Wikipedia says that â€œherding catsâ€ refers to an attempt to control or organize a class of entities that are uncontrollable or chaotic.
Cancer cells certainly qualify as uncontrollable or chaotic, so the metaphor could apply to a recent Nature Materials paper from Georgia Tech and Emoryâ€™s Ravi Bellamkonda â€“ a member of Winship Cancer Institute.
Glioblastoma is the worst of the worst: the most common and the most aggressive form of brain tumor in adults. The tumors are known to invade healthy tissue and migrate along white matter tracts and blood vessels.Â Bellamkonda and his colleagues devised a strategy for luring glioblastoma cells out of the brain by offering the cells attractive nanofibers that the cells will Ray Ban outlet attempt to invade. When the cells arrive, they undergo apoptosis — cellular suicide. He has called this â€œan engineerâ€™s approach to brain cancerâ€ (in a lecture a couple months ago) and â€œthe Pied Piper approach” (in the video below).
Bellamkondaâ€™s collaborator this time,Â Tobey Macdonald, director of pediatric neuro-oncology at Childrenâ€™s Healthcare of Atlanta, is credited in the paper with coming up with the aspect of the strategy that was based on the molecule cyclopamine. This earlier story from CHOA provides more background on how the collaboration came together.
Cyclopamine is key to the “lure ’em out and kill ’em” strategy. Most high-grade brain tumors overproduce a protein called Sonic Hedgehog, spurring their growth. Cyclopamine is selectively toxic only to cells that are dependent on Sonic Hedgehog. Cyclopamine’s name comes from how it was discovered: through its teratogenic effects on sheep in Idaho that ate corn lily flowers.
Brain cancer doesnâ€™t have a purpose or intent. Itâ€™s just a derangement of molecular biology, cells that keep growing when theyâ€™re not supposed to.
But itâ€™s difficult not to think in terms of purpose or intent when looking at what cancers do.Â For example, Winship Cancer Institute scientists Abdessamad (Samad) Zerrouqi, Beata Pyrzynska, Dan Brat and Erwin Van Meir have a recent paper in Cancer Research examining how glioblastoma cells regulate the process of blood clotting.*
Blood clots, often in the legs, are a frequent occurrence in patients fighting glioblastoma, the most common and the most aggressive form of brain cancer.Â Zerrouqi and http://www.gooakley.com/ Van Meir show that a tumor suppressor gene (p14ARF) that is often mutated in glioblastoma stops them from activating blood clotting. Take away the gene and glioblastoma cells activate the clotting process more.
At first glance, a puzzle emerges: why would a cancer â€œwantâ€ to induce blood clots?Â Cancer cells often send out growth factors that stimulate the growth of new blood vesselsÂ (angiogenesis). The cells are growing fast, thus they need their own blood supply. Activating clotting seems contradictory: why build a new highway and then induce a traffic jam?
The two left arrows indicate clots causing necrosis around the vessels. Cells at the edge of the necrotic zone (right arrow) tend to be more proliferative and invasive. Image courtesy of Zerrouqi.
In a way, tumor cells are acting somewhat Nietzschean, blindly managing their own cheap oakley evolution according to the principle â€œWhatever doesnâ€™t kill me makes me stronger.â€
Blood clots lead to both destruction of the healthy and tumor tissue and hypoxia, a shortage of oxygen that drives more aggressiveness in the tumor. The clots create “micro-necroses” at the leading edge of the tumor that over time probably fuse and create a big central necrosis.
“The paradox is that the tumor kills itself and the normal brain, yet the capacity of doing this is the hallmark of the most malignant form of this tumor,” Van Meir says.
â€œThe advantage of tumoral thrombosis will be selection of cells to progress to higher aggressiveness: infiltrative,Â resistant to death with conventional Oakley Sunglasses cheap therapies, metabolically adapted to low levels of oxygen and nutrients,â€ Zerrouqi says. “At this stage, the tumor seems to have a clear deadly intent.”
