Regulatory Landscape Research Articles

25 Years of Biologics For The Treatment of Pediatric Rheumatic Diseases - Advances in Prognosis and Ongoing Challenges.

There are over 100 rheumatic diseases and approximately 300,000 children with a pediatric rheumatic disease (PRD) in the United States (U.S.). The most common PRDs are juvenile idiopathic arthritis (JIA), childhood-onset systemic lupus erythematosus (cSLE), and juvenile dermatomyositis (JDM). Effective and safe medications are essential because there are generally no cures for these conditions. Etanercept was the first biologic therapy for the treatment of JIA, approved in 1999. Since then, other biologic disease modifying antirheumatic drugs (bDMARDs) and targeted synthetic DMARD (tsDMARDs) blocking relevant immunological pathways have been approved for the treatment of JIA, resulting in a marked improvement of disease prognosis. Conversely, there is only one bDMARD that has been approved for cSLE, but none are approved for the treatment of JDM. Lack of approved therapeutic options, with established dosing regimens and known efficacy and safety, remains a central challenge in the treatment of all PRDs, including autoinflammatory diseases, and for complications of PRDs. This review provides an overview of bDMARD and tsDMARD treatments studied for the treatment of various subtypes of JIA, summarizes information from bDMARD studies in other pediatric rheumatic diseases, with a focus on pivotal trials that led to regulatory approvals and highlights improved outcomes in JIA with the use of these newer medications. Further, we outline barriers and challenges in the treatment of other PRDs. Lastly, we summarize the current regulatory landscape for bDMARD studies and medication approvals in PRDs.

Strategic initiatives to address greenwashing

AbstractThis article examines the December 2023 report by the International Organisation of Securities Commissions (IOSCO) titled “Supervisory Practices to Address Greenwashing,” alongside the European Union’s regulatory framework aimed at curbing greenwashing in sustainable finance disclosures. Greenwashing—defined as the misrepresentation of sustainability credentials to attract investors—poses significant threats to investor protection and market integrity, potentially leading to a loss of trust in financial providers. Despite efforts by IOSCO and the EU to improve transparency, the persistence of greenwashing is fueled by fragmented regulations, complex disclosure requirements, and the rapid growth of Environmental, Social, and Governance (ESG) investing. This article argues for greater international harmonization, proportionate regulation, and effective enforcement of oversight mechanisms to preserve the credibility of sustainable finance. It highlights the crucial role of global cooperation and national initiatives, specifically those by the Malta Financial Services Authority (MFSA), in addressing these challenges. Structured into four sections—covering the role of IOSCO in the ESG regulatory landscape, EU initiatives for sustainable finance, supervision and enforcement against greenwashing, and MFSA’s local efforts—the article provides a comprehensive review of current ESG investment practices and the ongoing struggle for enhanced transparency and accountability in financial markets.

Optimizing dormant account management in UAE banking: Legal gaps and proposed reforms

The management of dormant accounts and unclaimed balances is a pressing challenge in the banking sector of the United Arab Emirates (UAE), particularly given the complex regulatory landscape. This study analyzes 150 dormant accounts across five major UAE banks (Emirates NBD, First Abu Dhabi Bank, Dubai Islamic Bank, Sharjah Islamic Bank, and Abu Dhabi Commercial Bank) and identifies gaps in the legal framework, including the absence of clear definitions and handling of non-monetary assets.The study investigates the legal framework governing dormant accounts, specifically focusing on the Dormant Accounts System No. 1 of 2020. The results highlight critical issues, including the lack of clear timelines for transferring unclaimed balances and inconsistencies in communication protocols for notifying account holders. Furthermore, the study emphasizes the need for standardized practices across financial institutions in the UAE.To address these challenges, the study proposes legislative amendments to improve asset management and consumer protection. Key recommendations include establishing standardized definitions, implementing automated tracking systems for dormant accounts, and integrating dormant balances into social welfare programs to enhance public trust. These reforms could significantly improve operational efficiency and legal clarity in the UAE banking sector, contributing to a more transparent and effective management of dormant accounts and unclaimed balances. Acknowledgments The authors are thankful to the Deanship of Graduate Studies and Scientific Research at the University of Bisha for supporting this work through the Fast-Track Research Support Program.

