Differential Epigenetic Regulation of TOX Subfamily High Mobility Group Box Genes in Lung and Breast Cancers

Aberrant cytosine methylation affects regulation of hundreds of genes during cancer development. In this study, a novel aberrantly hypermethylated CpG island in cancer was discovered within the TOX2 promoter. TOX2 was unmethylated in normal cells but 28% lung (n = 190) and 23% breast (n = 80) tumors were methylated. Expression of two novel TOX2 transcripts identified was significantly reduced in primary lung tumors than distant normal lung (p<0.05). These transcripts were silenced in methylated lung and breast cancer cells and 5-Aza-2-deoxycytidine treatment re-expressed both. Extension of these assays to TOX, TOX3, and TOX4 genes that share similar genomic structure and protein homology with TOX2 revealed distinct methylation profiles by smoking status, histology, and cancer type. TOX was almost exclusively methylated in breast (43%) than lung (5%) cancer, whereas TOX3 was frequently methylated in lung (58%) than breast (30%) tumors. TOX4 was unmethylated in all samples and showed the highest expression in normal lung. Compared to TOX4, expression of TOX, TOX2 and TOX3 in normal lung was 25, 44, and 88% lower, respectively, supporting the premise that reduced promoter activity confers increased susceptibility to methylation during lung carcinogenesis. Genome-wide assays revealed that siRNA-mediated TOX2 knockdown modulated multiple pathways while TOX3 inactivation targeted neuronal development and function. Although these knockdowns did not result in further phenotypic changes of lung cancer cells in vitro, the impact on tissue remodeling, inflammatory response, and cell differentiation pathways suggest a potential role for TOX2 in modulating tumor microenvironment

Current issues in medically assisted reproduction and genetics in Europe: research, clinical practice, ethics, legal issues and policy. European Society of Human Genetics and European Society of Human Reproduction and Embryology.

In March 2005, a group of experts from the European Society of Human Genetics and European Society of Human Reproduction and Embryology met to discuss the interface between genetics and assisted reproductive technology (ART), and published an extended background paper, recommendations and two Editorials. Seven years later, in March 2012, a follow-up interdisciplinary workshop was held, involving representatives of both professional societies, including experts from the European Union Eurogentest2 Coordination Action Project. The main goal of this meeting was to discuss developments at the interface between clinical genetics and ARTs. As more genetic causes of reproductive failure are now recognised and an increasing number of patients undergo testing of their genome before conception, either in regular health care or in the context of direct-to-consumer testing, the need for genetic counselling and preimplantation genetic diagnosis (PGD) may increase. Preimplantation genetic screening (PGS) thus far does not have evidence from randomised clinical trials to substantiate that the technique is both effective and efficient. Whole-genome sequencing may create greater challenges both in the technological and interpretational domains, and requires further reflection about the ethics of genetic testing in ART and PGD/PGS. Diagnostic laboratories should be reporting their results according to internationally accepted accreditation standards (International Standards Organisation - ISO 15189). Further studies are needed in order to address issues related to the impact of ART on epigenetic reprogramming of the early embryo. The legal landscape regarding assisted reproduction is evolving but still remains very heterogeneous and often contradictory. The lack of legal harmonisation and uneven access to infertility treatment and PGD/PGS fosters considerable cross-border reproductive care in Europe and beyond. The aim of this paper is to complement previous publications and provide an update of selected topics that have evolved since 2005

Access to government serial information in a digital environment

Access to government information is a fundamental principle of American democracy. The federal depository program is one of the main ways in which government information is distributed to the public. Much of this information is now available in electronic form, and libraries must consider several major technical service and public service issues surrounding the provision of access to these electronic serial documents

White-Box Cryptography: Don\u27t Forget About Grey Box Attacks

Despite the fact that all current scientific white-box approaches of standardized cryptographic primitives have been publicly broken, these attacks require knowledge of the internal data representation used by the implementation. In practice, the level of implementation knowledge required is only attainable through significant reverse engineering efforts. In this paper we describe new approaches to assess the security of white-box implementations which require neither knowledge about the look-up tables used nor expensive reverse engineering efforts. We introduce the differential computation analysis (DCA) attack which is the software counterpart of the differential power analysis attack as applied by the cryptographic hardware community. Similarly, the differential fault analysis (DFA) attack is the software counterpart of fault-injection attacks on cryptographic hardware. For DCA, we developed plugins to widely available dynamic binary instrumentation (DBI) frameworks to produce software execution traces which contain information about the memory addresses being accessed. For the DFA attack, we developed modified emulators and plugins for DBI frameworks that allow injecting faults at selected moments within the execution of the encryption or decryption process as well as a framework to automate static fault injection. To illustrate the effectiveness, we show how DCA and DFA can extract the secret key from numerous publicly available non-commercial white-box implementations of standardized cryptographic algorithms. These approaches allow one to extract the secret key material from white-box implementations significantly faster and without specific knowledge of the white-box design in an automated or semi-automated manner

White-box cryptography: don’t forget about grey-box attacks

Despite the fact that all current scientific white-box approaches of standardized cryptographic primitives have been publicly broken, these attacks require knowledge of the internal data representation used by the implementation. In practice, the level of implementation knowledge required is only attainable through significant reverse-engineering efforts. In this paper, we describe new approaches to assess the security of white-box implementations which require neither knowledge about the look-up tables used nor expensive reverse-engineering efforts. We introduce the differential computation analysis (DCA) attack which is the software counterpart of the differential power analysis attack as applied by the cryptographic hardware community. Similarly, the differential fault analysis (DFA) attack is the software counterpart of fault injection attacks on cryptographic hardware. For DCA, we developed plugins to widely available dynamic binary instrumentation (DBI) frameworks to produce software execution traces which contain information about the memory addresses being accessed. For the DFA attack, we developed modified emulators and plugins for DBI frameworks that allow injecting faults at selected moments within the execution of the encryption or decryption process as well as a framework to automate static fault injection. To illustrate the effectiveness, we show how DCA and DFA can extract the secret key from numerous publicly available non-commercial white-box implementations of standardized cryptographic algorithms. These approaches allow one to extract the secret key material from white-box implementations significantly faster and without specific knowledge of the white-box design in an automated or semi-automated manner