Potential Liability Research Articles

Porcupine Inhibition Disrupts Mitochondrial Function and Homeostasis in WNT Ligand-Addicted Pancreatic Cancer.

WNT signaling promotes pancreatic ductal adenocarcinoma (PDAC) through diverse effects on proliferation, differentiation, survival, and stemness. A subset of PDAC with inactivating mutations in ring finger protein 43 (RNF43) show growth dependency on autocrine WNT ligand signaling and are susceptible to agents that block WNT ligand acylation by Porcupine O-acyltransferase, which is required for proper WNT ligand processing and secretion. For this study, global transcriptomic, proteomic, and metabolomic analyses were performed to explore the therapeutic response of RNF43-mutant PDAC to the Porcupine inhibitor (PORCNi) LGK974. LGK974 disrupted cellular bioenergetics and mitochondrial function through actions that included rapid mitochondrial depolarization, reduced mitochondrial content, and inhibition of oxidative phosphorylation and tricarboxylic acid cycle. LGK974 also broadly altered transcriptional activity, downregulating genes involved in cell cycle, nucleotide metabolism, and ribosomal biogenesis and upregulating genes involved in epithelial-mesenchymal transition, hypoxia, endocytosis, and lysosomes. Autophagy and lysosomal activity were augmented in response to LGK974, which synergistically inhibited tumor cell viability in combination with chloroquine. Autocrine WNT ligand signaling dictates metabolic dependencies in RNF43-mutant PDAC through a combination of transcription dependent and independent effects linked to mitochondrial health and function. Metabolic adaptations to mitochondrial damage and bioenergetic stress represent potential targetable liabilities in combination with PORCNi for the treatment of WNT ligand-addicted PDAC.

Universal Accessible Biomarkers of Drug-Induced Tissue Injury and Systemic Inflammation in Rat: Performance Assessment of TIMP-1, A2M, AGP, NGAL, and Albumin.

The ability to monitor for general drug-induced tissue injury (DITI) or systemic inflammation in any tissue using blood-based accessible biomarkers would provide a valuable tool in early exploratory animal studies to understand potential drug liabilities. Here we describe the evaluation of 4 biomarkers of tissue remodeling and inflammation (α2-macroglobulin [A2M], α1-acid glycoprotein [AGP], neutrophil gelatinase-associated lipocalin [NGAL], and tissue inhibitor of metalloproteinases [TIMP-1]) as well as the traditional serum parameter albumin as potential blood-based biomarkers of DITI and systemic inflammatory response (SIR). Biomarker performance was assessed in 51 short-term rat in vivo studies with various end-organ toxicities or SIR and receiver operating characteristic curves were generated to compare relative performances. All 4 biomarkers performed well in their ability to detect DITI and SIR with an area under the curve (AUC) of 0.82-0.78, however TIMP-1 achieved the best sensitivity (at 95% specificity) of 61%; AGP, NGAL, and A2M sensitivity was 51%-52%. AUC for albumin was 0.72 with sensitivity of 39%. A2M was the best performer in studies with only SIR (AUC 0.91). In the subset of studies with drug-induced vascular injury, TIMP-1 performed best with an AUC of 0.96. Poor performance of all tested biomarkers was observed in samples with CNS toxicity. In summary, TIMP-1, A2M, AGP, and NGAL demonstrated performance as sensitive accessible biomarkers of DITI and SIR, supporting their potential application as universal accessible tissue toxicity biomarkers to quickly identify dose levels associated with drug-induced injury in early exploratory rat safety and other studies.

Off‐campus injuries, on‐campus third‐party conduct might present potential liability under Title IX

Higher education law has long been concerned with whether colleges and universities should be held liable for student injuries that happen off campus. The law has repeatedly examined whether these institutions should be held liable when nonstudent guests inflict injuries to students on campus. These questions have often found life in tort/negligence law, where the focus is whether there is a special (legal) relationship between institutions of higher education and their students.

Genotypic variation and plasticity in climate-adaptive traits after range expansion and fragmentation of red spruce (Picea rubens Sarg.).