Abstract A001: Navigating the future of therapeutic development: innovations in safety and efficacy through advanced research methodologies and nanotechnology

Abstract In recent years, the field of therapeutic development has experienced a significant paradigm shift driven by strategic scientific innovations that prioritize safety and efficacy in therapeutic agents. This paper explores the intersection of advanced research methodologies, novel material sciences, and biotechnological advancements that are revolutionizing the approach to drug formulation and delivery systems. The integration of precision medicine principles alongside cutting-edge technologies allows for the design of therapeutics that are not only effective in targeting specific diseases but are also engineered to minimize adverse effects associated with conventional therapies. One focal point of this exploration is the application of nanotechnology in drug delivery systems. By utilizing nanoparticles, researchers can enhance the bioavailability of therapeutic agents while reducing systemic toxicity. This targeted approach enables the delivery of higher concentrations of drugs to the affected areas, thereby maximizing therapeutic efficacy and minimizing side effects. Additionally, the paper highlights the role of computational modeling and simulations in predicting the interaction of therapeutic agents at the molecular level, facilitating the identification of safer compounds through virtual screening methods. Another significant aspect addressed in this paper is the development of biologics and biosimilars as safer alternatives to traditional synthetic drugs. The advancement of biomanufacturing processes has made it feasible to produce complex molecules with high specificity and reduced immunogenicity, paving the way for innovative therapies that cater to individual patient profiles. Furthermore, the strategic incorporation of pharmacogenomics in drug development allows for the customization of therapeutic agents, ensuring that treatment regimens are tailored to the genetic makeup of patients, which can drastically improve safety and treatment outcomes. The paper also discusses the regulatory landscape surrounding the introduction of these innovative therapeutic agents. It emphasizes the need for adaptive regulatory frameworks that keep pace with scientific advancements while ensuring patient safety and efficacy. Collaborative efforts between researchers, regulatory bodies, and pharmaceutical companies are essential to facilitate the translation of innovative therapies from the laboratory to clinical practice. In conclusion, this paper underscores the critical importance of strategic scientific innovations in the quest for safer therapeutic agents. By harnessing the potential of advanced technologies, researchers can develop therapeutics that not only meet the growing demand for efficacy but also uphold the highest standards of safety, ultimately improving patient care and health outcomes. The findings presented advocate for continued investment in research and collaboration across disciplines to drive future advancements in therapeutic development. Citation Format: Peter O. David. Navigating the future of therapeutic development: innovations in safety and efficacy through advanced research methodologies and nanotechnology. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Optimizing Therapeutic Efficacy and Tolerability through Cancer Chemistry; 2024 Dec 9-11; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(12_Suppl):Abstract nr A001

Insights into lncRNA-mediated regulatory networks in Hevea brasiliensis under anthracnose stress

In recent years, long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) have emerged as critical regulators in plant biology, governing complex gene regulatory networks. In the context of disease resistance in Hevea brasiliensis, the rubber tree, significant progress has been made in understanding its response to anthracnose disease, a serious threat posed by fungal pathogens impacting global rubber tree cultivation and latex quality. While advances have been achieved in unraveling the genetic and molecular foundations underlying anthracnose resistance, gaps persist in comprehending the regulatory roles of lncRNAs and miRNAs under such stress conditions. The specific contributions of these non-coding RNAs in orchestrating molecular responses against anthracnose in H. brasiliensis remain unclear, necessitating further exploration to uncover strategies that increase disease resistance. Here, we integrate lncRNA sequencing, miRNA sequencing, and degradome sequencing to decipher the regulatory landscape of lncRNAs and miRNAs in H. brasiliensis under anthracnose stress. We investigated the genomic and regulatory profiles of differentially expressed lncRNAs (DE-lncRNAs) and constructed a competitive endogenous RNA (ceRNA) regulatory network in response to pathogenic infection. Additionally, we elucidated the functional roles of HblncRNA29219 and its antisense hbr-miR482a, as well as the miR390-TAS3-ARF pathway, in enhancing anthracnose resistance. These findings provide valuable insights into plant-microbe interactions and hold promising implications for advancing agricultural crop protection strategies. This comprehensive analysis sheds light on non-coding RNA-mediated regulatory mechanisms in H. brasiliensis under pathogen stress, establishing a foundation for innovative approaches aimed at enhancing crop resilience and sustainability in agriculture.