A fragment of one of the proteins that cancer cells use to exert the clotting effect, called TFPI2, could be used to antagonize blood clotting Â therapeutically, they write in Cancer Research.Â The findings could also have implications for understanding the effects ofÂ current medications, such as the angiogenesis inhibitor bevacizumab, also known as Avastin.
*A paper by Van Meir and Dan Brat from 2005 is the top Google link under the search term â€œglioblastoma clotting.â€
For your viewing pleasure, we have two videos, courtesy of Winship Cancer Institute’s Adam Marcus.Â He and his colleagues are investigating whether Withania somnifera, a root used in Indian traditional medicine,Â could be a source for drugsÂ that inhibit breast cancer invasion and metastasis.Â Metastasis occurs when cells from a primary tumor migrate to a new location and invade the tissues at the new location.
The first video, the blob that grows, shows MCF10a mammary Ray Ban outlet epithelial cells undergoing epithelial-mesenchymal transition (EMT) in response to TGF-beta. This is a laboratory model for understanding breast cancer invasion and metastasis.
The second shows what happens when the same cells are treated with an extract from Withania somnifera. The blob doesn’t expand in such a threatening way anymore!Â The results were recently published in PLOS One.
Gina Kolata has a section front story in Tuesday’s New York Times exploring the potential of a relatively new class of anticancer drugs. The drugs break through “shields” built by cancers to ward off the threat posed by the patient’s immune system. Many are based on blocking PD-1, an immune regulatory molecule whose importance in chronic infections was first defined by Emory’s Rafi Ahmed.
Let’s take a moment to examine some of the roots of this story.Â Rafi Ahmed didnâ€™t set out to study cancer. For the last two decades, he and his colleagues have been studying T cells, parts of the immune system that are critical for responding to infections. Read more
This monthâ€™s intriguing images come from radiation oncologist Ian Crocker and colleagues. Each one shows a patient with a glioblastoma, an aggressive brain tumor. The patientâ€™s brain was scanned in two ways: on the left, MRI (magnetic resonance imaging) and on the right, PET (positron emission tomography), using a probe developed at Emory. We can see that the tumorâ€™s PET signal is more distinct than the tumorâ€™s appearance on MRI.
Since the 1990s, Mark Goodman, John Votaw and colleagues at Emoryâ€™s Center for Systems Imaging have been developing the probe FACBC (fluoro-1-amino-3-cyclobutyl carboxylic acid) as a probe for the detection of tumors.
Treatment strategies for several types of cancer have been transformed by the discovery of â€œtargeted therapies,â€ drugs directed specifically against the genetic mutations that drive tumor growth. So far, these strategies have been relatively unsuccessful when it comes to glioblastoma, the most common and most deadly form of brain tumor affecting adults. Glioblastoma was one of the first tumor types to be analyzed in the Cancer Genome Atlas mega-project, but many of the molecular features of glioblastoma have been difficult to exploit.
For example, about 40 percent of glioblastoma tumors ray ban baratas have extra copies of the EGFR (epidermal growth factor receptor) gene. EGFR provides a pedal-to-the-metal growth signal and is known to play a role in driving the growth of lung and colon cancers as well. But drugs targeted against EGFR that have extended patient survival in lung cancer have shown disappointing results with glioblastoma. The reason: the tumor cells can quickly mutate the EGFR gene or switch to reliance on other growth signals.
Keqiang Ye, PhD and colleagues recently described the discovery of a compound that may be valuable in fighting glioblastoma. The Emory researchers devised a scheme to stop tumor cells from using well-known escape routes to avoid EGFR-based drugs. Their results are published in the journal Science Signaling. Postdoctoral fellow Kunyan He, PhD, is the first author.
The compound they identified inhibits the enzyme JAK2, one of the apparent escape Ray Ban outlet routes taken by glioblastoma cells. The compound can pass the blood-brain barrier and inhibit glioblastoma growth while having low toxicity, the researchers report.
On January 8, Emory University School of Medicine’s Department of Medicine Grand Rounds had an unusual format: a debate between Otis Brawley, MD and John Petros, MD on the topic of PSA testing.