Shifting range limits are predicted for many species as the climate warms. However, the rapid pace of climate change will challenge the natural dispersal capacity of long-lived, sessile organisms such as forest trees. Adaptive responses of populations will, therefore, depend on levels of genetic variation and plasticity for climate-responsive traits, which likely vary across the range due to expansion history and current patterns of selection. Here, we study levels of genetic and plastic variation for phenology and growth traits in populations of red spruce (Picea rubens), from the range core to the highly fragmented trailing edge. We measured more than 5000 offspring sampled from three genetically distinct regions (core, margin and edge) grown in three common gardens replicated along a latitudinal gradient. Genetic variation in phenology and growth showed low to moderate heritability and differentiation among regions, suggesting some potential to respond to selection. Phenology traits were highly plastic, but this plasticity was generally neutral or maladaptive in the effect on growth, revealing a potential liability under warmer climates. These results suggest future climate adaptation will depend on the regional availability of genetic variation in red spruce and provide a resource for the design and management of assisted gene flow. This article is part of the theme issue 'Species' ranges in the face of changing environments (Part II)'.

Ethical perspectives of certified public accountants and the cannabis industry

BackgroundCertified public accountants must follow very high standards of ethical conduct as set forth by the AICPA Code of Professional Conduct and individual state licensing requirements. A 2019 grounded theory qualitative study posed that CPAs remain largely hesitant to serve the cannabis industry primarily because they fear federal prosecution as long as cannabis remains on the DEA’s Schedule I Drug List. The purpose of this research was to determine the perceptions of CPAs regarding providing accounting services to the cannabis industry in states that have legalized cannabis usage. This study investigated whether CPAs would serve the industry, why they might decline to serve the industry, what risks they believe serving the industry posed, and whether they believe serving the cannabis industry would create a moral or ethical issue.MethodsThis follow-up quantitative study investigated a small convenience sample of approximately one hundred CPAs in Colorado and Washington to learn more about their perceptions of serving the cannabis industry. Data was analyzed using chi-square and Mann-Whitney U tests to determine if there were any differences in perceptions between groups such as states, gender, and age categories.ResultsOf the participants, 77% responded that neither they nor their firm provided services to a cannabis-related business client compared to 23% that did serve cannabis clients. More Colorado CPAs were willing to turn down CRB work than were expected and fewer Colorado CPAs would be willing to take on CRB clients than were expected. While in Washington, fewer CPAs would turn down RB clients than expected, and more are willing to accept CRB clients than were expected. The risk due to potential liability coverage issues due to serving the cannabis industry was rated the highest while the risk of losing the CPA license was rated lowest. Data indicated that there was not a statistically significant difference between Colorado and Washington participants related to whether they were morally or religiously opposed to working in the industry or if they viewed serving the industry as an ethical violation.ConclusionCPAs remain largely unwilling to serve the cannabis industry primarily because CPAs fear federal prosecution as long as cannabis remains on the DEA’s Schedule I Drug Listing. The results of this study indicate that while most CPAs are not morally or religiously opposed to serving the industry, about half still believe doing so may constitute an ethical violation for a CPA.

Gamification and Its Application in Social Network Implementation

In this communication strategy, ideal audiences that are perceived to yield an effective influence of the stakeholders include national security or intelligence groups, as well as external firms that engage in regular monitoring of user information systems in collaboration with Visa’s internal group of experts. Indeed, the role of the national intelligence group(s) lies in addressing potential legal liabilities that could arise from any customer complaints relating to communication failures or lapses when malicious activities are detected. Similarly, the national intelligence group acts as a regulator to check trends in Visa Inc.’s conformity to standards shaping the state of communication about user information (in terms of frequency) and advising about some of the emerging technologies or platforms that ought to be incorporated to foster inclusivity and reach out to as many customer bases as possible. On the other hand, external firms responsible for regular monitoring of user information will play the role of examining some of the strengths of the communication strategies outlined and advising about possible improvements that could be made to avoid lapses regarding the duration and frequency of updates to the customers. It is also worth noting that the general public forms another audience group that the formulated strategy seeks to involve because this group plays a significant role of airing views about possible improvements that could be made to the company’s current communication goals. An ideal communication platform through which views from members of the public could be received and enacted accordingly is the social media, a trend that prompts Visa to have open forums from which these members could be allowed to channel their views about the merits and demerits accruing from the communication goals and their eventual implementation.

Who is an officer of a corporation? Australia and the United States Compared

ABSTRACT Over recent decades, both Australia and the US have been subjected to major corporate scandals. One response involves the Australian courts engaging in an observable expansive interpretation of the scope of the term ‘officer’ in the Corporations Act 2001. As a consequence, a broader range of actors can be held as officers. The US, on the other hand, in the context of officer duties, appears to be less inclined to take an approach that would recognise the potential liability of a broader range of actors, and has remained largely immovable in its interpretation of officer. This article outlines the divergent ways ‘officer’ is interpreted in Australia and in the US. Australian law and its evolving jurisprudence have taken a more realist consideration of who should be held as an ‘officer’, which better reflects the realities of the way modern corporations, especially large corporations, operate.