The current socioeconomic and regulatory landscape of immune effector cell therapies

Immune cell effector therapies, including chimeric antigen receptor (CAR)-T cells, T-cell receptor (TCR) T cells, natural killer (NK) cells, and macrophage-based therapies, represent a transformative approach to cancer treatment, harnessing the immune system to target and eradicate malignant cells. CAR-T cell therapy, the most established among these, involves engineering T cells to express CARs specific to cancer cell antigens, showing remarkable efficacy in hematologic malignancies like leukemias, B-cell lymphomas, and multiple myeloma. Similarly, TCR-modified therapies, which reprogram T cells to recognize intracellular tumor antigens presented by major histocompatibility complex (MHC) molecules, offer promise for a range of solid tumors. NK-cell therapies leverage NK cells’ innate cytotoxicity, providing an allogeneic approach that avoids some of the immune-related complications associated with T-cell-based therapies. Macrophage-based therapies, still in early stages of the development, focus on reprogramming macrophages to stimulate an immune response against cancer cells in the tumor microenvironment. Despite their promise, socioeconomic and regulatory challenges hinder the accessibility and scalability of immune cell effector therapies. These treatments are costly, with CAR-T therapies currently exceeding $400,000 per patient, creating significant disparities in access based on socioeconomic status and geographic location. The high manufacturing costs stem from the personalized, labor-intensive processes of harvesting, modifying, and expanding patients’ cells. Moreover, complex logistics for manufacturing and delivering these therapies limit their reach, particularly in low-resource settings. Regulatory pathways further complicate the landscape. In the United States., the Food and Drug Administrations’ (FDA) accelerated approval processes for cell-based therapies facilitate innovation but do not address cost-related barriers. In Europe, the European Medicines Agency (EMA) offers adaptive pathways, yet decentralized reimbursement systems create uneven access across member states. Additionally, differing regulatory standards for manufacturing and quality control worldwide pose hurdles for global harmonization and access. To expand the reach of immune effector cell therapies, a multipronged approach is needed—streamlined regulatory frameworks, policies to reduce treatment costs, and international collaborations to standardize manufacturing. Addressing these socioeconomic and regulatory obstacles is essential to make these life-saving therapies accessible to a broader patient population worldwide. We present a literature review on the current landscape of immune effector cell therapies and barriers of access to currently approved standard of care therapy at various levels.

Epigenetic regulation of complement C1Q gene expression

Human C1q is a multifaceted complement protein whose functions range from activating the complement classical pathway to immunomodulation and promoting placental development and tumorigenesis. It is encoded by the C1QA, C1QB, and C1QC genes located on chromosome 1. C1q, unlike most complement components, has extrahepatic expression by a range of cells including macrophages, monocytes and immature dendritic cells. Its local synthesis under the conditions of inflammation and for the purpose of removal of altered self requires its strict transcriptional regulation. To delve into C1Q transcriptional regulation and unravel potential epigenetic influences, we conducted an in silico analysis utilizing a range of online tools and datasets. Co-expression analysis revealed tight coordination between C1QA, C1QB, and C1QC genes. Strikingly, distinct epigenetic patterns emerged across various cell types expressing or lacking these genes, with unique histone marks and DNA methylation status characterizing their regulatory landscape. Notably, the investigation extended to tumor contexts, unveiled potential epigenetic roles in malignancies. The cell type and tumor-specific histone modifications and chromatin accessibility patterns underscore the dynamic nature of epigenetic regulation of C1Q, providing crucial insights into the intricate mechanisms governing the expression of these immunologically significant genes. The findings provide a foundation for future investigations into targeted epigenetic modulation, offering insights into potential therapeutic avenues for immune-related disorders and cancer mediated via C1q.