Otis Brawley, MD
Prostate cancer is the second leading cause of cancer death for American men. PSA (prostate specific antigen) is a protein produced by the prostate gland and its levels can be measured by a simple blood test.Â A higher number could indicate prostate cancer, but the test doesnâ€™t differentiate between an aggressive, fast-growing cancer, and one that is so slow-growing it wouldnâ€™t threaten a manâ€™s life.
Brawley, professor of hematology and medical oncology and chief medical officer for the American Cancer Society, led off the debate arguing that studies show PSA testing to be unreliable and possibly leading to too many diagnoses and unnecessary treatment for prostate cancer. Petros, a professor of urology who treats prostate cancer patients, looked at other studies (more details below), which show the PSA test to be a tool that has helped save lives by detecting prostate cancer at earlier stages.
In May 2012, the U.S. Preventive Services Task Force issued a “grade D” rating for PSA screening, saying the practice offers more harms — in terms of complications from PSA-test-driven treatment such as incontinence and blood clots — than benefits. Brawley agreed with this Ray Ban outlet assessment and says heâ€™s not convinced the PSA test saves lives, but he doesnâ€™t rule out its use. He framed this issue this way:
Pretend you are offered the choice of taking a pill that will double the risk of prostate cancer diagnosis from 10 to 20 percent, but could decrease risk of prostate cancer death by one fifth: from 3 to 2.4 percent.Â “Do you feel lucky?” Brawley quipped.
John Petros, MD
As a counterpoint, Petros cited National Cancer Institute epidemiology data indicating that the rate of metastatic prostate cancer has substantially decreased over the last few decades, since prostate cancers are now being diagnosed at an earlier stage. He also went over studies conducted in Sweden (Goteborg) and in Austria (Tyrol), which show significant reductions in prostate cancer-related mortality coming from PSA testing.
Five things Brawley and Petros agreed on:
PSA testing should be performed in the context of a physician-patient relationship, with men making an informed decision about the value of the information they will receive and the associated risks.
Vans in supermarket parking lots â€“ more broadly, community- or employer-based screeningÂ — are not the ideal setting for PSA testing.
The PLCO study, a NCI-sponsored randomized clinical trial to examine the effects of screening on cancer-related mortality, was flawed. In particular, the â€œcontrolâ€ arm had a substantial rate of PSA testing.
Brawley said: â€œSome cancers that are detected early do not pose a threat and do not need to be treated.â€ Similarly, Petros said: â€œProstate cancer can be low risk if safely observed, but high risk forms are lethal. We need to focus on cancers that matter.â€
Biomarkers that are better than PSA alone are needed. Brawley said: â€œWe need a 2013 definition of prostate cancer, informed by genomics, rather than going by what Virchow decided prostate cancer looks like under the microscope 160 years ago.â€
Petros agreed with this last point and noted that more sophisticated tests than PSA already have been identified such as the prostate health index, which measures levels for three forms of PSA and may be more cancer-specific. Research being conducted at Emory by Carlos Moreno and colleagues also moves toward this goal. In 2011, his team published results in the American Journal of Pathology on a panel of biomarkers that can predict prostate cancer outcomes after prostatectomy. The Atlanta Business Chronicle recently had a story on a patent related to Morenoâ€™s research.
Petros said a key question, and one he and Moreno are planning on testing, is whether the same biomarkers could be useful on prostate biopsy samples. This could help make treatment decisions regarding surgery vs radiation. Biopsy-based tests could be combined with data based on urine biomarkers, to get around the problem of tumor heterogeneity and imperfect sampling, Petros said.
For now, Petros said he believes in initiating a conversation about PSA screening with patients 50 and older, or younger if they have risk factors for the disease.Â Â He said the decision to have routine PSA testing, follow-up tests and prostate cancer treatments, is a very individualized process.
â€œIt comes down to, what do you tell the man standing in front of you?â€ he said. â€œYou have to consider where they are in life and what their goals are, and that varies with every man.â€
Before all the excitement about embryonic stem cells, doctors were using hematopoetic â€“ that is, blood-forming — stem cells. Hematopoetic stem cells can replenish all the types of cells in the blood, and are the centerpiece of transplantation as treatment for diseases such as multiple myeloma or leukemia. They can come from two different places: directly from the marrow of a donorâ€™s hip bone, or indirectly from the donorâ€™s blood after a drug nudges the stem cells out of the bone marrow.
