Almeida F.A.,Cleveland Clinic |
Bruno D.S.,Cancer Biology Program |
Faiz S.,University of Houston |
Hinrichs B.,Mary Lanning Memorial Hospital |
And 2 more authors.
Journal of Bronchology and Interventional Pulmonology | Year: 2011
Historically, patients presenting with a hemo-thorax of any cause have been treated with tube thoracostomy. We describe 2 patients with a hemothorax successfully treated with an indwelling tunneled pleural catheter. Our cases may suggest a new treatment modality for selected patients with hemothorax. © 2011 by Lippincott Williams & Wilkins.
Chen X.,Huazhong University of Science and Technology |
Wang X.,Huazhong University of Science and Technology |
Ruan A.,Huazhong University of Science and Technology |
Han W.,Huazhong University of Science and Technology |
And 10 more authors.
Clinical Cancer Research | Year: 2014
Purpose: Although microRNAs (miRNA) have been revealed as crucial modulators of tumorigenesis, our understanding of their roles in renal cell carcinoma (RCC) is limited. Here we sought to identify human miRNAs that act as key regulators of renal carcinogenesis. Experimental Design: We performed microarray-based miRNA profiling of clear cell RCC (ccRCC) and adjacent normal tissues and then explored the roles of miR-141 both in vitro and in vivo, which was the most significantly downregulated in ccRCC tissues. Results: A total of 74 miRNAs were dysregulated in ccRCC compared with normal tissues. miR-141 was remarkably downregulated in 92.6% (63/68) ccRCC tissues and would serve as a promising biomarker for discriminating ccRCC from normal tissues with an area under the receiver operating characteristics curve of 0.93. Overexpression of miR-141 robustly impaired ccRCC cell migratory and invasive properties and suppressed cell proliferation by arresting cells at G0-G1 phase in vitro and in human RCC orthotopic xenografts. Significantly, the antitumor activities of miR-141 were mediated by its reversal regulation of erythropoietin-producing hepatocellular (Eph) A2 (EphA2), which then relayed a signaling transduction cascade to attenuate the functions of focal adhesion kinase (FAK), AKT, and MMP2/9. In addition, a specific and inverse correlation between miR-141 and EphA2 expression was obtained in human ccRCC samples. Finally, miR-141 could be secreted from the ccRCC donor cells, and be taken up and function moderately in the ccRCC recipient cells. Conclusion: miR-141 serves as a potential biomarker for discriminating ccRCC from normal tissues and a crucial suppressor of ccRCC cell proliferation and metastasis by modulating the EphA2/p-FAK/p-AKT/MMPs signaling cascade. © 2014 American Association for Cancer Research.
Yang H.,Huazhong University of Science and Technology |
Chen X.,Huazhong University of Science and Technology |
Wang X.,Huazhong University of Science and Technology |
Li Y.,Huazhong University of Science and Technology |
And 9 more authors.
Molecular Cancer Research | Year: 2014
TRAIL is a promising anticancer agent because it induces apoptosis in the majority of human cancer cells but spares the normal cells. To determine the mechanistic nature of how normal cells acquire a TRAIL-sensitive phenotype during the process of malignant transformation, an experimental cell system was developed by sequential introduction of human telomerase reverse transcriptase and SV40 T antigens (large and small) into normal human prostatic epithelial cells (PrEC). This model system demonstrated that inhibition of protein phosphatase 2A (PP2A), either by SV40 small T antigen, okadaic acid, Calyculin A, or PP2A catalytic subunit siRNA, sensitized normal human PrEC and immortalized cells to TRAIL-induced apoptosis. Moreover, sensitization occurred during the premalignant period of tumorigenesis and PP2A exerted its antiapoptotic activity by negatively regulating c-Fos/ AP-1. In addition, low-dose okadaic acid treatment sensitized TRAIL-resistant cancer cells to TRAIL, suggesting that PP2A inhibitors could be used as an enhancer of apoptosis induced by TRAIL or TRAIL-like agents. These data indicate that downregulation of PP2A activity is a critical step for normal cells to acquire a TRAIL-sensitive phenotype during tumorigenesis and that the level of PP2A activity may foretell cellular sensitivity to TRAILinduced apoptosis. Implications: Inhibition of PP2A is a key determinant in acquiring TRAIL sensitivity during tumorigenesis, with c-Fos/AP-1 as an essential mediator. Mol Cancer Res; 12(2); 217-27. © 2013 AACR.
