Positive predictive value of ERBB2 copy number gain by tissue or circulating tumor DNA next-generation sequencing across advanced cancers

BACKGROUND: The correlation of ERBB2 copy number gain (CNG) from tissue or circulating tumor DNA (ctDNA) by next-generation sequencing (NGS) with standard HER2 tissue evaluation is not well understood. MATERIALS AND METHODS: We retrospectively identified patients with ERBB2 CNG on commercial NGS. We described their clinical-pathologic features and calculated the positive predictive value (PPV) of ERBB2 CNG by NGS for HER2-positivity by IHC and FISH testing. RESULTS: 176 patients had NGS revealing an ERBB2 CNG (112 by tumor tissue and 91 by ctDNA). The cancer subtypes with the most cases with ERBB2 CNG by NGS were breast ( CONCLUSIONS: ERBB2 CNG by NGS is detected in numerous malignancies for which HER2 testing is not standard. Detection of ERBB2 CNG by tissue NGS and ctDNA has a high PPV for true HER2-positivity by standard IHC and/or FISH testing in breast cancer

Enabling Technologies for Web 3.0: A Comprehensive Survey

Web 3.0 represents the next stage of Internet evolution, aiming to empower users with increased autonomy, efficiency, quality, security, and privacy. This evolution can potentially democratize content access by utilizing the latest developments in enabling technologies. In this paper, we conduct an in-depth survey of enabling technologies in the context of Web 3.0, such as blockchain, semantic web, 3D interactive web, Metaverse, Virtual reality/Augmented reality, Internet of Things technology, and their roles in shaping Web 3.0. We commence by providing a comprehensive background of Web 3.0, including its concept, basic architecture, potential applications, and industry adoption. Subsequently, we examine recent breakthroughs in IoT, 5G, and blockchain technologies that are pivotal to Web 3.0 development. Following that, other enabling technologies, including AI, semantic web, and 3D interactive web, are discussed. Utilizing these technologies can effectively address the critical challenges in realizing Web 3.0, such as ensuring decentralized identity, platform interoperability, data transparency, reducing latency, and enhancing the system's scalability. Finally, we highlight significant challenges associated with Web 3.0 implementation, emphasizing potential solutions and providing insights into future research directions in this field

Interplay between ESR1/PIK3CA codon variants, oncogenic pathway alterations and clinical phenotype in patients with metastatic breast cancer (MBC): comprehensive circulating tumor DNA (ctDNA) analysis

Background: although being central for the biology and druggability of hormone-receptor positive, HER2 negative metastatic breast cancer (MBC), ESR1 and PIK3CA mutations are simplistically dichotomized as mutated or wild type in current clinical practice. Methods: The study analyzed a multi-institutional cohort comprising 703 patients with luminal-like MBC characterized for circulating tumor DNA through next generation sequencing (NGS). Pathway classification was defined based on previous work (i.e., RTK, RAS, RAF, MEK, NRF2, ER, WNT, MYC, P53, cell cycle, notch, PI3K). Single nucleotide variations (SNVs) were annotated for their oncogenicity through OncoKB. Only pathogenic variants were included in the models. Associations among clinical characteristics, pathway classification, and ESR1/PIK3CA codon variants were explored. Results: The results showed a differential pattern of associations for ESR1 and PIK3CA codon variants in terms of co-occurring pathway alterations patterns of metastatic dissemination, and prognosis. ESR1 537 was associated with SNVs in the ER and RAF pathways, CNVs in the MYC pathway and bone metastases, while ESR1 538 with SNVs in the cell cycle pathway and liver metastases. PIK3CA 1047 and 542 were associated with CNVs in the PI3K pathway and with bone metastases. Conclusions: The study demonstrated how ESR1 and PIK3CA codon variants, together with alterations in specific oncogenic pathways, can differentially impact the biology and clinical phenotype of luminal-like MBC. As novel endocrine therapy agents such as selective estrogen receptor degraders (SERDS) and PI3K inhibitors are being developed, these results highlight the pivotal role of ctDNA NGS to describe tumor evolution and optimize clinical decision making

Reformism, Economic Liberalisation and Popular Mobilisation in Iran

Whereas in other MENA countries the impact of neo-liberal policies has been the subject of intense debate, there are at present few voices that directly analyse or critique its social and political consequences in Iran. This article seeks to address this lacuna by analysing the dynamics of reformism, economic liberalisation and popular mobilisation in Iran. It charts the country’s move from a post-revolutionary populism to a liberalised yet increasingly exclusivist model of politics and compares this to trajectories of economic liberalisation in Egypt. Two distinct outcomes of economic reform are analysed in the first part of the article: Socio-economic exclusion; and the contraction of political rights. In the second half, I investigate the ways successive post-war governments in Iran have packaged neo-liberal reforms, and how their re-imagining of the role of the state has led to differing levels of popular resistance. Finally I argue that under the present administration, political elites increasingly are oriented toward strengthening the state and seeking to limit opposition to their policies. However, the absence of neo-liberal hegemony in Iran means that growing mobilization on socio-economic issues is challenging these policies. The Right in Iranian politics is utilizing this mobilisation to present a populist challenge to the reformists in power

BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency.

The transcriptional programs that guide lymphocyte differentiation depend on the precise expression and timing of transcription factors (TFs). The TF BACH2 is essential for T and B lymphocytes and is associated with an archetypal super-enhancer (SE). Single-nucleotide variants in the BACH2 locus are associated with several autoimmune diseases, but BACH2 mutations that cause Mendelian monogenic primary immunodeficiency have not previously been identified. Here we describe a syndrome of BACH2-related immunodeficiency and autoimmunity (BRIDA) that results from BACH2 haploinsufficiency. Affected subjects had lymphocyte-maturation defects that caused immunoglobulin deficiency and intestinal inflammation. The mutations disrupted protein stability by interfering with homodimerization or by causing aggregation. We observed analogous lymphocyte defects in Bach2-heterozygous mice. More generally, we observed that genes that cause monogenic haploinsufficient diseases were substantially enriched for TFs and SE architecture. These findings reveal a previously unrecognized feature of SE architecture in Mendelian diseases of immunity: heterozygous mutations in SE-regulated genes identified by whole-exome/genome sequencing may have greater significance than previously recognized

Tri-Band Reconfigurable Antenna for RFID Applications

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