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PurposeCyberstalking is a growing threat to society, and policymakers should address it utilizing the input of constituents. For this, two key components are required: actionable objectives informed by the values of society and the means of implementation to maximize their potential benefits. The process should be guided by the constituent's values, requiring the elicitation of intrinsic values as individual preferences that are extrapolated to society at large.Design/methodology/approachThe authors utilize Keeney's (1990) public value forum and Sen's (1999) social choice theory (Sen, 1999) to elicit and convert these intrinsic values to serve as the basis for developing public policy to prevent cyberstalking.FindingsThe results demonstrate a strong desire by participants to have clear regulations, policies and procedures developed in concert with industry and enforced by the government that elucidate required protections against cyberstalking in combination with strong technical controls. These policies should guide technical control development and implementation, but leave ultimate control in the hands of technology users to decide what controls they want to utilize.Originality/valueThis study is the first to utilize Keeney's (1988) public value forum in the context of cyberstalking to develop quantitative measures regarding technology users' desired cybersecurity protections against cyberstalking. The authors provide a decision-making framework for policymakers to develop a new policy based on the input of their constituents in a manner that maximizes their potential utility and ultimate benefit.

Genomic analysis of the T-cell receptor (TCR) reveals the strength, breadth and clonal dynamics of the adaptive immune response to pathogens or cancer. The diversity of the TCR repertoire, however, means that sequencing is technically challenging, particularly for samples with low quality, degraded nucleic acids. Here, we have developed and validated FUME-TCRseq, a robust and sensitive RNA-based TCR sequencing methodology that is suitable for formalin-fixed paraffin-embedded samples and low amounts of input material. FUME-TCRseq incorporates unique molecular identifiers into each molecule of cDNA, allowing correction for sequencing errors and PCR bias. We used RNA extracted from colorectal and head and neck cancers to benchmark the accuracy and sensitivity of FUME-TCRseq against existing methods, and found excellent concordance between the datasets. Furthermore, FUME-TCRseq detected more clonotypes than a commercial RNA-based alternative, with shorter library preparation time and significantly lower cost. The high sensitivity and the ability to sequence RNA of poor quality and limited amount enables quantitative analysis of small numbers of cells from archival tissue sections, which is not possible with other methods. To demonstrate this we performed spatially-resolved FUME-TCRseq of colorectal cancers using macrodissected archival samples, revealing the shifting T-cell landscapes at the transition to an invasive phenotype, and between tumour subclones containing distinct driver alterations. In summary, FUME-TCRseq represents an accurate, sensitive and low-cost tool for the characterisation of T-cell repertoires, particularly in samples with low quality RNA that have not been accessible using existing methodology.

Locally advanced oesophageal adenocarcinoma (EAC) remains difficult to treat because of common resistance to neoadjuvant therapy and high recurrence rates. The ecological and evolutionary dynamics responsible for treatment failure are incompletely understood. Here, we performed a comprehensive multi-omic analysis of samples collected from EAC patients in the MEMORI clinical trial, revealing major changes in gene expression profiles and immune microenvironment composition that did not appear to be driven by changes in clonal composition. Multi-region multi-timepoint whole exome (300x depth) and paired transcriptome sequencing was performed on 27 patients pre-, during and after neoadjuvant treatment. EAC showed major transcriptomic changes during treatment with upregulation of immune and stromal pathways and oncogenic pathways such as KRAS, Hedgehog and WNT. However, genetic data revealed that clonal sweeps were rare, suggesting that gene expression changes were not clonally driven. Additional longitudinal image mass cytometry was performed in a subset of 15 patients and T-cell receptor sequencing in 10 patients, revealing remodelling of the T-cell compartment during treatment and other shifts in microenvironment composition. The presence of immune escape mechanisms and a lack of clonal T-cell expansions were linked to poor clinical treatment response. This study identifies profound transcriptional changes during treatment with limited evidence that clonal replacement is the cause, suggesting phenotypic plasticity and immune dynamics as mechanisms for therapy resistance with pharmacological relevance.

