Victims\u27 Participation at the Internatinal Criminal Court: Are Concessions of the Court Clouding the Promise?

The International Criminal Court (the ICC ), the world\u27s first permanent international criminal tribunal, is the first international criminal tribunal to grant to victims the right to participate in court proceedings, through their own representatives. This article, which is authored by a former ICC trial attorney, examines the ICC\u27s actual performance in providing victims\u27 participation in the Court\u27s first years of operation. The article posits, in part through statistical analysis, that the processing of applications to participate is consuming substantial Court resources while yielding participation for very few victims. The article attributes this failing to the readiness of the Pre-Trial and Trial Chambers to expand the participation right beyond the boundaries intended by the ICC\u27s creators, without agreeing on the standards for participation. The consequences, the article argues, have included the impairment of the efficiency of ICC proceedings, the undermining of defense rights, and the inability of most victims to obtain more than a theoretical right to participate. The article proposes means of strengthening the ICC victims\u27 participation framework and suggests ways in which victims and victims\u27 representatives might better vindicate the interests of victims of crimes within the ICC\u27s jurisdiction

Targeting the Mechanisms of Resistance to Chemotherapy and Radiotherapy with the Cancer Stem Cell Hypothesis

Despite advances in treatment, cancer remains the 2nd most common cause of death in the United States. Poor cure rates may result from the ability of cancer to recur and spread after initial therapies have seemingly eliminated detectable signs of disease. A growing body of evidence supports a role for cancer stem cells (CSCs) in tumor regrowth and spread after initial treatment. Thus, targeting CSCs in combination with traditional induction therapies may improve treatment outcomes and survival rates. Unfortunately, CSCs tend to be resistant to chemo- and radiation therapy, and a better understanding of the mechanisms underlying CSC resistance to treatment is necessary. This paper provides an update on evidence that supports a fundamental role for CSCs in cancer progression, summarizes potential mechanisms of CSC resistance to treatment, and discusses classes of drugs currently in preclinical or clinical testing that show promise at targeting CSCs

Gene expression signatures modulated by epidermal growth factor receptor activation and their relationship to cetuximab resistance in head and neck squamous cell carcinoma.

BACKGROUND: Aberrant activation of signaling pathways downstream of epidermal growth factor receptor (EGFR) has been hypothesized to be one of the mechanisms of cetuximab (a monoclonal antibody against EGFR) resistance in head and neck squamous cell carcinoma (HNSCC). To infer relevant and specific pathway activation downstream of EGFR from gene expression in HNSCC, we generated gene expression signatures using immortalized keratinocytes (HaCaT) subjected to ligand stimulation and transfected with EGFR, RELA/p65, or HRASVal12D. RESULTS: The gene expression patterns that distinguished the HaCaT variants and conditions were inferred using the Markov chain Monte Carlo (MCMC) matrix factorization algorithm Coordinated Gene Activity in Pattern Sets (CoGAPS). This approach inferred gene expression signatures with greater relevance to cell signaling pathway activation than the expression signatures inferred with standard linear models. Furthermore, the pathway signature generated using HaCaT-HRASVal12D further associated with the cetuximab treatment response in isogenic cetuximab-sensitive (UMSCC1) and -resistant (1CC8) cell lines. CONCLUSIONS: Our data suggest that the CoGAPS algorithm can generate gene expression signatures that are pertinent to downstream effects of receptor signaling pathway activation and potentially be useful in modeling resistance mechanisms to targeted therapies

Systems Analysis Implicates WAVE2 Complex in the Pathogenesis of Developmental Left-Sided Obstructive Heart Defects.

Genetic variants are the primary driver of congenital heart disease (CHD) pathogenesis. However, our ability to identify causative variants is limited. To identify causal CHD genes that are associated with specific molecular functions, the study used prior knowledge to filter de novo variants from 2,881 probands with sporadic severe CHD. This approach enabled the authors to identify an association between left ventricular outflow tract obstruction lesions and genes associated with the WAVE2 complex and regulation of small GTPase-mediated signal transduction. Using CRISPR zebrafish knockdowns, the study confirmed that WAVE2 complex proteins brk1, nckap1, and wasf2 and the regulators of small GTPase signaling cul3a and racgap1 are critical to cardiac development

