Early Developmental Processes Research Articles

Abstract 1389: In vitro killing assays for evaluation of immuno-oncology drug candidates

Abstract The need to better understand the tumor microenvironment (TME) dictates the characterization of the cell types involved, the roles they play and how they respond to treatment. To develop novel cancer immunotherapies, in vitro primary immune cell bioassays offer an early assessment of their effects on the various players of the TME. Cytotoxic cells are key players in the anti-tumor immune response. CD8+ T cells, also known as cytotoxic T lymphocytes, recognize and kill cells presenting antigens bound to MHC class I molecules, such as neoantigens present on the tumor cell surface. Activation of CD8+ T cells requires at least two signals from antigen presenting cells: binding of their T cell receptor (TCR) to the appropriate peptide presented on MHC I and co-stimulation by B7 binding to CD28. However, the TME possesses several mechanisms to reduce immune cell activity, such as the expression of checkpoint inhibitors dampening the immune system. Natural killer (NK) cells represent another type of cytotoxic cells, with their innate immune activity dictating an important role in anti-tumor immunity. NK cells induce apoptosis via the release of perforin and granzymes from granules, eliminating cells lacking expression MHC I, including cancer cells that have lost expression of MHC I. However, also the activity of NK cells can be hampered in the TME, notably by the PD1/PDL1 interaction.Increasing the activity of CD8+ T and NK cells as a therapeutic anti-tumor strategy has become an important point of attention. Such strategies can have several shapes, with Antibody-dependent cell-mediated cytotoxicity (ADCC) activity of IgG1 isotypes being one of the mechanisms that can be exploited by immunoglobulin-based therapeutics. Another way to increase the killing of tumor cells is to re-direct T cells to tumor cells by employing bi-specific antibodies targeting specific tumor associated antigens. Using this strategy, T cell activation can be concentrated in the TME, thereby also avoiding off-tumor activity. Real-time in vitro assessment of the potential enhanced killing capacity of CD8+ T and NK cells elicited by test molecules could further provide pivotal information on the functional dynamics of test molecules. Using high quality primary human immune cells, in vitro bioassays were developed with improved robustness and reproducibility to screen for the potential to enhance tumor cell killing by novel therapeutics. The ability to evaluate the compounds capacity to increase or induce a cytotoxic activity profile and thereby facilitate the anti-tumor immune response is essential in the early drug development process. Citation Format: Johan Arnold, Thibaut J. Janss, Simon Lefevre, Martijn Vlaming, Ellen Boelen, Sofie Pattijn. In vitro killing assays for evaluation of immuno-oncology drug candidates [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1389.

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Impact considerations of post-production processes on cell and gene drug products

Cell and gene therapies are demonstrating clinical efficacy, but prohibitive product costs and operational complexity bottlenecks may limit expanded patient access to these innovative and transformative products. An initial survey and subsequent article published through the International Society for Cell & Gene Therapy in 2017 presented a roadmap on how specific steps, from tissue procurement and material acquisition to facility operation and production, contribute to the high cost of cell and gene therapies. Herein the authors expanded the investigation to provide considerations to better understand how post-production procedures can impact a product's accessibility to patients. The administration of a drug product to and follow-up in a patient involve key decisions in several post-production process areas, such as product storage, distribution and handling logistics and compliance, across the value chain through integrated data management solutions. Understanding as well as carefully evaluating these specific components is not widely considered during early process development but is critical in developing a viable product life cycle.