Attachment to social media is a serious problem for iGen users. A recent study of social media use by 10,000 iGen users found 36% were on social media for 2 to 4 h daily, and 11% for more than 5 h. Further, users who reported spending more time on social media were significantly more likely to rate their mental health as poor. With the increasing awareness of the dire consequences of addiction to social media, calls have been made to take action against its continued proliferation. Instead of bans on social media, we call for mild policy-based interventions to guide appropriate positive social media use, while minimizing harmful experiences. Attachment Theory is adopted to understand the individual values and feelings of attachment of iGen to social media. We then use the Value-focused Thinking process to organize values to define iGen’s attachment objectives. In a final synthesis we present a mild policy-based interventions approach to suggest policy interventions and techniques for social media use to combat over-attachment by iGen users.

Introduction: Locally advanced esophageal adenocarcinoma (EAC) remains difficult to treat, and resistance is common. The ecological and evolutionary dynamics responsible for treatment failure are incompletely understood. Aim & Methods: We performed a multi-omic study with a multi-timepoint strategy to examine neoadjuvant treatment response at clonal resolution and in the surrounding tumor microenvironment. EAC samples from chemotherapy responding (REs) and chemotherapy non-responding (NRs) patients with locally advanced EAC were collected at three time points (prior, during, and after neoadjuvant therapy) within the multicenter MEMORI trial. Whole exome sequencing (mean depth 300x) was performed on 47 samples from 17 REs and on 24 samples from 10 NRs. Matched RNA sequencing was performed on 53 samples from 17 REs and on 26 samples from 10 NRs. To characterize immune response we performed imaging mass cytometry (IMC) with a 18-marker panel on 26 samples from 9 REs and 16 samples from 6 NRs and T-cell receptor sequencing in 18 RE-samples and 9 NR-samples. Results: We observed profound changes in mutation signatures over time, characterized by C>A transitions after exposure to neoadjuvant chemotherapy (FOLFOX), which is consistent with earlier observed oxaliplatin induced mutational signatures. Phylogenetic analysis showed no major changes in the clonal make-up during treatment, suggesting phenotypic plasticity rather than clonal evolution caused treatment resistance. EAC samples displayed widespread copy number alterations (CNAs), as previously described. CNAs arising during treatment were significantly more likely to be small, focal alterations rather than large alterations. At the transcriptome level neoadjuvant treatment led to significant changes with significant upregulation of immune and stromal pathways and oncogenic pathways such as KRAS, Hedgehog and WNT. The presence of immune escape mechanisms (defined as LOH or mutations in HLA, B2M mutations or PDL-1 overexpression) and a lack of clonal T-cell expansions were linked to poor clinical treatment response. Moreover, IMC analyses showed a less activated T-cell phenotype in NRs than in REs throughout treatment. Conclusion: Using a multi-timepoint approach, we integrated genetic analyses with transcriptomic analyses and analyses of the tumor immune microenvironment for a holistic understanding of treatment resistance. This study identifies profound transcriptional changes during treatment with limited evidence that clonal replacement is the cause, suggesting phenotypic plasticity as a mechanism for therapy resistance. The presence of immune escape, a less activated T-cell phenotype and a lack of clonal T-cell expansions in patients with poor clinical treatment response has high pharmacological relevance and could be exploited via combined immune-chemotherapy treatments. Citation Format: Melissa Barroux, Jacob Househam, Eszter Lakatos, Tahel Ronel, Ann-Marie Baker, Henrike Salié, Max Mossner, Kane Smith, Chris Kimberley, Salpie Nowinski, Alison Berner, Vinaya Gunasri, Marnix Jansen, Giulio Caravagna, Julia Slotta-Huspenina, Wilko Weichert, Markus Alberstmeier, Benny Chain, Helmut Friess, Bertram Bengsch, Roland M. Schmid, Jens T. Siveke, Michael Quante, Trevor A. Graham. Tumor evolution and immune microenvironment dynamics define response to neoadjuvant treatment of esophageal adenocarcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4539.

