Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disorder of skeletal malformations and progressive extraskeletal ossification. We mapped FOP to chromosome 2q23-24 by linkage ...analysis and identified an identical heterozygous mutation (617G → A; R206H) in the glycine-serine (GS) activation domain of ACVR1, a BMP type I receptor, in all affected individuals examined. Protein modeling predicts destabilization of the GS domain, consistent with constitutive activation of ACVR1 as the underlying cause of the ectopic chondrogenesis, osteogenesis and joint fusions seen in FOP.NOTE: In the version of this article initially published, several contributing authors were listed collectively under the name The International FOP Research Consortium. In order to facilitate the electronic citation of author contributions, the authors have chosen to delete the Consortium name and replace it with the names of the individual consortium authors in alphabetical order. This error has been corrected in the HTML and PDF versions of the article.
Full text
Available for:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Neurotrophins and their receptors are frequently expressed in malignant gliomas, yet their functions are largely unknown. Previously, we have shown that p75 neurotrophin receptor is required for ...glioma invasion and proliferation. However, the role of Trk receptors has not been examined. In this study, we investigated the importance of TrkB and TrkC in survival of brain tumor-initiating cells (BTICs). Here, we show that human malignant glioma tissues and also tumor-initiating cells isolated from fresh human malignant gliomas express the neurotrophin receptors TrkB and TrkC, not TrkA, and they also express neurotrophins NGF, BDNF, and neurotrophin 3 (NT3). Specific activation of TrkB and TrkC receptors by ligands BDNF and NT3 enhances tumor-initiating cell viability through activation of ERK and Akt pathways. Conversely, TrkB and TrkC knockdown or pharmacologic inhibition of Trk signaling decreases neurotrophin-dependent ERK activation and BTIC growth. Further, pharmacological inhibition of both ERK and Akt pathways blocked BDNF, and NT3 stimulated BTIC survival. Importantly, attenuation of BTIC growth by EGFR inhibitors could be overcome by activation of neurotrophin signaling, and neurotrophin signaling is sufficient for long term BTIC growth as spheres in the absence of EGF and FGF. Our results highlight a novel role for neurotrophin signaling in brain tumor and suggest that Trks could be a target for combinatorial treatment of malignant glioma.
Background: The role of Trk neurotrophin receptors in glioma is unknown.
Results: TrkB and TrkC are required for survival of brain tumor-initiating cells in the absence of EGF and FGF.
Conclusion: Trk receptors can control the survival of BTICs in the absence of EGF and FGF.
Significance: Trks may be important targets for treatment of malignant gliomas.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Many gene expression normalization algorithms exist for Affymetrix GeneChip microarrays. The most popular of these is RMA, primarily due to the precision and low noise produced during the process. A ...significant strength of this and similar approaches is the use of the entire set of arrays during both normalization and model-based estimation of signal. However, this leads to differing estimates of expression based on the starting set of arrays, and estimates can change when a single, additional chip is added to the set. Additionally, outlier chips can impact the signals of other arrays, and can themselves be skewed by the majority of the population.
We developed an approach, termed IRON, which uses the best-performing techniques from each of several popular processing methods while retaining the ability to incrementally renormalize data without altering previously normalized expression. This combination of approaches results in a method that performs comparably to existing approaches on artificial benchmark datasets (i.e. spike-in) and demonstrates promising improvements in segregating true signals within biologically complex experiments.
By combining approaches from existing normalization techniques, the IRON method offers several advantages. First, IRON normalization occurs pair-wise, thereby avoiding the need for all chips to be normalized together, which can be important for large data analyses. Secondly, the technique does not require similarity in signal distribution across chips for normalization, which can be important for maintaining biologically relevant differences in a heterogeneous background. Lastly, IRON introduces fewer post-processing artifacts, particularly in data whose behavior violates common assumptions. Thus, the IRON method provides a practical solution to common needs of expression analysis. A software implementation of IRON is available at http://gene.moffitt.org/libaffy/.
Full text
Available for:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We have interrogated a 12-chemokine gene expression signature (GES) on genomic arrays of 14,492 distinct solid tumors and show broad distribution across different histologies. We hypothesized that ...this 12-chemokine GES might accurately predict a unique intratumoral immune reaction in stage IV (non-locoregional) melanoma metastases. The 12-chemokine GES predicted the presence of unique, lymph node-like structures, containing CD20⁺ B cell follicles with prominent areas of CD3⁺ T cells (both CD4⁺ and CD8⁺ subsets). CD86⁺, but not FoxP3⁺, cells were present within these unique structures as well. The direct correlation between the 12-chemokine GES score and the presence of unique, lymph nodal structures was also associated with better overall survival of the subset of melanoma patients. The use of this novel 12-chemokine GES may reveal basic information on in situ mechanisms of the anti-tumor immune response, potentially leading to improvements in the identification and selection of melanoma patients most suitable for immunotherapy.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
7.
