicine magazine. This focuses on Read more

Aging, CVD risk factors and progenitor cells

Teasing apart the effects of time and CVD risk factors on cells that regenerate blood vessels. From Emory Clinical Cardiovascular Research Read more

Winship Cancer Institute

Outcomes in minimally invasive lung cancer surgery

To accompany our recent article on minimally invasive lung surgery for Winship magazine, please find a video featuring thoracic surgeon Manu Sancheti, MD.

As Sancheti explains, an advantage of minimally invasive approaches (sometimes called VATS for video-assisted thoracic surgery) is that surgeons do not open the patient’s chest, avoiding pain and potential complications and reducing length of stay in the hospital.

Among thoracic surgeons, the shift to this type of approach has taken place in the last few years — unevenly. Here’s a graph froLung surgery graphm one recent publication from Felix Fernandez, MD and colleagues, showing the percent of stage I lung cancer surgeries — compiled for individual surgeons in the Society of Thoracic Surgeons  — that are minimally invasive from 2011-2014. The average is about 63 percent, but it varies widely.

Attention medical journalists: if you want to ask questions like “Are these minimally invasive lung surgery approaches really good for long term patient outcomes?”, Fernandez is your guy. As the numbers come in, he is leading a team that is analyzing them. Read more

Posted on by Quinn Eastman in Cancer Leave a comment

Three-stage delivery for platinum-based “cluster bombs” against cancer

Scientists have devised a triple-stage “cluster bomb” system for delivering the chemotherapy drug cisplatin, via tiny nanoparticles designed to break up when they reach a tumor.

Details of the particles’ design and their potency against cancer in mice are described this week in PNAS Early Edition. They have not been tested in humans, although similar ways of packaging cisplatin have been in clinical trials. Anticancer cluster bombs

What makes these particles distinctive is that they start out relatively large — 100 nanometers wide – to enable smooth transport into the tumor through leaky blood vessels. Then, in acidic conditions found close to tumors, the particles discharge “bomblets” just 5 nanometers in size.

Inside tumor cells, a second chemical step activates the platinum-based cisplatin, which kills by crosslinking and damaging DNA. Doctors have used cisplatin to fight several types of cancer for decades, but toxic side effects – to the kidneys, nerves and inner ear — can limit its effectiveness.

The PNAS paper is the result of a collaboration between a team led by professor Jun Wang, PhD at the University of Science and Technology of China, and researchers led by professor Shuming Nie, PhD in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory. Nie is a member of the Discovery and Developmental Therapeutics research program at Winship Cancer Institute of Emory University. The lead authors are graduate student Hong-Jun Li and postdoctoral fellows Jinzhi Du, PhD and Xiao-Jiao Du, PhD.

“The negative side effects of cisplatin are a long-standing limitation for conventional chemotherapy,” says Jinzhi Du. “In our study, the delivery system was able to improve tumor penetration to reach more cancer cells, as well as release the drugs specifically inside cancer cells through their size-transition property.”

The researchers showed that their nanoparticles could enhance cisplatin drug accumulation in tumor tissues. When mice bearing human pancreatic tumors were given the same doses of free cisplatin or cisplatin clothed in pH-sensitive nanoparticles, the level of platinum in tumor tissues was seven times higher with the nanoparticles. This suggests the possibility that nanoparticle delivery could restrain the toxic side effects of cisplatin during cancer treatment. Read more

Posted on by Quinn Eastman in Cancer Leave a comment

Anticancer drug strategy: making cells choke on copper

What do cancer cells have in common with horseshoe crabs and Mr. Spock from Star Trek?

They all depend upon copper. Horseshoe crabs have blue blood because they use copper to transport oxygen in their blood instead of iron (hemocyanin vs hemoglobin). Vulcans’ blood was supposed to be green, for the same reason.

Horseshoe Crab (Limulus polyphemus)

Horseshoe crabs and Vulcans use copper to transport oxygen in their blood. Cancer cells seem to need the metal more than other cells.

To be sure, all our cells need copper. Many human enzymes use the metal to catalyze important reactions, but cancer cells seem to need it more than healthy cells. Manipulating the body’s flow of copper is emerging as an anticancer drug strategy.

