Cutaneous lesions as a clue to severe combined immunodeficiency.

A 2-month-old boy experienced cutaneous lesions that revealed an underlying severe, combined immunodeficiency (SCID). It is important to recognize cutaneous manifestations of primary immunodeficiency disorders, as they may provide the earliest clue to a defect in immune function.

Age-specific differences in oncogenic pathway deregulation seen in human breast tumors.

PURPOSE: To define the biology driving the aggressive nature of breast cancer arising in young women. EXPERIMENTAL DESIGN: Among 784 patients with early stage breast cancer, using prospectively-defined, age-specific cohorts (young or=65 years), 411 eligible patients (n = 200or=65 years) with clinically-annotated Affymetrix microarray data were identified. GSEA, signatures of oncogenic pathway deregulation and predictors of chemotherapy sensitivity were evaluated within the two age-defined cohorts. RESULTS: In comparing deregulation of oncogenic pathways between age groups, a higher probability of PI3K (p = 0.006) and Myc (p = 0.03) pathway deregulation was observed in breast tumors arising in younger women. When evaluating unique patterns of pathway deregulation, a low probability of Src and E2F deregulation in tumors of younger women, concurrent with a higher probability of PI3K, Myc, and beta-catenin, conferred a worse prognosis (HR = 4.15). In contrast, a higher probability of Src and E2F pathway activation in tumors of older women, with concurrent low probability of PI3K, Myc and beta-catenin deregulation, was associated with poorer outcome (HR = 2.7). In multivariate analyses, genomic clusters of pathway deregulation illustrate prognostic value. CONCLUSION: Results demonstrate that breast cancer arising in young women represents a distinct biologic entity characterized by unique patterns of deregulated signaling pathways that are prognostic, independent of currently available clinico-pathologic variables. These results should enable refinement of targeted treatment strategies in this clinically challenging situation.

Differential Apaf-1 levels allow cytochrome c to induce apoptosis in brain tumors but not in normal neural tissues.

Brain tumors are typically resistant to conventional chemotherapeutics, most of which initiate apoptosis upstream of mitochondrial cytochrome c release. In this study, we demonstrate that directly activating apoptosis downstream of the mitochondria, with cytosolic cytochrome c, kills brain tumor cells but not normal brain tissue. Specifically, cytosolic cytochrome c is sufficient to induce apoptosis in glioblastoma and medulloblastoma cell lines. In contrast, primary neurons from the cerebellum and cortex are remarkably resistant to cytosolic cytochrome c. Importantly, tumor tissue from mouse models of both high-grade astrocytoma and medulloblastoma display hypersensitivity to cytochrome c when compared with surrounding brain tissue. This differential sensitivity to cytochrome c is attributed to high Apaf-1 levels in the tumor tissue compared with low Apaf-1 levels in the adjacent brain tissue. These differences in Apaf-1 abundance correlate with differences in the levels of E2F1, a previously identified activator of Apaf-1 transcription. ChIP assays reveal that E2F1 binds the Apaf-1 promoter specifically in tumor tissue, suggesting that E2F1 contributes to the expression of Apaf-1 in brain tumors. Together, these results demonstrate an unexpected sensitivity of brain tumors to postmitochondrial induction of apoptosis. Moreover, they raise the possibility that this phenomenon could be exploited therapeutically to selectively kill brain cancer cells while sparing the surrounding brain parenchyma.

An active learning approach for rapid characterization of endothelial cells in human tumors.

Currently, no available pathological or molecular measures of tumor angiogenesis predict response to antiangiogenic therapies used in clinical practice. Recognizing that tumor endothelial cells (EC) and EC activation and survival signaling are the direct targets of these therapies, we sought to develop an automated platform for quantifying activity of critical signaling pathways and other biological events in EC of patient tumors by histopathology. Computer image analysis of EC in highly heterogeneous human tumors by a statistical classifier trained using examples selected by human experts performed poorly due to subjectivity and selection bias. We hypothesized that the analysis can be optimized by a more active process to aid experts in identifying informative training examples. To test this hypothesis, we incorporated a novel active learning (AL) algorithm into FARSIGHT image analysis software that aids the expert by seeking out informative examples for the operator to label. The resulting FARSIGHT-AL system identified EC with specificity and sensitivity consistently greater than 0.9 and outperformed traditional supervised classification algorithms. The system modeled individual operator preferences and generated reproducible results. Using the results of EC classification, we also quantified proliferation (Ki67) and activity in important signal transduction pathways (MAP kinase, STAT3) in immunostained human clear cell renal cell carcinoma and other tumors. FARSIGHT-AL enables characterization of EC in conventionally preserved human tumors in a more automated process suitable for testing and validating in clinical trials. The results of our study support a unique opportunity for quantifying angiogenesis in a manner that can now be tested for its ability to identify novel predictive and response biomarkers.

