Neurons can be cultured in one compartment of a microfluidic chamber (right side) and extend their axons through very small grooves into a separate compartment (left side).

Researchers from the University of North Carolina School of Medicine have uncovered some surprising insights about the process of axon amputation, or “pruning,” in a study published May 21 in the journal Nature Communications. Axon pruning has mystified scientists curious to know how a neuron can unleash a self -destruct mechanism within its axon, but keep it from spreading to the rest of the cell. The researchers’ findings could offer clues about the processes underlying some neurological disorders.

“Aberrant axon pruning is thought to underlie some of the causes for neurodevelopmental disorders, such as schizophrenia and autism,” said Mohanish Deshmukh, PhD, professor of cell biology and physiology  at UNC and the study’s senior author. “This study sheds light on some of the mechanisms by which neurons are able to regulate axon pruning.”

Axon pruning is part of normal development and plays a key role in learning and memory. Another important process, apoptosis — the purposeful death of an entire cell — is also crucial because it allows the body to cull broken or incorrectly placed neurons. But both processes have been linked with disease when improperly regulated.

The research team placed mouse neurons in special devices called microfluidic chambers that allowed the researchers to independently manipulate the environments surrounding the axon and cell body to induce axon pruning or apoptosis.

They found that although the nerve cell uses the same poison — a group of molecules known as Caspases — whether it intends to kill the whole cell or just the axon, it deploys the Caspases in a different way depending on the context.

“People had assumed that the mechanism was the same regardless of whether the context was axon pruning or apoptosis, but we found that it’s actually quite distinct,” said Deshmukh. “The neuron essentially uses the same components for both cases, but tweaks them in a very elegant way so the neuron knows whether it needs to undergo apoptosis or axon pruning.”

In apoptosis, the neuron deploys the deadly Caspases using an activator known as Apaf-1. In the case of axon pruning, Apaf-1 was simply not involved, despite the presence of Caspases. “This is really going to take the field by surprise,” said Deshmukh. “There’s very little precedent of Caspases being activated without Apaf-1. We just didn’t know they could be activated through a different mechanism.”

In addition, the team discovered that neurons employ other molecules as safety brakes to keep the “kill” signal contained to the axon alone. “Having this brake keeps that signal from spreading to the rest of the body,” said Deshmukh. “Remarkably, just removing one brake makes the neurons more vulnerable.”

Deshmukh said the findings offer a glimpse into how nerve cells reconfigure themselves during development and beyond. Enhancing our understanding of these basic processes could help illuminate what has gone wrong in the case of some neurological disorders.

The study’s co-authors include Corey L. Cusack, Vijay Swahari, W. Hampton Henley and J. Michael Ramsey of UNC.

_{Date: May 23, 2013}

^{Date: May 23, 2013}

The Society announced that Dr. Rimer was chosen for "her work in breast cancer screening, which has guided national research, practice and policy for more than 20 years. Her work has evolved with the field from raising awareness of screening and increasing screening initiation, to promoting screening maintenance.”

Dr. Rimer serves as chair of the President's Cancer Panel, vice-chair of the Center for Disease Control and Prevention's Task Force on Community Preventive Services and is a member of the Institute of Medicine. She served as the founding director of the National Cancer Institute (NCI) Division of Cancer Control and Population Sciences and chair of the NCI's National Cancer Advisory Board.

The Medal of Honor is the ACA's highest honor. Along with Dr. Rimer, the medal was awarded to Dr. Isaiah J. Fidler of the University of Texas MD Anderson Cancer Center and  Dr. Kathleen M. Foley of Memorial Sloan-Kettering Cancer Center in New York, NY.

_{Date: May 23, 2013}

Neil Hayes, MD, MPH, and Claire Dees, MD

Shelley Earp, MD, director of UNC Lineberger and UNC Cancer Care, said, “Claire Dees and Neil Hayes are first and foremost great doctors.  They have also built national reputations for their work in clinical and translational research.  As co-leaders of the Center’s Clinical Research Program, they will help move the newest discoveries into clinical practice by designing and implementing innovation into our clinical trials program.

Lisa Carey, MD, Cancer Center Associate Director for Clinical Research and Physician in Chief at the N.C. Cancer Hospital, said “In the modern era, leaders in clinical research have to have expertise in performance and application of genetic techniques and tumor sequencing as well as expertise in design, performance, and analysis of clinical trials from the earliest testing through to FDA approval.  Claire Dees and Neil Hayes have that kind of training and experience.”