A team of scientists from University of Chicago, Emory and Shanghai have developed compounds that interfere with copper transport inside cells. These compounds inhibit the growth of several types of cancer cells, with minimal effects on the growth of non-cancerous cells, the researchers report in Nature Chemistry.

“We’re taking a tactic that’s different from other approaches. These compounds actually cause copper to accumulate inside cells,” says co-senior author Jing Chen, PhD, professor of hematology and medical oncology at Emory University School of Medicine and Winship Cancer Institute. Read more

Posted on by Quinn Eastman in Cancer Leave a comment

Cancer metastasis: isolating invasive cells with a color change

The capacity of cancer cells to spread throughout the body and invade new tissues – to become metastatic — makes them deadly. What makes metastatic cells different? Scientists at Winship Cancer Institute of Emory University have developed a technique for isolating individual cells that display invasive behavior out of a large group in culture by changing their color.

Read more

Posted on by Quinn Eastman in Cancer Leave a comment

Adaptive mutation mechanism may drive some forms of antibiotic resistance

Evolutionary theory says mutations are blind and occur randomly. But in the controversial phenomenon of adaptive mutation, cells can peek under the blindfold, increasing their mutation rate in response to stress.

Scientists at Winship Cancer Institute, Emory University have observed that an apparent “back channel” for genetic information called retromutagenesis can encourage adaptive mutation to take place in bacteria.

The results were published Tuesday, August 25 in PLOS Genetics.

“This mechanism may explain how bacteria develop resistance to some types of antibiotics under selective pressure, as well as how mutations in cancer cells enable their growth or resistance to chemotherapy drugs,” says senior author Paul Doetsch, PhD.

Doetsch is professor of biochemistry, radiation oncology and hematology and medical oncology at Emory University School of Medicine and associate director of basic research at Winship Cancer Institute. The first author of the paper is Genetics and Molecular Biology graduate student Jordan Morreall, PhD, who defended his thesis in April.

Retromutagenesis resolves the puzzle: if cells aren’t growing because they’re under stress, which means their DNA isn’t being copied, how do the new mutants appear?

The answer: a mutation appears in the RNA first. Read more

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

CMV reactivation warps immune system after HSCT

As a followup to yesterday’s post on following troublemaker cells in patients with lupus, we’d like to highlight a recent paper in Blood that takes a similar approach to studying how the immune system comes back after bone marrow/blood stem cell transplant.

Leslie Kean, MD, PhD

The paper’s findings have implications for making this type of transplant safer and preventing graft-versus-host disease. In a bone marrow/blood stem cell transplant, to fight cancer, doctors are essentially clearing out someone’s immune system and then “planting” a new one with the help of a donor. What this paper shows is how much CMV (cytomegalovirus) distorts the new immune system.

CMV is often thought of as harmless — most adults in the United States have been infected with CMV by age 40 and don’t get sick because of it. But in this situation, CMV’s emergence from the shadows forces some of the new T cells to multiply, dominating the immune system so much that it creates gaps in the rest of the T cell repertoire, which can compromise protective immunity. Other seemingly innocuous viruses like BK cause trouble in immunosuppressed patients after kidney transplant.

The senior author, Leslie Kean, moved from Emory to Seattle Children’s Hospital in 2013, and her team began these studies here in 2010 (a host of Emory/Winship hematologists and immunologists are co-authors). This paper is sort of a mirror image of the Nature Immunology paper on lupus because it also uses next-generation sequencing to follow immune cells with DNA rearrangements — in this case, T cells. Read more

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

Low doses of imatinib can stimulate innate immunity

Low doses of the anti-cancer drug imatinib can spur the bone marrow to produce more innate immune cells to fight against bacterial infections, Emory and Winship Cancer Institute researchers have found.

The results were published this week in the journal PLOS Pathogens.

The findings suggest imatinib, known commercially as Gleevec, or related drugs could help doctors treat a wide variety of infections, including those that are resistant to antibiotics, or in patients who have weakened immune systems. The research was performed in mice and on human bone marrow cells in vitro, but provides information on how to dose imatinib for new clinical applications.

“We think that low doses of imatinib are mimicking ‘emergency hematopoiesis,’ a normal early response to infection,” says senior author Daniel Kalman, PhD, associate professor of pathology and laboratory medicine at Emory University School of Medicine.