Regulatory landscape with U.S. patient requirements and Clinical Trial Diversity expectations

The Food and Drug Administration (FDA) has an expectation that products filed for marketing authorization have to include data that are representative of the US patient population. Any foreign clinical data that is submitted has to represent an ethnically diverse population that is generated utilizing qualified Principal Investigators (PIs) and conducted according to Good Clinical Practices (GCP) requirements outlined in 21 CFR 312.120, Foreign clinical studies not conducted under an IND. With the recent passing of the Omnibus Legislation, FDA now also has the authority to require Diversity Plans for all Phase 3 clinical trials of new drugs or “as appropriate, another pivotal study of a new drug.” The FDA has released a guidance document, “Diversity Plans to Improve Enrollment of Participants from Underrepresented Racial and Ethnic Populations in Clinical Trials” (April 2022), for the industry with expectations to update the document in 2023 now that legislation is passed. This whitepaper discusses the FDA guidance and expectations of sponsors with regards to foreign clinical data and the intersection with enrolling ethnically diverse populations in clinical studies.

Design of a Pharmaceutical 3D Printer Using Quality-by-Design Approach

PurposePharmaceutical three-dimensional (3D) printing is an innovative production technique which enables the manufacturing of personalized medicine at the point-of-care. A reliable 3D printer is paramount for the successful implementation in clinical practice. In this paper, the design strategy of a pharmaceutical semi-solid extrusion 3D printer is described, where the concept of quality-by-design is applied.MethodsThe technical design stages are divided in the conceptual design and detailed design stage. The minimal viable product, critical process parameters and implemented control strategies were defined.ResultsThe critical process parameter with the highest impact is the temperature of the cartridge during preheating, i.e. prior to the production process. The temperature is controlled with an accurate thermistor, closed feedback loop and thermal isolation. The temperature can be monitored at all times using the graphical user interface and there is an audit trail using the logging system. Software was developed conforming to GAMP5.ConclusionsBuild-in control strategies in the design of the pharmaceutical 3D printer can mitigate risks during the production process of personalized medicine. The regulatory landscape surrounding 3D-printed drug products remains challenging. By using this design approach, relevant guidelines were taken into account during the design of a pharmaceutical 3D printer. Future development of the 3D printer should include the incorporation of process analytical technology tools and upscaling of feedstock production to further support the implementation of personalized medicine 3D-printed at the point-of-care.

Evaluating Regulatory Compliance In The FinanceAndInvestment Sector:AnAnalysis Of Current Practices, Challenges,And The Impact Of Emerging Technologies

The paper, in assessing the trends, challenges, and the emerging technologies in respect of regulations within finance and investment, notes how the subject-matter of law and finance, with the attribution of power becoming increasingly multidimensional, leads to regulatory scrutiny against banks and other financial institutions, so there must be good mechanisms to deal with compliance. The core findings of the study indicate that while traditional compliance frameworks are cracking, the introduction of technologies, including blockchain and artificial intelligence, would provide offbeat solutions to enhance compliance effectiveness. However, newer technologies introduce an array of challenges as well, including that of data privacy and the need for reinventing the existing legal framework. The study argues for an articulated work linkage between financial institutions and the regulators along with the developers of the technology to build a flexible regulatory landscape which accommodates innovation alongside compliance. The study points towards collaborative efforts involving all stakeholders to ensure technology-enabled solutions are always present on the plate for consideration

Challenges of Environmental Business Practices: A Proposed Sustainable Green Industrial Development Model for Manufacturing Enterprises in Guangdong Province, China

Grounded in Institutional Theory, Resource-Based View (RBV), and Diffusion of Innovation Theory, the study examines how SMEs navigate resource constraints, supply chain management, regulatory frameworks, and awareness gaps in pursuing sustainable green development. The research utilizes a quantitative-descriptive approach with a causal-comparative research design and employs purposive sampling to select 303 SME owners from Guangdong Province, China. Data were collected through a structured survey focusing on business practices like energy-efficient technologies, waste minimization, partnering with environmentally responsible suppliers, water-saving technologies, integrating environmental considerations into product designs, and renewable energy investment and implementing an Environmental Management System (EMS). Findings reveal that SMEs recognize the importance of environmental practices, and they face less challenges in resource allocation, awareness, supply chain management and regulatory landscape.