Transcriptome Sequencing Analysis Reveals Dynamic Changes in Major Biological Functions during the Early Development of Clearhead Icefish, Protosalanx chinensis

Early development, when many important developmental events occur, is a critical period for fish. However, research on the early development of clearhead icefish is very limited, especially in molecular research. In this study, we aimed to explore the dynamic changes in the biological functions of five key periods in clearhead icefish early development, namely the YL (embryonic), PM (first day after hatching), KK (fourth day after hatching), LC (seventh day after hatching), and SL (tenth day after hatching) stages, through transcriptome sequencing and different analysis strategies. A trend expression analysis and an enrichment analysis revealed that the expression ofgenes encoding G protein-coupled receptors and their ligands, i.e., prss1_2_3, pomc, npy, npb, sst, rln3, crh, gh, and prl that are associated with digestion and feeding regulation gradually increased during early development. In addition, a weighted gene co-expression network analysis (WGCNA) showed that eleven modules were significantly associated with early development, among which nine modules were significantly positively correlated. Through the enrichment analysis and hub gene identification results of these nine modules, it was found that the pathways related to eye, bone, and heart development were significantly enriched in the YL stage, and the ccnd2, seh1l, kdm6a, arf4, and ankrd28 genes that are associated with cell proliferation and differentiation played important roles in these developmental processes; the pak3, dlx3, dgat2, and tas1r1 genes that are associated with jaw and tooth development, TG (triacylglycerol) synthesis, and umami amino acid receptors were identified as hub genes for the PM stage; the pathways associated with aerobic metabolism and unsaturated fatty acid synthesis were significantly enriched in the KK stage, with the foxk, slc13a2_3_5, ndufa5, and lsc2 genes playing important roles; the pathways related to visual perception were significantly enriched in the LC stage; and the bile acid biosynthetic and serine-type peptidase activity pathways were significantly enriched in the SL stage. These results provide a more detailed understanding of the processes of early development of clearhead icefish.

Hinge point emergence in mammalian spinal neurulation

Neurulation is the process in early vertebrate embryonic development during which the neural plate folds to form the neural tube. Spinal neural tube folding in the posterior neuropore changes over time, first showing a median hinge point, then both the median hinge point and dorsolateral hinge points, followed by dorsolateral hinge points only. The biomechanical mechanism of hinge point formation in the mammalian neural tube is poorly understood. Here we employ a mechanical finite element model to study neural tube formation. The computational model mimics the mammalian neural tube using microscopy data from mouse and human embryos. While intrinsic curvature at the neural plate midline has been hypothesized to drive neural tube folding, intrinsic curvature was not sufficient for tube closure in our simulations. We achieved neural tube closure with an alternative model combining mesoderm expansion, nonneural ectoderm expansion, and neural plate adhesion to the notochord. Dorsolateral hinge points emerged in simulations with low mesoderm expansion and zippering. We propose that zippering provides the biomechanical force for dorsolateral hinge point formation in settings where the neural plate lateral sides extend above the mesoderm. Together, these results provide a perspective on the biomechanical and molecular mechanism of mammalian spinal neurulation.

Development of a miniature bioreactor model to study the impact of pH and DOT fluctuations on CHO cell culture performance as a tool to understanding heterogeneity effects at large-scale.

Understanding the impact of spatial heterogeneities that are known to occur in large‐scale cell culture bioreactors remains a significant challenge. This work presents a novel methodology for mimicking the effects of pH and dissolved oxygen heterogeneities on Chinese hamster ovary (CHO) cell culture performance and antibody quality characteristics, using an automated miniature bioreactor system. Cultures of 4 different cell lines, expressing 3 IgG molecules and one fusion protein, were exposed to repeated pH and dissolved oxygen tension (DOT) fluctuations between pH 7.0–7.5 and DOT 10%–30%, respectively, for durations of 15, 30, and 60 min. Fluctuations in pH had a minimal impact on growth, productivity, and product quality although some changes in lactate metabolism were observed. DOT fluctuations were found to have a more significant impact; a 35% decrease in cell growth and product titre was observed in the fastest growing cell line tested, while all cell lines exhibited a significant increase in lactate accumulation. Product quality analysis yielded varied results; two cell lines showed an increase in the G0F glycan and decrease in G1F, G2F, and Man5; however, another line showed the opposite trend. The study suggests that the response of CHO cells to the effects of fluctuating culture conditions is cell line specific and that higher growing cell lines are most impacted. The miniature bioreactor system described in this work therefore provides a platform for use during early stage cell culture process development to identify cell lines that may be adversely impacted by the pH and DOT heterogeneities encountered on scale‐up. This experimental data can be combined with computational modeling approaches to predict overall cell culture performance in large‐scale bioreactors.