Implementing personalized medicine in a cancer center Fenstermacher, David A; Wenham, Robert M; Rollison, Dana E ...
The cancer journal (Sudbury, Mass.),
2011 Nov-Dec, 2011-11-00, 20111101, Volume:
17, Issue:
6
Journal Article
Peer reviewed
Open access
In 2006, the Moffitt Cancer Center partnered with patients, community clinicians, industry, academia, and 17 hospitals in the United States to begin a personalized cancer care initiative called Total ...Cancer Care. Total Cancer Care was designed to collect tumor specimens and clinical data throughout a patient's lifetime, with the goal of finding "the right treatment, for the right patient, at the right time." Because Total Cancer Care is a partnership with the patient and involves collection of clinical data and tumor specimens for research purposes, a formal protocol and patient consent process was developed, and an information technology platform was constructed to provide a robust "warehouse" for clinical and molecular profiling data. To date, more than 76,000 cancer patients from Moffitt and consortium medical centers have been enrolled in the protocol. The Total Cancer Care initiative has developed many of the capabilities and resources that are building the foundation of personalized medicine.
Aquaporins (AQPs) facilitate water transport across epithelia and play an important role in normal physiology and disease in the human airways. We used in situ hybridization and immunofluorescence to ...determine the expression and cellular localization of AQPs 5, 4, and 3 in human airway sections. In nose and bronchial epithelia, AQP5 is expressed at the apical membrane of columnar cells of the superficial epithelium and submucosal gland acinar cells. AQP4 was detected in basolateral membranes in ciliated ducts and by in situ in gland acinar cells. AQP3 is present on basal cells of both superficial epithelium and gland acinus. In these regions AQPs 5, 4, and 3 are appropriately situated to permit transepithelial water permeability. In the small airways (proximal and terminal bronchioles) AQP3 distribution shifts from basal cell to surface expression (i.e., localized to the apical membrane of proximal and terminal bronchioles) and is the only AQP identified in this region of the human lung. The alveolar epithelium has all three AQPs represented, with AQP5 and AQP4 localized to type I pneumocytes and AQP3 to type II cells. This study describes an intricate network of AQP expression that mediates water transport across the human airway epithelium.
Malignant gliomas are highly invasive, proliferative, and resistant to treatment. Previously, we have shown that p75 neurotrophin receptor (p75NTR) is a novel mediator of invasion of human glioma ...cells. However, the role of p75NTR in glioma proliferation is unknown. Here we used brain tumor-initiating cells (BTICs) and show that BTICs express neurotrophin receptors (p75NTR, TrkA, TrkB, and TrkC) and their ligands (NGF, brain-derived neurotrophic factor, and neurotrophin 3) and secrete NGF. Down-regulation of p75NTR significantly decreased proliferation of BTICs. Conversely, exogenouous NGF stimulated BTIC proliferation through α- and γ-secretase-mediated p75NTR cleavage and release of its intracellular domain (ICD). In contrast, overexpression of the p75NTR ICD induced proliferation. Interestingly, inhibition of Trk signaling blocked NGF-stimulated BTIC proliferation and p75NTR cleavage, indicating a role of Trk in p75NTR signaling. Further, blocking p75NTR cleavage attenuated Akt activation in BTICs, suggesting role of Akt in p75NTR-mediated proliferation. We also found that p75NTR, α-secretases, and the four subunits of the γ-secretase enzyme were elevated in glioblastoma multiformes patients. Importantly, the ICD of p75NTR was commonly found in malignant glioma patient specimens, suggesting that the receptor is activated and cleaved in patient tumors. These results suggest that p75NTR proteolysis is required for BTIC proliferation and is a novel potential clinical target.
Background: p75 neurotrophin receptor (p75NTR) is an important mediator of invasion of malignant gliomas, but its role in glioma proliferation is unknown.
Results: p75NTR mediates proliferation of brain tumor-initiating cells (BTICs) via its cleavage and release of an intracellular domain.
Conclusion: p75NTR also regulates proliferation of BTICs.
Significance: p75NTR is a potential target for the treatment of malignant gliomas.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
PDF