Imatinib, is an example of a “targeted therapy” against certain types of cancer. It blocks tyrosine kinase enzymes, which are dysregulated in cancers such as chronic myelogenous leukemia and gastrointestinal stromal tumors.

Imatinib also inhibits normal forms of these enzymes that are found in healthy cells. Several pathogens – both bacteria and viruses – exploit these enzymes as they transit into, through, or out of human cells. Researchers have previously found that imatinib or related drugs can inhibit infection of cells by pathogens that are very different from each other, including tuberculosis bacteria and Ebola virus. Read more

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

BAI1: a very multifunctional protein

Everything is connected, especially in the brain. A protein called BAI1 involved in limiting the growth of brain tumors is also critical for spatial learning and memory, researchers have discovered.

Mice missing BAI1 have trouble learning and remembering where they have been. Because of the loss of BAI1, their neurons have changes in how they respond to electrical stimulation, and subtle alterations in parts of the cell needed for information processing.

The findings may have implications for developing treatments for neurological diseases, because BAI1 is part of a protein regulatory network neuroscientists think is connected with autism spectrum disorders.

The results were published online March 9 in Journal of Clinical Investigation.

Erwin Van Meir, PhD, and his colleagues at Winship Cancer Institute of Emory University have been studying BAI1 (brain-specific angiogenesis inhibitor 1) for several years. Part of the BAI1 protein can stop the growth of new blood vessels, which growing cancers need. Normally highly active in the brain, the BAI1 gene is lost or silenced in brain tumors, suggesting that it acts as a tumor suppressor.

The researchers were surprised to find that the brains of mice lacking the BAI1 gene looked normal anatomically. They didn’t develop tumors any faster than normal, and they didn’t have any alterations in their blood vessels, which the researchers had anticipated based on BAI1’s role in regulating blood vessel growth. What they did have was problems with spatial memory.

Read more

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

Rules of thumb for drug discovery

People interested in drug discovery may have heard of “Lipinski’s rule of five,” a rough-and-ready set of rules for determining whether a chemical structure is going to be viable as a orally administered drug or not. They basically say that if a compound is too big, too greasy or too complicated, it’s not going to get into the body and make it to the cells you want to affect. These guidelines have been the topic of much debate among medicinal chemists and pharmacologists.

The namesake for this set of rules, Chris Lipinski, will be speaking at Winship Cancer Institute Wednesday afternoon (4:30 pm, Nov 5, C5012) on “The Rule of 5, Public Chemistry-Biology Databases and Their Impact on Chemical Biology and Drug Discovery.” Lipinski spent most of his career at Pfizer (while there, he published the “rule of 5 paper“) and now is a consultant at Melior Discovery.

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

Pilot human trial for image-guided cancer surgery tool

The Spectropen, a hand-held device developed by Emory and Georgia Tech scientists, was designed to help surgeons see the margins of tumors during surgery.

Some of the first results from procedures undertaken with the aid of the Spectropen in human cancer patients were recently published by the journal PLOS One. A related paper discussing image-guided removal of pulmonary nodules was just published in Annals of Thoracic Surgery.

To test the Spectropen, biomedical engineer Shuming Nie and his colleagues have been collaborating with thoracic surgeon Sunil Singhal at the University of Pennsylvania.

As described in the PLOS One paper, five patients with cancer in their lungs or chest participated in a pilot study at Penn. They received an injection of the fluorescent dye indocyanine green (ICG) before surgery.

ICG is already FDA-approved for in vivo diagnostics and now used to assess cardiac and liver function. ICG accumulates in tumors more than normal tissue because tumors have leaky blood vessels and membranes. The Spectropen shines light close to the infrared range on the tumor, causing it to glow because of the fluorescent dye.

[This technique resembles the 5-aminolevulinic acid imaging technique for brain tumor surgery being tested by Costas Hadjipanayis, described in Emory Medicine.]

In one case from the PLOS One article, the imaging procedure had some tangible benefits, allowing the surgeons to detect the spread of cancerous cells when other modes of imaging did not. Read more

Posted on by Quinn Eastman in Cancer Leave a comment