National study on use of artificial intelligence in breast disease and cancer.

The aim of this study was to examine the thoughts, reservations, approaches and perspectives on the future of artificial intelligence (AI) held by physicians specializing in breast healthcare in our country. Our survey was sent to the members of the Federation of Turkish Breast Disease Associations (MHDF) by e-mail. The survey investigates the attitudes towards the use of AI in breast disease and cancer, including demographic characteristics of the participants, their daily practice and approaches, and their stance on the future. The questionnaire was sent to a total of 1,890 people via e-mail. 108 (40.1 %) participants believed that the use of AI in breast disease would improve their field of expertise moderately, 103 (38.3 %) expected this improvement to be considerable. 169 (70.3 %) respondents identified 'rapid diagnosis' as the most important advantage of AI. 123 (45.7 %) participants considered concerns about potential medical errors and liability issues to be the most worrying aspects of AI. According to our study, the use of AI technology in the diagnosis and treatment of breast disease and cancer seems to be beneficial for both physicians and patients. However, physicians have some concerns about possible medical errors and liability issues that AI might cause (Tab. 1, Ref. 25).

Dento-Legal Issues in Malaysia: A General Guide for Dental Practitioners

Dentistry is a noble profession where dentists often manage to bring smiles and create confidence in patients. Nonetheless, as with other medical professionals, dentists too often encounter legal suits brought against them by their patients. Legal actions against dentists are not new in Malaysia, where several actions have been litigated in court. The rise in legal actions against medical professionals including dentists is associated with the increased awareness of patient’s rights and autonomy. Legal actions can cause several repercussions on dentists such as loss of reputation, shame and anxiety. As such, it is imperative for dentists to have the basic legal knowledge on the potential legal liability that they may face should something go wrong during the course of dental treatment. This is the main crux of this paper where several dento-legal cases that have been reported in Malaysian law journals are identified and analysed. This is followed with a brief discussion on the legal issues surrounding those cases. Legal principles governing the issues identified are provided in brief so as to provide dentists with basic legal knowledge on the legal aspect of dentistry.

Release from Liability of Member of the Board by Decision of the Shareholder: Abstract

The current legislation in force in the Republic of Latvia grants to any member of the board of any capital company wide powers to dispose of the company’s property. The duty to act with the care and diligence of a prudent and careful manager does not allow a CEO to act contrary to the company’s interest. However, if a member of the board has caused damage to the company, they may be released from liability by a lawful resolution of the shareholder. The current study analysed the standard of an honest and careful manager in accordance to Article 169 of the Commercial Law and the obligation to follow this pattern of conduct in order to avoid potential liability for losses. However, a member of the Management Board may also be released from liability if such a decision is taken by the shareholders in accordance with Article 173 of the Commercial Code. Although a decision may obviously release a Member of the Board, such a decision is not binding in all cases. Only if there is a belief that the board member has performed their duties in good faith, they can enjoy the immunity afforded by a decision of a shareholder.

Introduction to this special section: Seismic acquisition

In the life cycle of a seismic product, the lion's share of the budget and personnel hours is spent on acquisition. In most modern seismic surveys, acquisition involves hundreds of specialized personnel working for months or years. Seismic acquisition also must overcome potential liabilities and health, safety, and environmental concerns that rival facility, pipeline, construction, and other operational risks. As only properly acquired data can contribute effectively to processing and interpretation strategies, a great deal of importance is placed on acquisition quality. Arguably, many of the advances the seismic industry has experienced find their origin arising from advances in acquisition techniques. Full-waveform inversion (FWI), for example, can reach its full potential only when seismic acquisition has provided both low frequencies and long offsets.