As an active member of the UNC Breast Center, Dees chaired the breast cancer clinical trials group and leads the Lineberger Developmental Therapeutics Working Group. She chairs the Protocol Review Committee and the Protocol Specific Research core. She also serves as the medical director of the Clinical Trials Unit in the N.C. Cancer Hospital. Dr. Dees joined the University of North Carolina faculty in 1999. Before coming to UNC, she completed her internship and residency in internal medicine at the Brigham and Women's Hospital in Boston and her medical oncology fellowship training at the Johns Hopkins Oncology Center where she worked with the Phase I trials group and the breast cancer program. She obtained a master’s degree in clinical investigations while at Hopkins.

Hayes served as national co-chair of the Data Analysis Sub-Group for The Cancer Genome Atlas Project at UNC and chairs the UNCSequencing Project (UNCseq). UNCseq serves as resource for patients with difficult to treat tumors, identifying and targeting the molecular weaknesses specific to the patient’s cancer. The ultimate aim for UNCseq is to provide every patient with tumor analyses that will allow their physicians to prescribe targeted and efficient therapies on an individualized basis.

A native of North Carolina, Dr. Hayes graduated from Davidson College coming to UNC School of Medicine in 2004.  During his post-graduate training, he completed a Masters in Public Health at Harvard University, an internship at Boston University School of Medicine, a clinical fellowship at Tufts University Medical Center and a postdoctoral fellowship at Dana-Farber Cancer Institute.

Date: 05/09/2013

L-R: James P. Evans, MD, PhD; David Ollila, MD; and Keith D. Amos, MD, FACS

With the recent announcement from actress and director Angelina Jolie in the New York Times Op-Ed section about her choice to have a double mastectomy in order to drastically reduce her chances of getting breast cancer, many women are wondering whether they should be screened to determine their genetic risk of getting breast cancer.

At UNC Lineberger Comprehensive Cancer Center, we help patients determine their risk of developing cancer and provide genetic testing through our Cancer Genetics Program. UNC Lineberger members James P. Evans, MD, PhD, Director of Clinical Cancer Genetics and the Bryson Program in Human Genetics; David Ollila, MD, surgical oncologist with the Melanoma Program & UNC Breast Center; and Keith D. Amos, MD, FACS, surgical oncologist at UNC Breast Center help answer questions about genetic testing.

To which of your patients would you recommend genetic testing for BRCA 1 and BRCA 2 mutations?

Evans: It is now recommended for women who have a strong family history of breast cancer or ovarian cancer, or who are diagnosed with breast cancer at a young age (typically under 45, but this precise age cut-off is not hard and fast). Other things that can prompt consideration of testing would be bilateral disease diagnosed in an individual. Finally, women of Ashkenazi Jewish ancestry have an increased risk of carrying certain BRCA1/2 mutations.

Who should a patient consult if they want to know if they carry a BRCA 1 or BRCA 2 mutation?

Evans: A geneticist and/or genetic counselor who specializes in assessing cancer risk. The interpretation of genetic testing is sometimes not straight-forward. Thus, it is imperative that women have expert advice so that their genetic situation and their risk is properly calculated. There are also important considerations for other family members and a genetics specialist will help determine the impact of the mutation on other family members who may share it.

It is important for a patient to also consult with a surgeon with experience in risk-reducing mastectomy if the BRCA 1 or BRCA 2 mutations are present. The surgery has to be done right and this kind of context demands a careful approach to ensure that maximal risk reduction is achieved.

Ollila: Risk-reduction in gene carriers is maximized by removing all of the breast tissue on both sides.

Evans: A patient will also want to consult with a plastic surgeon since most women desire reconstructive surgery and there are many options with different advantages and disadvantages, as well as a gynecologist since women who carry such mutations are at a high risk of ovarian cancer and specific strategies (such as removal of the ovaries to prevent ovarian cancer) are important at the appropriate time in a woman’s life.

To what extent is a prophylactic mastectomy a recommended procedure after discovering that a patient carries either a BRCA 1 or BRCA 2 mutation?

Evans: This is a standard strategy recommended to and chosen by many women who are found to have such mutations. Some women opt for increased surveillance instead but certainly prophylactic mastectomy is the most effective means of reducing breast cancer risk in this setting.

