Ethics of AI in Pathology: Current Paradigms and Emerging Issues.

Deep learning has rapidly advanced artificial intelligence (AI) and algorithmic decision-making (ADM) paradigms, affecting many traditional fields of medicine, including pathology, which is a heavily data-centric specialty of medicine. The structured nature of pathology data repositories makes it highly attractive to AI researchers to train deep learning models to improve health care delivery. Additionally, there are enormous financial incentives driving adoption of AI and ADM due to promise of increased efficiency of the health care delivery process. AI, if used unethically, may exacerbate existing inequities of health care, especially if not implemented correctly. There is an urgent need to harness the vast power of AI in an ethically and morally justifiable manner. This review explores the key issues involving AI ethics in pathology. Issues related to ethical design of pathology AI studies and the potential risks associated with implementation of AI and ADM within the pathology workflow are discussed. Three key foundational principles of ethical AI: transparency, accountability, and governance, are described in the context of pathology. The future practice of pathology must be guided by these principles. Pathologists should be aware of the potential of AI to deliver superlative health care and the ethical pitfalls associated with it. Finally, pathologists must have a seat at the table to drive future implementation of ethical AI in the practice of pathology.

Understanding Lung Development, Injury, and Repair.

This Editorial introduces the Lung Ontogeny and Injury Theme Issue, which provides critical insights into lung development, injury, and repair as well as key pulmonary diseases.

Histone recognition and nuclear receptor co-activator functions of Drosophila cara mitad, a homolog of the N-terminal portion of mammalian MLL2 and MLL3.

MLL2 and MLL3 histone lysine methyltransferases are conserved components of COMPASS-like co-activator complexes. In vertebrates, the paralogous MLL2 and MLL3 contain multiple domains required for epigenetic reading and writing of the histone code involved in hormone-stimulated gene programming, including receptor-binding motifs, SET methyltransferase, HMG and PHD domains. The genes encoding MLL2 and MLL3 arose from a common ancestor. Phylogenetic analyses reveal that the ancestral gene underwent a fission event in some Brachycera dipterans, including Drosophila species, creating two independent genes corresponding to the N- and C-terminal portions. In Drosophila, the C-terminal SET domain is encoded by trithorax-related (trr), which is required for hormone-dependent gene activation. We identified the cara mitad (cmi) gene, which encodes the previously undiscovered N-terminal region consisting of PHD and HMG domains and receptor-binding motifs. The cmi gene is essential and its functions are dosage sensitive. CMI associates with TRR, as well as the EcR-USP receptor, and is required for hormone-dependent transcription. Unexpectedly, although the CMI and MLL2 PHDf3 domains could bind histone H3, neither showed preference for trimethylated lysine 4. Genetic tests reveal that cmi is required for proper global trimethylation of H3K4 and that hormone-stimulated transcription requires chromatin binding by CMI, methylation of H3K4 by TRR and demethylation of H3K27 by the demethylase UTX. The evolutionary split of MLL2 into two distinct genes in Drosophila provides important insight into distinct epigenetic functions of conserved readers and writers of the histone code.

The Drosophila COMPASS-like Cmi-Trr coactivator complex regulates dpp/BMP signaling in pattern formation.

Drosophila Cara Mitad (Cmi, also known as Lpt) is the N-terminal homolog of mammalian Mixed Lineage Leukemia 2 (MLL2/ALR), a core component of COMPASS-like nuclear receptor coactivator complexes. Cmi is required for the activation of ecdysone hormone targets and plays a critical role in development and tissue patterning. Using multiple approaches that include genetic interaction tests and tissue specific knockdown and overexpression of cmi, we demonstrate that Cmi has important functions in controlling wing vein patterning through regulation of the conserved Decapentaplegic (Dpp) signaling pathway. The loss of function allele, cmi(1), enhances loss of dpp function phenotypes in genetic epistasis tests. Wing specific knockdown of cmi results in incomplete veins towards the distal wing margin that are enhanced by the simultaneous knockdown of dpp. In contrast, the overexpression of a tagged full-length HA-cmi transgene results in ectopic veins that are sensitive to Dpp levels. The knockdown and overexpression of cmi result in reduced and increased Dpp signaling as observed by immunostaining for phospho-MAD (Mother against DPP), a downstream effector of Dpp function. shRNAi depletion of cmi suppresses a tkv reduced function phenotype while the overexpression of HA-cmi enhances tkv RNAi phenotypes. We further show by enhancer reporter assays and chromatin immunoprecipitation that Cmi controls wing vein patterning by regulating dpp transcription directly or indirectly through the 3' disc regulatory region at the larval stage and through the 5' shortvein (shv) regulatory region at the pupal stage. Our data reveals that Cmi is a key part of the mechanism that controls wing vein patterning through nuclear receptor regulation of the Dpp signaling pathway.

Stem cells in the Drosophila digestive system.