The Effects of Global Change Upon United States Air Quality

To understand more fully the effects of global changes on ambient concentrations of ozone and particulate matter with aerodynamic diameter smaller than 2.5 μm (PM2.5) in the United States (US), we conducted a comprehensive modeling effort to evaluate explicitly the effects of changes in climate, biogenic emissions, land use and global/regional anthropogenic emissions on ozone and PM2.5 concentrations and composition. Results from the ECHAM5 global climate model driven with the A1B emission scenario from the Intergovernmental Panel on Climate Change (IPCC) were downscaled using the Weather Research and Forecasting (WRF) model to provide regional meteorological fields. We developed air quality simulations using the Community Multiscale Air Quality Model (CMAQ) chemical transport model for two nested domains with 220 and 36 km horizontal grid cell resolution for a semi-hemispheric domain and a continental United States (US) domain, respectively. The semi-hemispheric domain was used to evaluate the impact of projected global emissions changes on US air quality. WRF meteorological fields were used to calculate current (2000s) and future (2050s) biogenic emissions using the Model of Emissions of Gases and Aerosols from Nature (MEGAN). For the semi-hemispheric domain CMAQ simulations, present-day global emissions inventories were used and projected to the 2050s based on the IPCC A1B scenario. Regional anthropogenic emissions were obtained from the US Environmental Protection Agency National Emission Inventory 2002 (EPA NEI2002) and projected to the future using the MARKet ALlocation (MARKAL) energy system model assuming a business as usual scenario that extends current decade emission regulations through 2050. Our results suggest that daily maximum 8 h average ozone (DM8O) concentrations will increase in a range between 2 to 12 parts per billion (ppb) across most of the continental US. The highest increase occurs in the South, Central and Midwest regions of the US due to increases in temperature, enhanced biogenic emissions and changes in land use. The model predicts an average increase of 1–6 ppb in DM8O due to projected increase in global emissions of ozone precursors. The effects of these factors are only partially offset by reductions in DM8O associated with decreasing US anthropogenic emissions. Increases in PM2.5 levels between 4 and 10 μg m−3 in the Northeast, Southeast, Midwest and South regions are mostly a result of increase in primary anthropogenic particulate matter (PM), enhanced biogenic emissions and land use changes. Changes in boundary conditions shift the composition but do not alter overall simulated PM2.5 mass concentrations

Loss of Trop2 causes ErbB3 activation through a neuregulin-1-dependent mechanism in the mesenchymal subtype of HNSCC

In head and neck squamous cell cancer (HNSCC), four intrinsic subtypes (or groups) have been identified, and each one possesses a unique biology that will require specific treatment strategies. We previously reported that mesenchymal (group 2) tumors exhibit reduced levels of Trop2 expression. In this study, we investigated the functional role of Trop2 in HNSCC and find that loss results in autocrine activation of the EGFR family member ErbB3 via neuregulin-1. Trop2 localizes to both the cell surface and cytosol of HNSCC cells and forms a complex with neuregulin-1, which is predominantly cytosolic. Inactivation of Trop2 increases the concentration of neuregulin-1 at the cell surface where it is cleaved to activate ErbB3. In primary HNSCC, detection of ErbB3 activation was limited to Trop2 negative tumors. An analysis of the Cancer Genome Atlas (TCGA) HNSCC dataset confirms enrichment for ErbB3 activity in mesenchymal tumors. Notably, Trop2 loss triggers sensitivity to anti-ErbB3 antibodies, which results in reduced proliferation and tumorigenic growth of Trop2 negative HNSCC cancer cells. These results uncover a molecular mechanism by which tumor cells control the amount of cell-surface neuregulin-1 available for cleavage and ErbB3 activation. Moreover, we demonstrate that Trop2 is a potential surrogate biomarker to identify tumors with ErbB3 activation and may therefore respond to anti-ErbB3 therapeutics

Taselisib (GDC-0032), a Potent -Sparing Small Molecule Inhibitor of PI3K, Radiosensitizes Head and Neck Squamous Carcinomas Containing Activating PIK3CA Alterations

Activating PIK3CA genomic alterations are frequent in head and neck squamous cell carcinoma (HNSCC), and there is an association between phosphoinositide 3-kinase (PI3K) signaling and radioresistance. Hence, we investigated the therapeutic efficacy of inhibiting PI3K with GDC-0032, a PI3K inhibitor with potent activity against p110α, in combination with radiation in HNSCC