Ollila: It is important for each individual to understand their lifetime risk of developing breast cancer and make informed choices based upon that risk assessment.

Is a prophylactic mastectomy typically covered by insurance?

Evans: Yes, as is subsequent reconstruction.

To what extent is a prophylactic oophorectomy (removal of the ovaries) a recommended procedure after discovering that a patient carries either a BRCA 1 or BRCA 2 mutation?

Amos: It is challenging to screen for ovarian cancer. For breast disease, physicians use mammograms for screening. For the ovaries, ultrasound of the ovaries and blood tests for tumor markers are used for screening, which have not been as effective as mammograms have been for catching a breast cancer at early stages.

The benefit is that preventive surgery can significantly reduce a woman's chance of getting ovarian cancer which is very difficult to treat. Ovarian Cancer usually is found at advanced stages where patients need radical pelvic surgery and chemotherapy. The downsides are removing the ovaries which affect a woman's ability to have children.

Gehrig: I agree with Dr. Amos that we do not have a good screening test for ovarian cancer.  In women who have not completed their families or are less than 40 year of age, we can screen them with ultrasound and CA-125 every 6 months.  In addition, these women can be offered birth control pills that have been shown to decrease the risk of ovarian cancer by as much as 50%.  Removal of the ovaries can also help decrease the risk of breast cancer.

What would be your advice to a patient who was considering a prophylactic oopherectomy after a BRCA mutation finding?

Amos: I would ask the patient whether they are interested in getting pregnant again. If the patient is not interested in getting pregnant again and having more children, I would recommend proceeding with prophylactic removal of the ovaries and fallopian tubes.

Gehrig: I agree with Dr. Amos.  In addition, recent studies have shown that a rare but aggressive type of endometrial cancer (uterine papillary serous carcinoma) is also in the BRCA spectrum, so a hysterectomy should also be included in the discussion of prophylactic surgery.

Any final comments?

Evans: The most important thing is that a woman who may be carrying a mutation in BRCA 1 or BRCA 2 have a team of experts to help her make the decisions that are right for her. A mutation in one of these genes confers a very high risk of both breast and ovarian cancer. The strategy that Ms. Jolie used is perfectly appropriate. Indeed, it is the most effective means of reducing risk. That said, these decisions hinge upon many factors and are very personal in nature and it is not necessarily the decision that other women might take in the same situation. Thus, it is important that women in her position consult with the right team of experts.

Finally, it should be pointed out that Ms. Jolie’s situation is not typical. She was at an especially elevated risk of breast cancer due to the mutation which she carries. Most women do not have such mutations and are therefore not at the very high risk for breast cancer that existed in Ms. Jolie.

_{Date: May 15, 2013}

The article can be read here.

_{Date: May 14, 2013}

“Patient-centered care is not possible without patients and their caregivers playing a central role in care decisions, and, importantly, in the research that informs those decisions,” the authors write.

The priorities of researchers when evaluating new therapies, especially for patients with chronic conditions, must take into account how potential side effects and complications will impact both a patient’s health and willingness to continue treatment. Using the example of the disconnect between a diabetes researcher who focuses on the ability of a therapy to regulate hemoglobin levels against the needs of a patient who worries about how to balance the therapy’s side effects with life issues such as depression and unemployment, the authors write that the practical realities of a patients’ life must be taken into consideration when evaluating potential benefits and side effects of care.

“The millions of individuals with chronic conditions such as diabetes have different perspectives on what is most important to them. These varied perspectives must inform the research if the research is to inform decision making,” write the authors.

In order to accomplish this shift, researchers must make greater use of tools to facilitate communication between patients and researchers. Online portals, pen-and-paper questionnaires, integration of patient-reported outcomes into digital medical records and other tools should be used to give researchers access to data that can inform their evaluation of new therapies.

“Although some individuals are concerned about these blurred boundaries and hesitant about expecting patients to be involved in research, it is worth considering that clinicians implicitly experiment every time a diagnostic test or treatment is ordered that was evaluated in individuals who differ from the patient in personal characteristics, disease severity and manifestations, overall health, or health priorities,” write the authors.

_{Date: May 13, 2013}

See more on OncLive.

