Abusive Tax Shelters And Government Misconduct

Congress reacted quickly to the accounting profession’s involvement in the Enron/Tyco International financial collapses in 2001. The Sarbanes-Oxley Act of 2002 was enacted and the Securities and Exchange Commission promulgated new reporting regulations aimed at preventing such losses in the future. A more remote effect occurred a year later in 2003 when Congress enacted sweeping reforms affecting the tax shelter industry. Congress targeted accounting firms and related professionals who created, marketed and sold abusive tax shelters. While the culpability of these professionals was clear the resulting criminal prosecutions against some of the accounting professionals were tainted by an overzealous prosecution which relied on unconstitutional tactics to obtain convictions

SciClone: Inferring clonal architecture and tracking the spatial and temporal patterns of tumor evolution

The sensitivity of massively-parallel sequencing has confirmed that most cancers are oligoclonal, with subpopulations of neoplastic cells harboring distinct mutations. A fine resolution view of this clonal architecture provides insight into tumor heterogeneity, evolution, and treatment response, all of which may have clinical implications. Single tumor analysis already contributes to understanding these phenomena. However, cryptic subclones are frequently revealed by additional patient samples (e.g., collected at relapse or following treatment), indicating that accurately characterizing a tumor requires analyzing multiple samples from the same patient. To address this need, we present SciClone, a computational method that identifies the number and genetic composition of subclones by analyzing the variant allele frequencies of somatic mutations. We use it to detect subclones in acute myeloid leukemia and breast cancer samples that, though present at disease onset, are not evident from a single primary tumor sample. By doing so, we can track tumor evolution and identify the spatial origins of cells resisting therapy

Mutations in pericentrin cause Seckel syndrome with defective ATR-dependent DNA damage signaling

Large brain size is one of the defining characteristics of modern humans. Seckel syndrome (MIM 210600), a disorder of markedly reduced brain and body size, is associated with defective ATR-dependent DNA damage signaling. Only a single hypomorphic mutation of ATR has been identified in this genetically heterogeneous condition. We now report that mutations in the gene encoding pericentrin (PCNT)--resulting in the loss of pericentrin from the centrosome, where it has key functions anchoring both structural and regulatory proteins--also cause Seckel syndrome. Furthermore, we find that cells of individuals with Seckel syndrome due to mutations in PCNT (PCNT-Seckel) have defects in ATR-dependent checkpoint signaling, providing the first evidence linking a structural centrosomal protein with DNA damage signaling. These findings also suggest that other known microcephaly genes implicated in either DNA repair responses or centrosomal function may act in common developmental pathways determining human brain and body size

Modular ‘Click-in-Emulsion’ Bone-Targeted Nanogels

A new class of nanogel demonstrates modular biodistribution and affinity for bone. Nanogels, ~70 nm in diameter and synthesized via an astoichiometric click-chemistry in-emulsion method, controllably display residual, free clickable functional groups. Functionalization with a bisphosphonate ligand results in significant binding to bone on the inner walls of marrow cavities, liver avoidance, and anti-osteoporotic effects.National Institutes of Health (U.S.) (RO1 DE016516)National Institutes of Health (U.S.) (R01 EB000244)Damon Runyon Cancer Research Foundation (DFS-#2050-10

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

Melanoma cells break down LPA to establish local gradients that drive chemotactic dispersal.