Understanding the Role of the Gut Microbiome in Brain Development and Its Association With Neurodevelopmental Psychiatric Disorders.

The gut microbiome has a tremendous influence on human physiology, including the nervous system. During fetal development, the initial colonization of the microbiome coincides with the development of the nervous system in a timely, coordinated manner. Emerging studies suggest an active involvement of the microbiome and its metabolic by-products in regulating early brain development. However, any disruption during this early developmental process can negatively impact brain functionality, leading to a range of neurodevelopment and neuropsychiatric disorders (NPD). In this review, we summarize recent evidence as to how the gut microbiome can influence the process of early human brain development and its association with major neurodevelopmental psychiatric disorders such as autism spectrum disorders, attention-deficit hyperactivity disorder, and schizophrenia. Further, we discuss how gut microbiome alterations can also play a role in inducing drug resistance in the affected individuals. We propose a model that establishes a direct link of microbiome dysbiosis with the exacerbated inflammatory state, leading to functional brain deficits associated with NPD. Based on the existing research, we discuss a framework whereby early diet intervention can boost mental wellness in the affected subjects and call for further research for a better understanding of mechanisms that govern the gut-brain axis may lead to novel approaches to the study of the pathophysiology and treatment of neuropsychiatric disorders.

Genetic variants associated with longitudinal changes in brain structure across the lifespan.

Human brain structure changes throughout the lifespan. Altered brain growth or rates of decline are implicated in a vast range of psychiatric, developmental and neurodegenerative diseases. In this study, we identified common genetic variants that affect rates of brain growth or atrophy in what is, to our knowledge, the first genome-wide association meta-analysis of changes in brain morphology across the lifespan. Longitudinal magnetic resonance imaging data from 15,640 individuals were used to compute rates of change for 15 brain structures. The most robustly identified genes GPR139, DACH1 and APOE are associated with metabolic processes. We demonstrate global genetic overlap with depression, schizophrenia, cognitive functioning, insomnia, height, body mass index and smoking. Gene set findings implicate both early brain development and neurodegenerative processes in the rates of brain changes. Identifying variants involved in structural brain changes may help to determine biological pathways underlying optimal and dysfunctional brain development and aging.

PlatypOUs-A Mobile Robot Platform and Demonstration Tool Supporting STEM Education.

Given the rising popularity of robotics, student-driven robot development projects are playing a key role in attracting more people towards engineering and science studies. This article presents the early development process of an open-source mobile robot platform—named PlatypOUs—which can be remotely controlled via an electromyography (EMG) appliance using the MindRove brain–computer interface (BCI) headset as a sensor for the purpose of signal acquisition. The gathered bio-signals are classified by a Support Vector Machine (SVM) whose results are translated into motion commands for the mobile platform. Along with the physical mobile robot platform, a virtual environment was implemented using Gazebo (an open-source 3D robotic simulator) inside the Robot Operating System (ROS) framework, which has the same capabilities as the real-world device. This can be used for development and test purposes. The main goal of the PlatypOUs project is to create a tool for STEM education and extracurricular activities, particularly laboratory practices and demonstrations. With the physical robot, the aim is to improve awareness of STEM outside and beyond the scope of regular education programmes. It implies several disciplines, including system design, control engineering, mobile robotics and machine learning with several application aspects in each. Using the PlatypOUs platform and the simulator provides students and self-learners with a firsthand exercise, and teaches them to deal with complex engineering problems in a professional, yet intriguing way.