_{Date: May 10, 2013}

The UNC research, which was carried out in a frog model as well as human cells, will be published April 29, 2013, in the journal Developmental Cell.

"There has been a lot of interest in studying the vasculature because of its role in a wide range of disease states, as well as human development. But there are very few transcription factors that are known to affect the vasculature. To find a new one is quite unique, and then to be able to link it up to a known network of vascular development is surprising and encouraging," said senior study author Frank Conlon, PhD, an associate professor of genetics in the UNC School of Medicine.

During vascular development, specialized cells coalesce into three-dimensional "cords" that then hollow out to provide a path for transporting blood throughout the body. This process involves the complex coordination of molecular entities like growth factors and signaling molecules, defects that have been associated with human illnesses such as cancer, stroke, and atherosclerosis.

Conlon has long been interested in understanding how these various molecular players come together in the cardiovascular system. In 2008, his laboratory showed that a gene called CASZ1 is involved in the development of heart muscle. In this study, he and his colleagues decided to look for its role in the development of blood vessels.

The images shown are examples from a cellular assay in which human endothelial cells, cells that comprise blood vessels, can be induced to extend sprouts that form a vascular-like network. The image on the left demonstrates control cells extending elongated branches that interconnect with one another while the image on the right shows that in the absence of the transcription factor CASZ1, the cells are unable to sprout properly.

Marta S. Charpentier and Kathleen S. Christine, lead authors of the study and graduate students in Conlon's laboratory, removed CASZ1 from frog embryos and looked to see how its absence affected the development of the vasculature. Without CASZ1, the frogs failed to form branched and functional blood vessels. When they removed the CASZ1 gene from cultured human cells, Charpentier and Christine saw similar defects: the cells did not sprout or branch correctly due to their inability to maintain proper adhesions with the surrounding extracellular matrix.

"If you take out CASZ1, these cultured human cells try to migrate by sending out these filopodia or little feet, but what happens is it is like someone nails down the back end of those growing vessels. They try to move and keep getting thinner and thinner, and like an elastic band it gets to be too much and just snaps back. It appears to cause an adhesion defect that makes the cells too sticky to form normal vessels," said Conlon.

CASZ1 is a transcription factor, a master switch that controls when and where other genes are expressed. Therefore, Charpentier and Christine did a series of experiments to explore CASZ1's influence on a known vascular network, involving other genes called Egfl7 and RhoA. When Charpentier and Christine added the Egfl7 gene to her CASZ1-depleted cells, the defect in blood vessel formation went away, suggesting that the two genes are connected. They then showed that CASZ1 directly acts on the Egfl7 gene, and that this activity in turn activates the RhoA gene, which is known to be required for cellular behaviors associated with adhesion and migration.

Transcription factors themselves are so essential that they are generally considered to be "undruggable," but the researchers say that further studies into how specific transcription factors work and the targets they control could eventually lead to new drug candidates.

"Egfl7 is a therapeutic target of interest, because companies such as Genentech are already working on it for cancer therapy," said Charpentier. "Figuring out how it is regulated is important not just for understanding the biology of it, but also for discovering targets that could trigger the development of innovative therapeutic strategies for cardiovascular disease."

The research was a collaboration between the Conlon, Taylor, and Bautch labs at the McAllister Heart Institute at UNC and was funded by the National Institutes of Health and the American Heart Association. Study co-authors from UNC were Nirav M. Amin, PhD; Kerry M. Dorr; Erich J. Kushner, PhD; Victoria L. Bautch, PhD; and Joan M. Taylor, PhD.

_{Date: April 30, 2013}

The study, published online by the journal Sexually Transmitted Diseases, collected data from 350 female sex workers in the Korogocho slum area of Nairobi from August 2009 to March 2011. Due to high HPV and HIV prevalence, these women have a higher risk of cervical cancer and associated high grade lesions than the general population. Recruited by community peer leaders at public meetings, participants attending the study clinic were first instructed to self-collect genital specimens for HPV testing using a brush provided by the study.

The self-collection was followed-up with a pelvic examination, where a physician collected cervical samples for Pap smear and HPV testing. The Pap smears were independently evaluated by two cytopathologists from the University of Nairobi, with discrepancies reviewed by a third. The HPV testing results showed strong agreement between the samples collected by the physician and those collected by the women themselves.