Ulotaront, a novel TAAR1 agonist with 5-HT1A agonist activity, lacks abuse liability and attenuates cocaine cue-induced relapse in rats

BackgroundUlotaront (SEP-363856) is a trace amine-associated receptor 1 (TAAR1) agonist with 5-hydroxytryptamine type 1A (5-HT1A) agonist activity that is currently in Phase 3 clinical development for the treatment of schizophrenia. Unlike available antipsychotics, the efficacy of ulotaront is not mediated by blockade of dopamine D2 or serotonin 5-HT2A receptors. In a short-term randomized clinical trial, ulotaront has demonstrated significant efficacy in the treatment of adults with an acute exacerbation of schizophrenia. Given ulotaront’s novel mechanism of action a series of preclinical studies were performed to evaluate its potential abuse liability. MethodsA battery of studies were conducted in male and female rats to evaluate whether ulotaront produces behavioral changes suggestive of human abuse potential. In addition, studies were undertaken to probe the potential for ulotaront to block reinstatement of cocaine-seeking behavior in male rats. ResultsUlotaront was not self-administered by rats trained to self-administer amphetamine, cocaine, or heroin. The subjective qualities of ulotaront were distinct from those produced by amphetamine in a drug discrimination procedure. Ulotaront, and buspirone, a non-scheduled anxiolytic with 5-HT1A agonism, partially generalized to the interoceptive cue elicited by 3, 4-methylenedioxymethamphetamine (MDMA). In addition, ulotaront demonstrated a trend to reduce cocaine-primed induced reinstatement, and dose-dependently reduced cue-reinstated responding. ConclusionThe current results suggest that the TAAR1/5-HT1A agonist ulotaront is not likely to pose a risk for recreational abuse in humans and may have potential therapeutic utility as a treatment of substance use disorders.

The Future of Music Copyright Collectives in the Digital Streaming Age

The Future of Music Copyright Collectives in the Digital Streaming Age

Breakthrough in Parent Company Liability

Two English and two Dutch cases have recently clarified the (potential) liability of parent companies vis-à-vis third parties in relation to damage caused by their subsidiaries. They concern the decisions of the UK Supreme Court in Vedanta v Lungowe and Okpabi v Shell, the Hague Court of Appeal in Oguru v Shell and the Hague District Court in Milieudefensie v Shell (climate change case).

What does it all meme? An exploration of meme stock litigation, regulatory scrutiny and defences for broker-dealers

US financial market regulators have taken a renewed interest in retail trading and brokerdealer practices following the January 2021 ‘meme stock’ extreme market volatility. In this paper, the authors examine broker-dealer practices and trading rules that are the subject of pending litigation. Specifically, this paper examines areas of potential regulatory interest in the aftermath of the trading frenzy, including payment for order flow and related customer disclosures. It also examines the rationale for certain trading restrictions implemented by some broker-dealers during the period of extreme volatility. It then analyses legal defences for broker-dealers in pending investor litigation. Lastly, this paper discusses potential criminal and regulatory liability for amateur traders active on social media and online forums.

Design, synthesis and biological evaluation of quinazoline derivatives as potent and selective FGFR4 inhibitors.

Aberrant activation of the fibroblast growth factor 19-fibroblast growth factor receptor 4 (FGF19-FGFR4) signaling pathway has been proved to promote hepatocellular carcinoma (HCC) proliferation. It is assumed that the first FGFR4 inhibitor BLU9931 did not enter clinical studies, presumably due to its rapid metabolism in liver microsomes. Here, we report the development of series of quinazoline derivatives based on FGFR4 inhibitor BLU9931 through structural modification of its solvent region pocket to minimize its potential metabolic liability. Among them, compound 35a exhibited comparable or superior kinase inhibitory activity (IC50=8.5nM) and selectivity in cells. More importantly, compound 35a improved liver microsomes stability compared to BLU9931. Cellular mechanistic studies demonstrated that 35a induced apoptosis via the FGFR4 signaling pathway blockage. In addition, the computational simulation revealed the possible binding mode to FGFR4 protein, which provides a plausible explanation of high potent and metabolic stability.

Crops, Livestock, and COVID-19, Oh My: An Overview Of Potential Covid-19 Liability In Agricultural Operations

The year 2020 presented a new potential risk of which many business owners, including agricultural operators, were unaware: a global pandemic related to the SARS-CoV-2 virus, also known as COVID-19. Starting in March 2020, the United States worked to contain this virus, while businesses sought to protect their workers (who had to continue working to work) as well as their customers. At the same time, a number of businesses had concerns about how to limit liability from customers arguing later that the business had spread the virus. This Article explores the potential liability agricultural operations face and ways to manage the risks associated with COVID-19. Part II looks at what the virus is. Part III explores potential liability, and Part IV details potential methods to manage and limit that liability. Part V concludes.