Purpose Blockchain holds promise as a potential solution to the problem of cybersecurity in financial transactions. However, difficulty exists for both the industry and organizations in assessing this potential solution. Hence, it is important to understand how organizations in the financial sector can address these concerns by exploring blockchain implementation for financial transactions in the context of cybersecurity. To do this, the problem question is threefold: first, what objectives are important based on the strategic values of an organization for evaluating cybersecurity to improve the security of financial transactions? Second, how can they be used to ensure the cybersecurity of financial transactions in a financial organization? Third, how can these objectives be used to evaluate blockchain as a potential solution for enhancing the cybersecurity of organizations in the financial sector relative to existing cybersecurity methods? The paper aims to discuss this issue. Design/methodology/approach To accomplish this goal we utilize Keeney’s (1992) multi-objective decision analytics technique, termed value-focused thinking (VFT), to demonstrate how organizations can assess a blockchain solution’s value to maximize value-add within financial organization. Findings The presented model clearly demonstrates the viability of using Keeney’s (1992) VFT technique as a multi-criteria decision analysis tool for assessing blockchain technology. Further, a clear explanation of how this model can be extended and adapted for individual organizational use is provided. Originality/value This paper engages both the academic literature as well as an expert panel to develop an assessment model for blockchain technology related to financial transactions by providing a useful method for structuring the decision-making process of organizations around blockchain technology.

BackgroundRepeat expansion (RE) disorders affect ~1 in 3000 individuals and are clinically heterogeneous diseases caused by expansions of short tandem DNA repeats. Genetic testing is often locus-specific, resulting in under diagnosis of atypical clinical presentations, especially in paediatric patients without a prior positive family history. Whole genome sequencing (WGS) is emerging as a first-line test for rare genetic disorders, but until recently REs were thought to be undetectable by this approach.MethodsWGS pipelines for RE disorder detection were deployed by the 100,000 Genomes Project and Illumina Clinical Services Laboratory. Performance was retrospectively assessed across the 13 most common neurological RE loci using 793 samples with prior orthogonal testing (182 with expanded alleles and 611 with alleles within normal size) and prospectively interrogated in 13,331 patients with suspected genetic neurological disorders.FindingsWGS RE detection showed minimum 97·3% sensitivity and 99·6% specificity across all 13 disease-associated loci. Applying the pipeline to patients from the 100,000 Genomes Project identified pathogenic repeat expansions which were confirmed in 69 patients, including seven paediatric patients with no reported family history of RE disorders, with a 0.09% false positive rate.InterpretationWe show here for the first time that WGS enables the detection of causative repeat expansions with high sensitivity and specificity, and that it can be used to resolve previously undiagnosed neurological disorders. This includes children with no prior suspicion of a RE disorder. These findings are leading to diagnostic implementation of this analytical pipeline in the NHS Genomic Medicine Centres in England.FundingMedical Research Council, Department of Health and Social Care, National Health Service England, National Institute for Health Research, Illumina Inc

Aneuploidy, defined as the loss and gain of whole and part chromosomes, is a near-ubiquitous feature of cancer genomes, is prognostic, and likely an important determinant of cancer cell biology. In colorectal cancer (CRC), aneuploidy is found in virtually all tumours, including precursor adenomas. However, the temporal evolutionary dynamics that select for aneuploidy remain broadly uncharacterised. Here we perform genomic analysis of 755 samples from a total of 167 patients with colorectal-derived neoplastic lesions that cross-sectionally represent the distinct stages of tumour evolution, and longitudinally track individual tumours through metastasis and treatment. Precancer lesions (adenomas) exhibited low levels of aneuploidy but high intra-tumour heterogeneity, whereas cancers had high aneuploidy but low heterogeneity, indicating that progression is through a genetic bottleneck that suppresses diversity. Individual CRC glands from the same tumour have similar karyotypes, despite prior evidence of ongoing instability at the cell level. Pseudo-stable aneuploid genomes were observed in metastatic lesions sampled from liver and other organs, after chemo- or targeted therapies, and late recurrences detected many years after the diagnosis of a primary tumour. Modelling indicates that these data are consistent with the action of stabilising selection that ‘traps’ cancer cell genomes on a fitness peak defined by the specific pattern of aneuploidy. These data show that the initial progression of CRC requires the traversal of a rugged fitness landscape and subsequent genomic evolution, including metastatic dissemination and therapeutic resistance, is constrained by stabilising selection.