Adult stem cells maintain tissue homeostasis by continuously replenishing damaged, aged and dead cells in any organism. Five types of region and organ-specific multipotent adult stem cells have been identified in the Drosophila digestive system: intestinal stem cells (ISCs) in the posterior midgut; hindgut intestinal stem cells (HISCs) at the midgut/hindgut junction; renal and nephric stem cells (RNSCs) in the Malpighian Tubules; type I gastric stem cells (GaSCs) at foregut/midgut junction; and type II gastric stem cells (GSSCs) at the middle of the midgut. Despite the fact that each type of stem cell is unique to a particular organ, they share common molecular markers and some regulatory signaling pathways. Due to the simpler tissue structure, ease of performing genetic analysis, and availability of abundant mutants, Drosophila serves as an elegant and powerful model system to study complex stem cell biology. The recent discoveries, particularly in the Drosophila ISC system, have greatly advanced our understanding of stem cell self-renewal, differentiation, and the role of stem cells play in tissue homeostasis/regeneration and adaptive tissue growth.

Pathology Education Powered by Virtual and Digital Transformation: Now and the Future.

CONTEXT.­: Myriad forces are changing teaching and learning strategies throughout all stages and types of pathology education. Pathology educators and learners face the challenge of adapting to and adopting new methods and tools. The digital pathology transformation and the associated educational ecosystem are major factors in this setting of change. OBJECTIVE.­: To identify and collect resources, tools, and examples of educational innovations involving digital pathology that are valuable to pathology learners and teachers at each phase of professional development. DATA SOURCES.­: Sources were a literature review and the personal experience of authors and educators. CONCLUSIONS.­: High-quality digital pathology tools and resources have permeated all the major niches within anatomic pathology and are increasingly well applied to clinical pathology for learners at all levels. Coupled with other virtual tools, the training landscape in pathology is highly enriched and much more accessible than in the past. Digital pathology is well suited to the demands of peer-to-peer education, such as in the introduction of new testing, grading, or other standardized practices. We found that digital pathology was well adapted to apply our current understanding of optimal teaching strategies and was effective at the undergraduate, graduate, postgraduate, and peer-to-peer levels. We curated and tabulated many existing resources within some segments of pathology. We identified several best practices for each training or educational stage based on current materials and proposed high-priority areas for potential future development.

Rules of engagement: Promoting academic-industry partnership in the era of digital pathology and artificial intelligence.

Academic industry partnership (AIP) represents an important alliance between academic researchers and industry that helps translate technology and complete the innovation cycle within academic health systems. Despite diverging missions and skillsets the culture for academia and industry is changing in response to the current digital era which is spawning greater collaboration between physicians and businesses in this marketplace. In the field of pathology, this is further driven by the fact that traditional funding sources cannot keep pace with the innovation needed in digital pathology and artificial intelligence. This concept article from the Digital Pathology Association (DPA) describes the rules of engagement for pathology innovators in academia and for their corporate partners to help establish best practices in this critical area. Stakeholders include pathologists, basic and translational researchers, university technology transfer and sponsored research offices, as well as industry relations officers. The article discusses the benefits and pitfalls of an AIP, reviews different partnership models, examines the role of pathologists in the innovation cycle, explains various agreements that may need to be signed, covers conflict of interest and intellectual property issues, and offers recommendations for ensuring successful partnerships.

Spermatogonial stem cells, infertility and testicular cancer.

The spermatogonial stem cells (SSCs) are responsible for the transmission of genetic information from an individual to the next generation. SSCs play critical roles in understanding the basic reproductive biology of gametes and treatments of human infertility. SSCs not only maintain normal spermatogenesis, but also sustain fertility by critically balancing both SSC self-renewal and differentiation. This self-renewal and differentiation in turn is tightly regulated by a combination of intrinsic gene expression within the SSC as well as the extrinsic gene signals from the niche. Increased SSCs self-renewal at the expense of differentiation result in germ cell tumours, on the other hand, higher differentiation at the expense of self-renewal can result in male sterility. Testicular germ cell cancers are the most frequent cancers among young men in industrialized countries. However, understanding the pathogenesis of testis cancer has been difficult because it is formed during foetal development. Recent studies suggest that SSCs can be reprogrammed to become embryonic stem (ES)-like cells to acquire pluripotency. In the present review, we summarize the recent developments in SSCs biology and role of SSC in testicular cancer. We believe that studying the biology of SSCs will not only provide better understanding of stem cell regulation in the testis, but eventually will also be a novel target for male infertility and testicular cancers.

Characterization of midgut stem cell- and enteroblast-specific Gal4 lines in drosophila.

The homeostasis of Drosophila midgut is maintained by multipotent intestinal stem cells (ISCs), each of which gives rise to a new ISC and an immature daughter cell, enteroblast (EB), after one asymmetric cell division. In Drosophila, the Gal4-UAS system is widely used to manipulate gene expression in a tissue- or cell-specific manner, but in Drosophila midgut, there are no ISC- or EB-specific Gal4 lines available. Here we report the generation and characterization of Dl-Gal4 and Su(H)GBE-Gal4 lines, which are expressed specifically in the ISCs and EBs separately. Additionally, we demonstrate that Dl-Gal4 and Su(H)GBE-Gal4 are expressed in adult midgut progenitors (AMPs) and niche peripheral cells (PCs) separately in larval midgut. These two Gal4 lines will serve as invaluable tools for navigating ISC behaviors.

Navigating the Peer Review Process.

This editorial provides insights and guidelines for publishing in The Journal of Molecular Diagnostics.