Most hematopoetic stem cell transplants in the United States now use the indirect method of obtaining the stem cells. Until this fall, gold-standard randomized clinical trial results were not available to say which method is best for patient outcomes. Winship Cancer Institute hematologist Ned Waller was a key co-author of a study that was published in October in the New England Journal of Medicine addressing this question.
The trial involved 48 centers enrolling 551 patients as part of the Bone Marrow and Clinical Trials Network (BMT CTN).Â Waller helped design the study, and his lab at Winship analyzed the cells in each type of graft as the central core lab for the trial.
The study found no significant difference in the overall Ray Ban Italia survival rate at two years, and no difference in relapse rates or in acute graft-versus-host-disease (GVHD). However, there was a significantly higher rate of chronic GVHD with the use of blood stem cells.
GVHD, a difficult and sometimes life-threatening complication for this type of transplant, involves damage inflicted by the transplant recipientâ€™s new immune system upon the liver, skin and digestive system.
This finding will generate serious discussion among leaders in the transplant field about whether bone marrow or peripheral blood stem cell transplantation is a better treatment option, Waller says. A text Q + A with him follows.
What was surprising about the results of this study?
The equivalent survival was expected, and the increased chronic GvHD in recipients of blood stem cell grafts was suspected. What is surprising is that the relapse rate was similar between the two arms, in spite of the PBSC arm having more chronic GvHD.
The accompanying editorial argues bone marrow should be the standard for unrelated-donor transplants. Do you agree?
Yes, with the exceptions that Fred mentioned: patients with life-threatening infections and patients at high risk for graft rejection.
What are the differences, procedurally, between bone marrow and peripheral blood as sources for hematopoetic stem cell transplant?
Donating bone marrow involves a two or three hour surgical procedure requiring general anesthesia, in which bone marrow is removed from the hip bone with a needle and syringe.Â For peripheral blood stem cells, the donor undergoes five days of injections of granulocyte colony-stimulating factor and then a four-hour apheresis procedure to harvest stem cells from the blood. Blood stem cell donors have bone pain during the 5-day period of cytokine treatment, and bone marrow donors have more discomfort early after donation, but symptoms for both BM and PBSC donors have typically resolved by four weeks after donation.
What proportion of each is now in use here?
Marrow is the graft source in about 25% of recipients of grafts from unrelated donors, 10% in recipients of grafts from related donors.
What proportion of HSCT is unrelated donor?
For allogeneic transplants, about 60% receive grafts form unrelated donors (33% matched related donors and 7% mis-matched related donors).
What kind of information does this study provide oncologists/hematologists about which option to use in which situation?
Marrow should be preferred in recipients of grafts from unrelated donors when the conditioning regimen is myeloablative [substantially damages the patient’s existing bone marrow].
Does it depend on the type of leukemia/myeloma, the age or other conditions of the patient etc?
This study only enrolled patients with acute leukemia and MDS [myelodysplastic syndrome]. It excluded patients with myeloma or lymphoma. Ages included children, adults up to 60.
What other types of studies in this area are being conducted at Winship?
We are studying the role of different constituents in the graft (BM and PBSC) to determine which are most important in shaping transplant outcomes (relapse, GvHD). We have an active pre-clinical research program utilizing mouse models to address specific questions related to engraftment cell homing and specific pathways related to immune activation. In addition, we will participate in a clinical trial of a new way of mobilizing blood stems that avoids the need for five days of G-CSF and uses a CXCR4 antagonist called plerixafor to mobilize PBSC. The properties of the plerixafor-mobilized PBSC may be more similar to BM cells with respect to GvHD.
A recent article in Chemical & Engineering News describes the promising properties of curcumin, a compound derived from turmeric, in models of Alzheimerâ€™s disease.