The high mortality of melanoma is caused by rapid spread of cancer cells, which occurs unusually early in tumour evolution. Unlike most solid tumours, thickness rather than cytological markers or differentiation is the best guide to metastatic potential. Multiple stimuli that drive melanoma cell migration have been described, but it is not clear which are responsible for invasion, nor if chemotactic gradients exist in real tumours. In a chamber-based assay for melanoma dispersal, we find that cells migrate efficiently away from one another, even in initially homogeneous medium. This dispersal is driven by positive chemotaxis rather than chemorepulsion or contact inhibition. The principal chemoattractant, unexpectedly active across all tumour stages, is the lipid agonist lysophosphatidic acid (LPA) acting through the LPA receptor LPAR1. LPA induces chemotaxis of remarkable accuracy, and is both necessary and sufficient for chemotaxis and invasion in 2-D and 3-D assays. Growth factors, often described as tumour attractants, cause negligible chemotaxis themselves, but potentiate chemotaxis to LPA. Cells rapidly break down LPA present at substantial levels in culture medium and normal skin to generate outward-facing gradients. We measure LPA gradients across the margins of melanomas in vivo, confirming the physiological importance of our results. We conclude that LPA chemotaxis provides a strong drive for melanoma cells to invade outwards. Cells create their own gradients by acting as a sink, breaking down locally present LPA, and thus forming a gradient that is low in the tumour and high in the surrounding areas. The key step is not acquisition of sensitivity to the chemoattractant, but rather the tumour growing to break down enough LPA to form a gradient. Thus the stimulus that drives cell dispersal is not the presence of LPA itself, but the self-generated, outward-directed gradient

Clouds in the Coldest Brown Dwarfs: FIRE Spectroscopy of Ross 458C

Condensate clouds are a salient feature of L dwarf atmospheres, but have been assumed to play little role in shaping the spectra of the coldest T-type brown dwarfs. Here we report evidence of condensate opacity in the near-infrared spectrum of the brown dwarf candidate Ross 458C, obtained with the Folded-Port Infrared Echellette (FIRE) spectrograph at the Magellan Telescopes. These data verify the low-temperature nature of this source, indicating a T8 spectral classification, log Lbol/Lsun = -5.62+/-0.03, Teff = 650+/-25 K, and a mass at or below the deuterium burning limit. The data also reveal enhanced emission at K-band associated with youth (low surface gravity) and supersolar metallicity, reflecting the properties of the Ross 458 system (age = 150-800 Myr, [Fe/H] = +0.2 to +0.3). We present fits of FIRE data for Ross 458C, the T9 dwarf ULAS J133553.45+113005.2, and the blue T7.5 dwarf SDSS J141624.08+134826.7B, to cloudless and cloudy spectral models from Saumon & Marley. For Ross 458C we confirm a low surface gravity and supersolar metallicity, while the temperature differs depending on the presence (635 [+25,-35] K) or absence (760 [+70,-45] K) of cloud extinction. ULAS J1335+1130 and SDSS J1416+1348B have similar temperatures (595 [+25,-45] K), but distinct surface gravities (log g = 4.0-4.5 cgs versus 5.0-5.5 cgs) and metallicities ([M/H] ~ +0.2 versus -0.2). In all three cases, cloudy models provide better fits to the spectral data, significantly so for Ross 458C. These results indicate that clouds are an important opacity source in the spectra of young cold T dwarfs, and should be considered when characterizing the spectra of planetary-mass objects in young clusters and directly-imaged exoplanets. The characteristics of Ross 458C suggest it could itself be regarded as a planet, albeit one whose cosmogony does not conform with current planet formation theories.Comment: Accepted for publication to ApJ: 18 pages, 11 figures in emulateapj forma

The clonal evolution of metastatic colorectal cancer

Tumor heterogeneity and evolution drive treatment resistance in metastatic colorectal cancer (mCRC). Patient-derived xenografts (PDXs) can model mCRC biology; however, their ability to accurately mimic human tumor heterogeneity is unclear. Current genomic studies in mCRC have limited scope and lack matched PDXs. Therefore, the landscape of tumor heterogeneity and its impact on the evolution of metastasis and PDXs remain undefined. We performed whole-genome, deep exome, and targeted validation sequencing of multiple primary regions, matched distant metastases, and PDXs from 11 patients with mCRC. We observed intricate clonal heterogeneity and evolution affecting metastasis dissemination and PDX clonal selection. Metastasis formation followed both monoclonal and polyclonal seeding models. In four cases, metastasis-seeding clones were not identified in any primary region, consistent with a metastasis-seeding-metastasis model. PDXs underrepresented the subclonal heterogeneity of parental tumors. These suggest that single sample tumor sequencing and current PDX models may be insufficient to guide precision medicine