A comprehensive model for ensuring data compliance in cloud computing environment

As organizations increasingly adopt cloud computing, ensuring data compliance has become a critical priority. Cloud environments pose unique challenges in meeting regulatory requirements due to their distributed and often multi-tenant nature. This review presents a comprehensive model for achieving data compliance in cloud computing, addressing essential aspects such as data privacy, security, sovereignty, and governance. The model emphasizes a structured, layered approach to compliance, integrating risk assessment, data governance, continuous monitoring, and incident management to ensure compliance throughout the data lifecycle. Key components of the proposed model include robust data privacy and protection mechanisms aligned with global regulations such as GDPR and CCPA, data security protocols for safeguarding confidentiality and access control, and data sovereignty policies to handle jurisdictional requirements and cross-border data flows. Additionally, continuous monitoring and automated auditing tools enhance real-time compliance management, while incident management procedures prepare organizations to respond promptly to breaches or policy violations. The framework also incorporates advanced technological solutions, including compliance automation, data loss prevention, and blockchain for traceability, to streamline compliance tasks and improve transparency. By addressing both the technical and governance aspects of data compliance, this model supports organizations in navigating complex regulatory landscapes across multi-cloud and hybrid environments. The review highlights best practices for ensuring compliance, such as regular policy updates, employee training, and third-party compliance management, to sustain long-term adherence. As the regulatory landscape evolves and new privacy-preserving technologies emerge, this model offers a scalable and adaptive approach, positioning organizations to manage data compliance effectively within dynamic cloud infrastructures. This comprehensive approach ensures secure, compliant data operations, fostering trust and accountability in cloud computing environments.

ESG Disclosure Based on Regulatory Landscape: An Enquiry Into the Stock Exchange Enlisted Banks in a Fastest Growing Economy

This research aims to reveal the extent, modes, and trend of ESG disclosure by the banks in Bangladesh. Analyses involve annual reports of 28 banks from 2016 to 2022 through the content analysis method using a ‘checklist’ comprised of 143 ESG disclosure items compiled from several policy guidelines regarding environmental and social performance disclosure circulated by the central bank, Bangladesh Bank. The study finds a spontaneously increasing tendency for ESG disclosure during the study period. Banks disclose information in both financial and non-financial modes, along with necessary details. However, information non-disclosure results in 75.18%, 63.38%, and 67.40% of environmental, social, and governance information, including many important ESG aspects that should not be ignored. The study result represents an optimistic scenario of ESG disclosure; nonetheless, Bangladeshi banks are yet to develop ESG disclosure practices.

Corporate Governance, Internal Control, Risk Management of Cooperative Banks in the Philippines: Inputs to Bank Strategic Improvement Plan

This study evaluated the compliance of Philippine cooperative banks with the governance, internal control, and risk management standards established by the Bangko Sentral ng Pilipinas (BSP). A comprehensive assessment was conducted to examine corporate governance practices in terms of governance structure, board-level committees, and related party transactions; internal control mechanisms focusing on compliance frameworks, internal control frameworks, and internal audit functions; and risk management strategies and practices related to risk identification, risk assessment, and risk management evaluation. Furthermore, the study examined the relationship between corporate governance, internal control, and risk management, proposing a strategic improvement plan based on the findings. The findings revealed that cooperative banks generally adhere to BSP’s governance standards, demonstrating strong practices in governance structures, board-level committees, and related party transactions. Additionally, the banks maintain robust internal control frameworks and rigorous internal audit procedures. While risk management practices are generally effective, areas such as IT and social media risk management require further attention. A significant correlation was observed among corporate governance, internal control, and risk management practices, suggesting that improvements in one area can positively impact the others. Based on these findings, a strategic improvement plan is proposed to enhance the overall effectiveness of cooperative banks. The study recommends continuous improvement of governance structures, investment in advanced monitoring systems for internal controls, and prioritization of risk management improvements, particularly in IT and social media. Future research is suggested to explore the long-term impact of these recommendations on the sustainability and growth of cooperative banks in the evolving regulatory and technological landscape.