THE CORPORATE GROUP: SYSTEM, DESIGN AND RESPONSIBILITY

AbstractLungowe v Vedanta Resources plc presages more liberal criteria for determining when a parent company owes a duty of care to third parties injured by subsidiary activities. It invokes systems language and points to potential parent company liability for omissions in managing the group. This article develops these ideas. It portrays the corporate group in systems-managerial terms. The parent creates group-wide structures and deploys management strategies and integrating mechanisms that facilitate achievement of its purposes. It has a substantial causal influence upon subsidiary acts and omissions. Prima facie the parent cannot avoid extended liability claims by hiding behind the “pure omissions” rule.

Framework for preliminary risk assessment of brownfield sites

The complexity of hazards, risk and environmental legislation surrounding the reuse of brownfield sites necessitates a preliminary risk assessment prior to their redevelopment. Most prevailing efforts have been targeted at indepth site investigations, which are often costly, time–consuming, and may not be required at the early stages of a site development. However, there is a collective absence of knowledge, methods and computer models that can present a complete framework to carry out a preliminary risk assessment that is simpler, quicker and sufficient, not only for risk assessor but also effectively communicative for a diverse range of stakeholders with or without risk assessment expertise. Therefore, this study aims to bridge this gap by designing and creating a framework, by not only identifying hazards but also exposing the degree of presence. Sixty-five potential hazards have been identified from a comprehensive literature review. A questionnaire survey was then shared with brownfield site experts (n = 76) that asked then to rank the priority of the potential hazards. Kendall's W test and Kruskal–Wallis H test were subsequently conducted to determine the level of agreement among the respondents. Mean weightings were calculated by using the Voting Analytic Hierarchy Process (VAHP) to prioritize the potential hazards from ‘more likely’ to ‘least likely’. Based on this information, the framework has been developed. It is anticipated that the framework can assist professionals to conduct a preliminary assessment of brownfield sites, which enables them to gain informative and rapid guidance on any potential liabilities or risks related to a site's suitability for acquisition or redevelopment. In this context, the framework outlines a systematic structure to collect appropriate data and information in the three main categories which are sources, pathways and receptors.

104 Barriers and Facilitators to Implementation of a Regional Disaster Teleconsultation System for New England Hospitals and Emergency Departments

The Region 1 Disaster Health Response System (RDHRS) Project is developing a novel teleconsultation system to expand regional access to clinical experts in disasters. Our objectives were to identify barriers and facilitators to implementation, and determine willingness to use a regional disaster teleconsultation system at a hospital-level in New England. In Spring 2021, we conducted a telephone survey of all New England hospitals and freestanding EDs (hospitals/EDs) using the National ED Inventory-USA database. Key respondents were emergency managers. We collected hospital/ED information about: notification systems for large no-notice emergency events; access to disaster specialists (toxicology, radiation/nuclear medicine, trauma, burn care, high-consequence infectious disease, critical care); disaster credentialing/privileging requirements of teleconsultants before system use; reliability and redundancy of internet/cellular service; and willingness to use a disaster teleconsultation system to access specialists (primary outcome). We report descriptive statistics as preliminary analysis, and plan to test association of willingness to use with hospital/ED characteristics, access to non-disaster telehealth services, and interstate differences with logistic regression models once ≥80% data collection is complete (by ACEP Research Forum). To date, 121 (64%) of 189 New England hospitals/EDs have responded. Most (89%) are notified of large no-notice events via hospital network emergency notification systems activated at the state level. One in four hospitals/EDs lacked any access to burn and toxicology specialists; ≥80% had in-person, telephone or telehealth access to other disaster specialists. Overall, 76 (63%) hospitals/EDs would require disaster credentialing/privileging of teleconsultants prior to system use where 12 (16%) expected to complete this process in <4 hours, 14 (19%) in 4-24 hours, and 38 (51%) in >24 hours. However, 52 (68%) would use a third-party verification system for disaster privileging. Most hospitals/EDs can reliably stream video in clinical spaces (110, 91%) and maintain cellular service despite internet disruption (83, 75%). Overall, 92 (76%) hospitals/ED were somewhat or very likely to use the RDHRS system to access specialists if a no-notice event affected their hospital. Among the 21 hospitals/EDs somewhat or very unlikely to use the system, leading barriers were sufficient access to specialists (33%) and reluctance to use new technology during a disaster (24%); potential time delays (14%), liability (14%), privacy (10%), and hospital information system security restrictions (10%) were infrequent concerns. Most New England hospitals/EDs have the necessary emergency notification systems, telecommunication infrastructure, and willingness to use a regional disaster teleconsultation system, but policies and procedures to speed disaster privileging are needed for implementation.