Synthesis design using mass related metrics, environmental metrics, and health metrics

AbstractThe efforts to integrate environmental aspects, health aspects as well as safety aspects into chemical production has led to the development of measurable and thus objectifying metrics. The application of these metrics is considered to be most promising, especially during the earliest phases of synthesis design. However, the operability in daily work suffers from the lack of available data, or a large variety of data, and the complexity of data processing. If a life cycle assessment is not practical in the early development phase, environmental factor and process mass intensity can give a quick and reliable overview. I will show that this often says the same in advance as a subsequently prepared life cycle assessment. Readers will realise that, based on preparative descriptions, they can quickly determine these metrics for individual syntheses or extensive synthesis sequences applying the available software support. Environmental relevance in terms of persistence, bioaccumulation and toxicity (PBT) can be presented using a modification of the European ranking method ‘DART’ (Decision Analysis by Ranking Techniques). Based on corresponding PBT data, readers can determine a hazard score between 0 and 1 for any substance using the spreadsheet file provided, with which the mass of (potentially emitted) substances can be weighted. Occupational health can be represented using a modification of the recognized ‘Stoffenmanager’. Both concepts are presented and spreadsheet files are offered. This article is based on a presentation which was given at the Green Chemistry Postgraduate Summer School in Venice, 6th–10thJuly 2020.

Protective Effect of Minocycline Hydrochloride on the Mouse Embryonic Development Against Suboptimal Environment.

Numerous studies have reported how inner cell mass (ICM) and trophectoderm (TE) was determined during the process of early mouse embryonic development from zygotes into organized blastocysts, however, multiple mysteries still remain. It is noteworthy that pluripotent stem cells (PSCs), which are derived from embryos at different developmental stages, have identical developmental potential and molecular characteristics to their counterpart embryos. Advances of PSCs research may provide us a distinctive perspective of deciphering embryonic development mechanism. Minocycline hydrochloride (MiH), a critical component for maintaining medium of novel type of extended pluripotent stem cells, which possesses developmental potential similar to both ICM and TE, can be substituted with genetic disruption of Parp1 in our previous study. Though Parp1-deficient mouse ESCs are more susceptible to differentiate into trophoblast derivatives, what role of MiH plays in mouse preimplantation embryonic development is still a subject of concern. Here, by incubating mouse zygotes in a medium containing MiH till 100 h after fertilization, we found that MiH could slow down embryonic developmental kinetics during cleavage stage without impairing blastocyst formation potential. Olaparib and Talazoparib, two FDA approved PARP1 inhibitors, exhibited similar effects on mouse embryos, indicating the aforementioned effects of MiH were through inhibiting of PARP1. Besides, we showed an embryonic protective role of MiH against suboptimal environment including long term exposure to external environment and H2O2 treatment, which could mimic inevitable manipulation during embryo culture procedures in clinical IVF laboratory. To our knowledge, it is not only for the first time to study MiH in the field of embryo development, but also for the first time to propose MiH as a protective supplement for embryo culture, giving the way to more studies on exploring the multiple molecular mechanisms on embryonic development that might be useful in assisted reproductive technology.

Investigation of Chloroquine Resinate Feasibility and In Vitro Taste Masking Evaluation for Pediatric Formulations.