Optimizing food transportation processes for grocery stores across the US

In the rapidly evolving landscape of food logistics, optimizing transportation processes for grocery stores across the United States has become paramount to enhancing operational efficiency and ensuring the delivery of high-quality, perishable goods. This article examines the multifaceted challenges inherent in food transportation, including logistical complexities, environmental concerns, and rising operational costs. It highlights the importance of data-driven strategies, such as route optimization and machine learning algorithms, to improve delivery times and reduce waste. Additionally, the integration of advanced technologies, such as Internet of Things (IoT) sensors for temperature monitoring and automation in warehouse management, is explored to enhance the cold chain and ensure food safety. Moreover, the article emphasizes the critical role of strategic partnerships with third-party logistics providers and suppliers in streamlining operations and enhancing overall performance. Through in-depth case studies of successful grocery chains, it illustrates effective practices that have led to significant improvements in food transportation processes. The regulatory landscape surrounding food transportation is also analysed, underscoring compliance with safety standards and sustainability initiatives. Finally, the article looks ahead to future trends, including the potential impact of autonomous vehicles, blockchain technology, and sustainable practices on the food supply chain. By providing a comprehensive overview of best practices and innovative solutions, this article aims to equip grocery store operators and stakeholders with actionable insights to optimize their food transportation processes, ultimately leading to improved customer satisfaction and reduced environmental impact.

Peer-to-peer energy trading: Innovations, regulatory challenges, and the future of decentralized energy systems

Peer-to-peer (P2P) energy trading represents a transformative approach to energy distribution, where consumers, referred to as prosumers, generate and exchange electricity directly with one another. This decentralized model promotes local generation and consumption balancing, reducing reliance on centralized grids and encouraging the use of renewable energy. The development of platforms and technologies, such as blockchain, smart contracts, and Internet of Things (IoT)-)-enabled devices, has enabled secure, transparent, and automated transactions. These innovations facilitate real-time monitoring and energy matching, while artificial intelligence (AI) optimizes pricing and supply-demand dynamics. Microgrids and energy storage solutions further enhance the efficiency and reliability of local energy balancing in P2P systems. However, the widespread adoption of P2P energy trading faces significant regulatory and market challenges. Current regulatory frameworks, designed for traditional, centralized energy markets, often lack provisions for decentralized trading models. Key issues include grid access, tariffs, consumer protection, and data privacy. Furthermore, regulatory barriers differ widely by region, affecting the pace of P2P adoption. Market mechanisms that support P2P energy trading, such as dynamic pricing, demand-response programs, and real-time settlement systems, are also critical for its success. The role of aggregators and intermediaries in facilitating transactions is evolving, as regulatory bodies explore sandbox environments to test these innovative models. This review explores the technological advancements and regulatory landscape shaping P2P energy trading, highlighting successful case studies and identifying future trends. It underscores the need for adaptable policies and robust platforms to unlock the potential of P2P energy trading in building resilient, sustainable, and decentralized energy systems.

State Aid for Green Technologies in The European Union: Limitations and Risks

This article analyzes the recently adopted European Union State aid rules designed to facilitate the implementation of “green” technologies. This initiative is in line with European objectives to combat climate change and transition to an emission-free economy. By contextualizing State aid rules within the broader regulatory policy landscape, the author aims to assess the inherent limitations of these tools. Based on this evaluation, the article attempts to determine if and to what extent EU State aid law can be successfully utilized to promote environmental objectives. The analysis begins with an overview of the State aid toolbox and its role in regulatory policies, situated on a spectrum between incentive-based and obligation-based approaches. Subsequently, it delves into the evaluation of potential consequences, encompassing risks such as the deepening disparities between wealthier and poorer Member States, inadequate safeguards against offshoring in pursuit of lenient environmental norms, and the peril of fostering subsidy dependence.