Curcumin is a component of turmeric
In addition to contributing to curry dishesâ€™ yellow color and pungent flavor, curcumin has been a medicine in India for thousands of years. Doctors practicing traditional Hindu medicine admire turmericâ€™s active ingredient for its anti-inflammatory properties and have used it to treat patients for ailments including digestive disorders and joint pain.
Only in the 1970s did Western researchers catch up with Eastern practices and confirm curcuminâ€™s anti-inflammatory properties in the laboratory. Scientists also eventually determined that the polyphenolic compound is an antioxidant and has chemotherapeutic activity.
Several research groups at Emory are investigating curcumin-related compounds.
Dermatologist Jack Arbiser has been interested in curcumin’s antiangiogenic (inhibiting blood vessel growth) properties for several years and reports that he is studying how the compound is metabolized. Chemist Dennis Liotta and his colleagues have identified relatives of curcumin that are more soluble, and thus could be more easily taken up by the body. In particular, chemist James Snyder has been a key driver in designing and synthesizing curcumin-related compounds used by several investigators at Emory and elsewhere (see figure):
Psychiatrists Thaddeus Pace and Andrew Miller have been testing whetherÂ curcumin relatives may have useful properties with depression. Specifically, the curcumin-related compounds may have the ability to interfere with the connection (YouTube video) between inflammation and depression.
Winship Cancer Institute researcher Mamoru Shoji has been exploring how to target curcumin compounds to tumor-associated endothelial cells by linking themÂ to a clotting factor.Â In the Department of Gynecology and Obstetrics, Friedrich Wieser is examining whether curcumin compounds can be helpful with endometriosis.
Cells sometimes â€œfixâ€ DNA the wrong way, creating an extra mutation, Emory scientists have revealed.
Biologist Gray Crouse, PhD, and radiation oncologist Yoke Wah Kow, PhD, recently published a paper in Proceedings of the National Academy of Sciences that shows how mismatch repair can introduce mutations in nondividing cells. Their paper was recognized by the National Institute of Environmental Health Sciences as an extramural paper of the month. The first author is lead research specialist Gina Rodriguez.
In DNA, a mismatch is when the bases on the two DNA strands do not conform to Watson-Crick rules, such as G with T or A with C. Mismatches can be introduced into DNA through copying errors as well as some kinds of DNA damage.
If the cell â€œfixesâ€ the wrong side, that will introduce a mutation (see diagram). So how does the cell know which side of the mismatch needs to be repaired? Usually mismatch repair is tied to DNA replication. Replication enzymes appear to somehow mark the recently copied strand as being the one to replace — exactly how cells accomplish this is an active area of research.
In some situations, mismatch repair could introduce mutations into DNA.
Overall, mismatch repair is a good thing, from the point of view of preventing cancer. Inherited deficiencies in mismatch repair enzymes lead to an accumulation of mutations and an increased risk of colon cancer and other types of cancer.
But many of the cells in our bodies, such as muscle cells and neurons, have stopped dividing more or less permanently (in contrast with the colon). That means they no longer need to replicate their DNA. Other cells, such as resting white blood cells, have stopped dividing temporarily. Mutations in nondividing cells may have implications for aging and cancer formation in some tissues.
Through clever experimental design, Crouseâ€™s team was able to isolate examples of when mismatch repair occurred in the absence of DNA replication.
As the NIEHS Newsletter notes:
â€œThe researchers introduced specific mispairs into the DNA of yeast cells in a way that let them observe the very rare event of non-strand dependent DNA repair. They found that mispairs, not repaired during replication, sometimes underwent mismatch repair later when the cells were no longer dividing. This repair was not strand dependent and sometimes introduced mutations into the DNA sequence that allowed cells to resume growth. In one case, they observed such mutations arising in cells that had been in a non-dividing state for several days.â€
Although the Emory teamâ€™s research was performed on yeast, the mechanisms of mismatch repair are highly conserved in mammalian cells. Their results could also shed light on a process that takes place in the immune system called somatic hypermutation, in which mutations fine-tune antibody genes to make the most potent antibodies.