In this study, chloroquine resinates were prepared at a 1:1 (w:w) drug-to-resin ratio using the batch method with polacrilex (PC), sodium polystyrene sulfonate (SPS), and polacrilin potassium (PP) ion exchange resins (IER). The influence of drug/resin ratio and pH of the medium on drug loading efficiency was explored. UV-VIS spectrophotometric analysis showed that SPS resin had high loading efficiency for chloroquine diphosphate (CLP), above 89%, regardless of the pH. PP resin was more effective at pH 5.0 (90.68%) than at pH 1.0 (2.09%), and PC resin had only 27.63% of CLP loading efficiency. CLP complexation with IER yielded amorphous mixtures according to results from differential scanning calorimetry (DSC) and X-ray powder diffraction (XRPD), thus indicating drug-resin interaction. The taste masking efficiency was evaluated with in vitro methods using an adapted dissolution test and an electronic tongue system. During dissolution tests, SPS released only 1.0% of CLP after 300 s, while PP released over 10% after 90 s in simulated saliva solution. The electronic tongue distinguished the samples containing CLP, resins, and resinates by using multidimensional projection techniques that indicated an effective drug taste masking. In an accelerated stability study, the drug contents did not decrease in chloroquine resinates, and there was no physical degradation of the resinates after 60 days. Using chloroquine resinates therefore represents a novel way to evaluate taste masking in vitro which is relevant for the early formulation development process.

Advances in Continuous Flow Calorimetry

Calorimetric data from chemical reactions such as reaction enthalpy, adiabatic temperature rise, and activation energy are essential for reaction safety and scale-up from laboratory investigations to reactor design and operation. Typically, these data are gained from batch calorimeters with sophisticated setups and elaborate measurement procedures. Continuous flow calorimeters, compared with batch setups, have different mixing and heat transfer characteristics and enable harsh reaction conditions, particularly within microstructured reactors with their enhanced heat transfer capability. This review provides an overview of currently investigated and applied flow calorimeters in research and development in relation to existing concepts. Novel approaches for heat flux measurements as well as integrated sensors are presented. Safety aspects of flow chemistry are a main driver, but additionally, low material consumption is important in early process development. Limitations of the concepts are presented with a comprehensive literature overview of flow calorimetry to show that continuous flow calorimeters form a new tool in process development and safety engineering, particularly with microstructured devices and novel sensing techniques.

Microtubular TRIM36 E3 Ubiquitin Ligase in Embryonic Development and Spermatogenesis.

TRIM36 is a member of the tripartite motif (TRIM) family of RING-containing proteins, also known as Haprin, which was first discovered for its abundance in testis and found to be implicated in the spermatozoa acrosome reaction. TRIM36 is a microtubule-associated E3 ubiquitin ligase that plays a role in cytoskeletal organization, and according to data gathered in different species, coordinates growth speed and stability, acting on the microtubules’ plus end, and impacting on cell cycle progression. TRIM36 is also crucial for early developmental processes, in Xenopus, where it is needed for dorso-ventral axis formation, but also in humans as bi-allelic mutations in the TRIM36 gene cause a form of severe neural tube closure defect, called anencephaly. Here, we review TRIM36-related mechanisms implicated in such composite physiological and pathological processes.

Circumventing Zygotic Lethality to Generate Maternal Mutants in Zebrafish.