Two coacting shadow enhancers regulate twin of eyeless expression during early Drosophila development.

The Drosophila PAX6 homolog twin of eyeless (toy) sits at the pinnacle of the genetic pathway controlling eye development, the retinal determination network. Expression of toy in the embryo is first detectable at cellular blastoderm stage 5 in an anterior-dorsal band in the presumptive procephalic neuroectoderm, which gives rise to the primordia of the visual system and brain. Although several maternal and gap transcription factors that generate positional information in the embryo have been implicated in controlling toy, the regulation of toy expression in the early embryo is currently not well characterized. In this study, we adopt an integrated experimental approach utilizing bioinformatics, molecular genetic testing of putative enhancers in transgenic reporter gene assays and quantitative analysis of expression patterns in the early embryo, to identify 2 novel coacting enhancers at the toy gene. In addition, we apply mathematical modeling to dissect the regulatory landscape for toy. We demonstrate that relatively simple thermodynamic-based models, incorporating only 5 TF binding sites, can accurately predict gene expression from the 2 coacting enhancers and that the HUNCHBACK TF plays a critical regulatory role through a dual-modality function as an activator and repressor. Our analysis also reveals that the molecular architecture of the 2 enhancers is very different, indicating that the underlying regulatory logic they employ is distinct.

Paired CRISPR screens to map gene regulation in cis and trans.

Recent massively-parallel approaches to decipher gene regulatory circuits have focused on the discovery of either cis -regulatory elements (CREs) or trans -acting factors. Here, we develop a scalable approach that pairs cis - and trans -regulatory CRISPR screens to systematically dissect how the key immune checkpoint PD-L1 is regulated. In human pancreatic ductal adenocarcinoma (PDAC) cells, we tile the PD-L1 locus using ∼25,000 CRISPR perturbations in constitutive and IFNγ-stimulated conditions. We discover 67 enhancer- or repressor-like CREs and show that distal CREs tend to contact the promoter of PD-L1 and related genes. Next, we measure how loss of all ∼2,000 transcription factors (TFs) in the human genome impacts PD-L1 expression and, using this, we link specific TFs to individual CREs and reveal novel PD-L1 regulatory circuits. For one of these regulatory circuits, we confirm the binding of predicted trans -factors (SRF and BPTF) using CUT&RUN and show that loss of either the CRE or TFs potentiates the anti-cancer activity of primary T cells engineered with a chimeric antigen receptor. Finally, we show that expression of these TFs correlates with PD-L1 expression in vivo in primary PDAC tumors and that somatic mutations in TFs can alter response and overall survival in immune checkpoint blockade-treated patients. Taken together, our approach establishes a generalizable toolkit for decoding the regulatory landscape of any gene or locus in the human genome, yielding insights into gene regulation and clinical impact.

Beyond the ‘spaghetti bowl’: assessing the role of the AfCFTA Protocol on Intellectual Property in Africa’s complex regulatory environment

Abstract For decades, international IP frameworks have been criticized for neglecting forms of IP, such as traditional knowledge, that are crucial to middle- and low-income economies but often do not conform to the global standards set by Western conceptions of IP. This oversight continues to shape IP policy development even in African countries, many of which struggle to create IP policies that align with their unique economic and developmental needs. In response to these challenges and driven by an expressed commitment to fostering and safeguarding African innovation and forms of IP, 54 African nations have recently adopted an IP Protocol to the African Continental Free Trade Agreement (AfCFTA). However, given the continent’s already fragmented IP regulatory landscape, this article questions whether the AfCFTA Protocol on IP (AfCFTA IP Protocol) can successfully foster the development of frameworks that reflect Africa’s distinctive socio-economic realities and priorities. This article evaluates the protocol in relation to previous attempts at continental IP harmonization efforts in Africa and examines the extent to which the AfCFTA IP Protocol can be deployed to achieve its stated goals of IP harmonization on the continent. While the AfCFTA IP Protocol is a positive initiative, its introduction and adoption may be somewhat premature, given the continent’s ‘spaghetti bowl’ of IP regulations.