Background Patients with ulcerative colitis (UC) are enrolled into surveillance programs for the early detection of colorectal cancer (CRC). However, most patients under surveillance are low-risk and never progress to CRC, while a significant proportion of CRCs in UC form without a preceding confirmed diagnosis of dysplasia. High resolution chromosomal copy-number alteration (CNA) analysis of unselected formalin-fixed paraffin embedded biopsies taken at surveillance colonoscopies using low pass whole genome sequencing (lpWGS) offers an appealing approach to CRC stratification. Methods We conducted a retrospective case-control study to compare the CNA burden in four unselected non-neoplastic left-sided colorectal biopsies from patients with E2/E3 UC derived 1–5 years prior to HGD/CRC detection (cases), with that of biopsies from patients who subsequently remained HGD/CRC-free for at least 5 years (controls). The two patient groups were matched by age, gender, duration of IBD and PSC status. lpWGS was performed using a standardised pipeline for epithelial enrichment, DNA extraction, library preparation, next generation sequencing and bioinformatic analysis. Results 476 biopsies, derived from 42 cases and 77 controls, were analysed. Nearly 80% of patients had a detectable CNA in at least one of their biopsies, with the maximal CNA burden in a typical biopsy involving a median 1.1% of that biopsy’s genome. The CNA burden was significantly greater in the rectum compared to the sigmoid colon and descending colon. The most common CNA events were losses of between 1–30 megabases involving the sub-telomeric regions of chromosomes 5–9 and 22, which were found in similar proportion in both case and control biopsies. However, losses extending beyond sub-telomeric regions, as well as copy number gains, were found more frequently in cases biopsies (p Conclusion We identified multiple biopsies, predominantly in cases, with a surprisingly marked CNA burden involving over 10% of the genome, highlighting the fluid phenotype-genotype relationship. Non-dysplastic colitic epithelium can bear a significant burden of CNAs and maintain phenotypic stability for years without neoplastic transformation. Remarkably, by analysing the CNA burden of only four random biopsies, derived from less than 0.05% of the colonic surface area, we can significantly discriminate between case and control cohorts.

Public administrators, entrusted to develop public policy to manage the growing complexities of the IoT, face significant challenges. The challenges exist because of three reasons; First, there is a lack of policy direction. Second, user values related to cybersecurity are not well understood. Third, there is a lack of clarity as to how IoT public policy should be developed. In this paper we argue that new IoT policy should be guided by key stakeholder values (i.e. what users think to be important). We utilize the Public Value Forum to elicit public values to inform decision-making surrounding IoT policy by public administrators, conceptually informed by Rational choice theory. We use a five-phase process to introduce the decision context (i.e. the policy problem), define fundamental objectives, rank these objectives, identify value-based trade-offs between them and construct a multi-attribute utility model. The findings indicate several key themes for IoT security from the citizens themselves and decision-making administrators in diverse public agencies developing IoT cybersecurity public policy.

Within an organization, it is critical that all employees possess a security awareness and thus play a part in the protection of said organization's information assets. Some employees will have key roles and responsibilities and require specific skills to support them. However, organizations can face challenges in regard to recognizing the required specialized skills as well as where to obtain them. For this reason, whether an organization chooses to hire new staff, developing existing staff, or outsource the activities altogether, it is necessary to know the type and level of expertise required. To this end, this chapter discusses the need for organizations to understand and identify the essential skills related to cybersecurity in order for their employees to develop core competencies in these areas.

In this chapter, through the lens of information security, we discuss the use of blockchain technology as a mechanism for facilitating trust between various supply chain agents. The goal is to explicate the use of blockchain technology as a distributed ledger to mitigate a varied set of risks to supply chain virtualization, whereby various agents within the supply chain context can engage in transactions with an immutable and cryptographically secure record. This immutable and secure record would then serve as the foundation of a mutually beneficial relationship, built upon the blockchain technology, by engendering greater trust among supply chain agents. The usefulness of blockchain technology is such that it enables information to be stored using a cryptographically secure hash and be distributed among multiple record-keeping nodes. Each agent within the supply chain context can act as a node and, by maintaining a copy of the record, create a distributed ledger of information. This provides two distinct benefits that facilitate trust among agents within the supply chain context; first, agents acting as nodes within the blockchain possess a copy of the information record, which cannot be altered without their consent. Second, information is stored on the blockchain using a secure method of encryption that provides protection against tampering from malicious sources and security of the information contained on the chain. Therefore, these two benefits of blockchain technology provide supply chain agents with powerful trust-building mechanisms, which extricate fear and allay concerns when interacting with new or unknown agents.