News Article | April 8, 2016
Nearly 40% of men and women will be diagnosed with cancer in their lifetimes, with about 1.7 million of those cases expected in 2016 in the United States (according to the National Cancer Institute). These patients are hoping for better treatments and, hopefully someday, cures. They could also be valuable resources, helping experts develop better therapies, if only staff at research centers like Dana-Farber Cancer Institute in Boston could study their unique cases. Even patients with the same diagnosis, such as breast cancer, have different genetic makeups, both in their healthy cells and in their tumors. These differences provide clues to new genetic factors that may cause the disease, why some patients respond especially well to certain treatments, why some tumors are so resistant to treatment, and how people of different ages or ethnicities are affected. "A very small fraction of adult cancer patients in the U.S. gets seen at these big centers, probably less than 15%," says Nikhil Wagle, an oncologist at Dana Farber specializing in breast cancer. "The vast majority…get treated in community hospitals where they get clinical care, but their tissue [sample] goes to the pathology department and sits there." It's a classic "long tail" problem: There's a large community of people, but they are spread out. So Broad Institute/Dana-Farber Integrative Cancer Biology Program in Cambridge, Massachusetts, formed the Metastatic Breast Cancer Project to find a long tail solution: Find people on the Internet. "The traditional way is that when a patient is at [a research] institution, someone will approach them and ask them in person," says Wagle. "We're trying to complement that by doing this 21st century, go directly to patients." That strategy has already netted about 1,700 people (both women and men) with metastatic breast cancer—cancer that has spread beyond the breast, threatening other parts of the body. Wagle says that 95% of them have provided some information about their condition, and that more than 900 have agreed to share medical records, tumor samples, and saliva (for genetic sequencing). Those are huge numbers for the coalition's first study project, just launched in October 2015. This is not a "build it and they will come" approach. Sending out a tweet and creating a hashtag isn't going get people to come flocking (although the team has also done that, at @MBC_Project and #mbcproject). "I've seen a lot of other people trying to do research studies or recruitment efforts in the space of social media just by launching something without patient input, and they haven't been necessarily as successful," says Corrie Painter, a cancer researcher and Wagle's partner on the project. Instead, they spent a year finding allies. "We built a lot of in-person support among movers and shakers in the metastatic breast cancer community," says Wagle, "people who have blogs or highly followed Twitter feeds or had their own Facebook pages." Early supporters included the Metastatic Breast Cancer network; and the project now has 15 support organizations. Painter already had personal experience with online support networks. "I'm six years out of a very rare cancer called angiosarcoma," she says. "I currently don't have disease, but it's a highly aggressive, very rare, understudied cancer." Angiosarcoma, which affects the inner lining of blood vessels, will be the next outreach project, expected to launch at the end of the summer. It's a perfect candidate because it is so rare: It takes the power of the Internet to find enough patients for a meaningful study. In dealing with and advocating for her condition, Painter has worked through the Angiosarcoma cancer group on Facebook. "As I build this study, I am building it out with them," says Painter. "When it comes from the patients themselves, it's so much more powerful." She was a postdoc at UMASS Medical School studying cancer immunology when she applied for the job at the Broad. "As a scientist, as an insider, I just really felt very strongly…that doing traditional academic medicine was not going to be impactful," says Painter. One thing researchers decided along with patients was to set a low barrier for entry. People who sign up online get a link to a participant consent form and then provide the names of the places where they've been treated and of the doctors who have treated them. Staff at the Broad (rhymes with "road") Institute then call to get all the records, as well as already-biopsied tumor samples it can do advanced genetic analysis on. "What's sad is that somehow it's easier for the doctor or another hospital to get someone's records than it is [for patients] to get their own records," says Wagle. Participants also provide a bit of saliva in a kit that the Broad Institute sends them. One of the most valuable things patients provide—one that these studies are especially good at collecting—is continual feedback. Researchers can ask patients about other medical conditions they have and request additional records. "We can create this really detailed genomic map of their tumor, connected to all of their clinical information," says Wagle, "and then, if we want, connected to additional questions we can ask the patients." All this data will feed both into studies at the institute as well as an open database of anonymized records that any cancer researchers can access. By the end of 2016 the goal is for the Broad to have its own data portal and also contribute records to a new, soon-to-launched U.S. government database called the "National Cancer Institute Genomic Data Commons." The institute will add new data every six months. "If patients are willing to share their samples, share their stories, and share their data, and they are willing to selflessly give them up, we shouldn't hoard them," says Wagle. Once the word gets to patients, they have been very willing to join in, say the researchers. "We felt that the community of patients with metastatic breast cancer were crying out for more research and would rally around this kind of idea," says Wagle. That made this condition a good one to start with, he says, but the Broad Institute wants to expand to several other cancer types, beyond the upcoming angiosarcoma project. The Broad Institute's approach caught the eye of the White House, which listed it as an example of innovation during its Precision Medicine Initiative summit in February. PMI is an overarching concept that medical treatments should be targeted to and customized for individual patients—for example, by sequencing their unique genetic makeup. It overlaps with the White House's Cancer Moonshot, led by Vice President Joe Biden, and focuses on tailored treatments that go beyond using general approaches like high doses of popular chemotherapy drugs. Both White House projects also emphasize bringing in as wide a coalition as possible, including government, industry, and patients themselves. The Obama administration has made a big push to bring outside tech experts into government—especially after the disastrous debut of the original Healthcare.gov site. This includes bringing in a lot of young people—those millennials for whom things like social media are second nature. But you don't have to be young to network online, say Wagle, an enthusiastic Twitter user who is about to turn 38, and Painter, a Facebook aficionado in her early 40s. "We're non-millennials who like social media," says Wagle. "Just don't ask us to start our Snapchat channel, because we don't know how to do that."
Zheng Y.,Cancer Biology Program |
Moore H.,Pharsight |
Piryatinska A.,San Francisco State University |
Solis T.,Cancer Biology Program |
And 2 more authors.
Cancer Research | Year: 2013
Slowly cycling tumor cells that may be present in human tumors may evade cytotoxic therapies, which tend to be more ef ficient at destroying cells with faster growth rates. However, the proportion and growth rate of slowly cycling tumor cells is often unknown in preclinical model systems used for drug discovery. Here, we report a quantitative approach to quantitate slowly cycling malignant cells in solid tumors, using a well-established mouse model of Kras-induced lung cancer (KrasG12D/+). 5-Bromo-2-deoxyuridine (BrdUrd) was administered to tumor-bearing mice, and samples were collected at de fined times during pulse and chase phases. Mathematical and statistical modeling of the label-retention data during the chase phase supported the existence of a slowly cycling label-retaining population in this tumor model and permitted the estimation of its proportion and proliferation rate within a tumor. The doubling time of the slowly cycling population was estimated at approximately 5.7 weeks, and this population represented approximately 31% of the total tumor cells in this model system. The mathematical modeling techniques implemented here may be useful in other tumor models where direct observation of cell-cycle kinetics is difficult and may help evaluate tumor cell subpopulations with distinct cell-cycling rates. ©2013 AACR.