Functional Variants in Notch Pathway Genes NCOR2, NCSTN, and MAML2 Predict Survival of Patients with Cutaneous Melanoma.

BACKGROUND: The Notch signaling pathway is constitutively activated in human cutaneous melanoma to promote growth and aggressive metastatic potential of primary melanoma cells. Therefore, genetic variants in Notch pathway genes may affect the prognosis of cutaneous melanoma patients. METHODS: We identified 6,256 SNPs in 48 Notch genes in 858 cutaneous melanoma patients included in a previously published cutaneous melanoma genome-wide association study dataset. Multivariate and stepwise Cox proportional hazards regression and false-positive report probability corrections were performed to evaluate associations between putative functional SNPs and cutaneous melanoma disease-specific survival. Receiver operating characteristic curve was constructed, and area under the curve was used to assess the classification performance of the model. RESULTS: Four putative functional SNPs of Notch pathway genes had independent and joint predictive roles in survival of cutaneous melanoma patients. The most significant variant was NCOR2 rs2342924 T>C (adjusted HR, 2.71; 95% confidence interval, 1.73-4.23; Ptrend = 9.62 × 10(-7)), followed by NCSTN rs1124379 G>A, NCOR2 rs10846684 G>A, and MAML2 rs7953425 G>A (Ptrend = 0.005, 0.005, and 0.013, respectively). The receiver operating characteristic analysis revealed that area under the curve was significantly increased after adding the combined unfavorable genotype score to the model containing the known clinicopathologic factors. CONCLUSIONS: Our results suggest that SNPs in Notch pathway genes may be predictors of cutaneous melanoma disease-specific survival. IMPACT: Our discovery offers a translational potential for using genetic variants in Notch pathway genes as a genotype score of biomarkers for developing an improved prognostic assessment and personalized management of cutaneous melanoma patients.

Time-reversal ultrawideband breast imaging: pulse design criteria considering multiple tumors with unknown tissue properties

Pulse design is investigated for time-reversal (TR) imaging as applied to ultrawideband (UWB) breast cancer detection. Earlier it has been shown that a suitably-designed UWB pulse may help to improve imaging performance for a single-tumor breast phantom with predetermined lesion properties. The current work considers the following more general and practical situations: presence of multiple malignancies with unknown tumor size and dielectric properties. Four pulse selection criteria are proposed with each focusing on one of the following aspects: eliminating signal clutter generated by tissue inhomogeneities, canceling mutual interference among tumors, improving image resolution, and suppressing artifacts created by sidelobe of the target response. By applying the proposed criteria, the shape parameters of UWB waveforms with desirable characteristics are identified through search of all the possible pulses. Simulation example using a numerical breast phantom, comprised of two tumors and structured clutter distribution, demonstrates the effectiveness of the proposed approach. Specifically, a tradeoff between the image resolution and signal-to-clutter contrast (SCC) is observed in terms of selection of the excitation waveforms.

Cutaneous Grooves: Composing for the Sense of Touch

What if the traditional relationship between touch and music was essentially turned upside down, making the tactile sensation the aesthetic end? This paper presents a novel coupling of haptics technology and music, introducing the notion of tactile composition or aesthetic composition for the sense of touch. A system that facilitates the composition and perception of intricate, musically structured spatio-temporal patterns of vibration on the surface of the body is described. Relevant work from disciplines including sensory substitution, electronic musical instrument design, simulation design, entertainment technology, and visual music is considered. The psychophysical parameter space for our sense of touch is summarized and the building blocks of a compositional language for touch are explored. A series of concerts held for the skin and ears is described, as well as some of the lessons learned along the way. In conclusion, some potential evolutionary branches of tactile composition are posited.

Potential role of intensity-modulated radiotherapy in the treatment of tumors of the maxillary sinus.

To assess 3-dimensional conformal radiotherapy (3D-CRT) and intensity-modulated radiotherapy (IMRT) techniques to see whether doses to critical structures could be reduced while maintaining planning target volume (PTV) coverage in patients receiving conventional radiotherapy (RT) for carcinoma of the maxillary sinus because of the risk of radiation-induced complications, particularly visual loss. Six patients who had recently received conventional RT for carcinoma of the maxillary sinus were studied. Conventional RT, 3D-CRT, and step-and-shoot IMRT plans were prepared using the same 2-field arrangement. The effect of reducing the number of segments in the IMRT beams was investigated. 3D-CRT and IMRT reduced the brain and ipsilateral parotid gland doses compared with the conventional plans. IMRT reduced doses to both optic nerves; for the contralateral optic nerve, 15-segment IMRT plans delivered an average maximal dose of 56.4 Gy (range 53.9–59.3) compared with 65.7 Gy (range 65.3–65.9) and 64.2 Gy (range 61.4–65.6) for conventional RT and 3D-CRT, respectively. IMRT also gave improved PTV homogeneity and improved coverage, with an average of 8.5% (range 7.0–11.7%) of the volume receiving