"In our study in Nairobi, women were able to follow the self-collection instructions, and the specimens collected by the women were of high quality. We compared physician- and self-collected samples for HPV testing, and our results show that HPV testing of the two sample types performed equally well in detecting high-grade lesions. These findings indicate that self-collection for HPV testing may be a viable means to increase cervical cancer screening coverage in low-resource regions," said the study's lead author Jie Ting, PhD, postdoctoral fellow in epidemiology at UNC.

HPV testing is effective in early detection of cervical pre-cancerous and cancerous tumors and is currently recommended for co-testing with Pap smear for women aged 30 years or older in the United States. In traditional clinical settings, collection of cervical specimens for HPV testing is performed by a physician.

"What will also be interesting is to look at how self-collection will work in a setting other than a clinical one. For example, if the women were to perform self-collection at home, how would that to compare to when she does it in the clinic?" said Ting.

_{Date: May 8, 2013}

_{May 6, 2013}

Maria Abreu, MD, professor of medicine and microbiology and immunology, University of Miami School of Medicine; Frances Balkwill, professor of cancer biology, Barts & The London School of Medicine & Dentistry; Shelley Earp, MD, director, UNC Lineberger Comprehensive Cancer Center; Peter Nelson, MD, Human Biology Division, Fred Hutchinson Cancer Center; Drew Pardoll, MD, PhD, Seraph Professor in Oncology, Johns Hopkins University; Jeffrey Pollard, MRC Center for Reproductive Health, Edinburgh, Scotland; Nicholas Restifo, MD, senior investigator, surgery branch, National Cancer Institute; Michel Sadelain, MD, PhD, director, Center for Cell Engineering & Gene Transfer and Gene Expression Laboratory, Memorial Sloan-Kettering Cancer Center; and Robert Vonderheide, MD, PhD, associate professor of medicine, University of Pennsylvania.

Sessions chairs were Blossom Damania, PhD, professor of microbiology and immunology and director of the UNC Lineberger Global Oncology Program; Balfour Sartor, MD, professor of medicine; and Lishan Su, PhD, professor of microbiology and immunology.

Many thanks to our symposium sponsors:

Leadership Sponsor

Laboratory Corporation of America

Associate Sponsors

Accelerate Brain Cancer Cure
Pfizer 
Gilead Sciences
North Carolina Biotechnology Center 

Patron Sponsors

Burroughs Wellcome Fund
Eli Lilly and Company
The Hamner Institutes for Health Sciences
Hatteras Venture Partners 
Myers Bigel Sibley & Sajovec, PA 

Friend Sponsors

Cell Signaling Technology
New England Biolabs, Inc.

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_{May 3, 2013}

In this study, the scientists used an intracranial model of aggressive triple negative breast cancer to evaluate the pharmacokinetics of a chemotherapy drug, anthracycline doxorubicin in a PEGYlated liposomal-formulation, compared to a non-liposomal formulation. They augmented the liposomal doxorubicin with ABT-888, an inhibitor of an enzyme involved in many cellular functions, called poly (ADP-ribose) polymerase (PARP). 

Their results showed that treatment with PEGylated liposomal doxorubicin resulted in a 1500-fold higher plasma and 20-fold higher intracranial tumor bioavailability compared with the non-liposomal doxorubicin.  In addition, PEGylated liposomal doxorubicin was detected in in plasma and the intracranial tumor 96 hours following treatment compared to the drug being undetectable in plasma and the tumor after 24 hours in the non-liposomal doxorubicin. Survival rates for the PEGylated liposomal doxorubicin treatment were significantly prolonged as compared to non-liposomal doxorubicin in the study.

UNC authors are: Olga Karginova, MS; Allison Deal, MS; Sumit Rawal, PhD; David Darr, MS; Allison Schorzman, PhD; Charlene Santos, BS; Ryan Bash, MS; Tal Kafri, PhD; Lisa Carey, MD; C. Ryan Miller, MD, PhD; Charles Perou, PhD; Norman Sharpless, MD; and William Zamboni, PharmD, PhD. Barbara Adamo, PhD, is affiliated with UNC and with the University of Messina, Italy.

The research was funded by the National Cancer Institute (K23 and Specialized Program of Research Excellence in Breast Cancer SPORE) and the Breast Cancer Research Foundation.

_{Date: May 3, 2013}

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_{Date: May 2, 2013}