Simple SummaryMaternal gene products accumulated during oogenesis as mRNAs and proteins, which are referred to as maternal contributions, play essential roles in proper development before and after the transcription of the zygotic genome. Zebrafish represent an attractive model for the systematic characterization of genetic mutants using the CRISPR/Cas9 genome editing technology. The traditional approach for generating maternal mutants to study the functions of maternal gene products consists of creating founder fish with germ-line transmission of mutated genes, followed by successive crossing to obtain zygotic homozygous mutant females, which can produce offspring lacking the corresponding maternal gene products. This is time-consuming and normally requires three generations. Nevertheless, zygotic mutations of many genes often lead to embryonic lethality or adult sterility, making it impossible to study their maternal functions. Different approaches were used to overcome this difficulty and allowed for the characterization of several important maternal-effect genes. However, they are often technically challenging or lack versatile applications. Recently, an oocyte-specific knockout strategy has been developed, which inactivates genes of interest in the developing oocytes. It is particularly accessible, generating maternal mutants in one fish generation. By further improving its efficiency, this method can be used for the large-scale analysis of maternal gene functions.Maternal gene products accumulated during oogenesis are essential for supporting early developmental processes in both invertebrates and vertebrates. Therefore, understanding their regulatory functions should provide insights into the maternal control of embryogenesis. The CRISPR/Cas9 genome editing technology has provided a powerful tool for creating genetic mutations to study gene functions and developing disease models to identify new therapeutics. However, many maternal genes are also essential after zygotic genome activation; as a result, loss of their zygotic functions often leads to lethality or sterility, thus preventing the generation of maternal mutants by classical crossing between zygotic homozygous mutant adult animals. Although several approaches, such as the rescue of mutant phenotypes through an injection of the wild-type mRNA, germ-line replacement, and the generation of genetically mosaic females, have been developed to overcome this difficulty, they are often technically challenging and time-consuming or inappropriate for many genes that are essential for late developmental events or for germ-line formation. Recently, a method based on the oocyte transgenic expression of CRISPR/Cas9 and guide RNAs has been designed to eliminate maternal gene products in zebrafish. This approach introduces several tandem guide RNA expression cassettes and a GFP reporter into transgenic embryos expressing Cas9 to create biallelic mutations and inactivate genes of interest specifically in the developing oocytes. It is particularly accessible and allows for the elimination of maternal gene products in one fish generation. By further improving its efficiency, this method can be used for the systematic characterization of maternal-effect genes.

Using a process simulation platform for reviewing automated airport baggage handling system configurations

The use of digital manufacturing platforms is becoming increasingly important since they facilitate process visualisation, optimisation, and validation, allowing engineers to make informed decisions at early product and process development phases. In this paper, the potential of using process simulation platforms is explored in order to visualise and validate baggage handling processes involving robotic handling systems and human operators. Multiple baggage handling layout configurations are digitally constructed and reviewed with the aim to investigate cost, time, and flexibility performance indicators. Furthermore, the advantages of using digital manufacturing and process simulation platforms are discussed.

O impacto do desenvolvimento da consciência fonológica na aprendizagem da leitura de jovens e adultos

The article presents results of a research about the infl uence of a teaching phonological awareness skills and grapheme phoneme correspondences program and its impact over adults and young people who where in diff erent stages of learning skills acquirement proposed by Linnea Ehri. Nine students, from an early literacy class at a Youth and Adult Education Center in the city of Rio do Sul – SC - Brazil, were subjects of this study. The intervention research, methodologically applied, was the application of a teaching program which aimed to contribute to the development of the aforementioned skills and knowledge, and two assessments applied at the program beginning and when fi nishing. The qualitative and quantitative analysis data results found shows that after the intervention the research subjects experienced a performance boost on phonological awareness skills, graphemes recognition and reading at all learning stages, especially those who were in transition from the partial alphabetic phase to the alphabetic phase complete. These results suggest that pedagogical practices that promote the graphophonemic correspondences and the phonological awareness development, especially phonemic awareness teaching, can be benefi cial for the reading in young people and adults in the early literacy development process

Centering Lived Experience in Developing Digital Interventions for Suicide and Self-injurious Behaviors: User-Centered Design Approach.

BackgroundThe prevalence of self-injurious thoughts and behaviors (SITB) signals a growing public health crisis. Despite a recognized need for improved and scalable interventions, the field of SITB intervention faces several challenges: existing interventions are often time and resource intensive, most individuals with SITB do not seek formal mental health care, and efficacious treatments are characterized by small effects. Combined, these challenges indicate a need for improved SITB interventions for individuals in formal treatment and those who are not treatment engaged but are at high risk of worsening mental health and future suicide attempts.ObjectiveWe present a methodological approach and set of techniques that may address these challenges by centering the lived experience of individuals with SITB in the process of developing needed services: user-centered design (UCD).MethodsWe highlight the value of UCD in the context of digital interventions for SITB by describing the UCD approach and explicating how it can be leveraged to include lived experience throughout the development and evaluation process. We provide a detailed case example highlighting 3 phases of the early development process that can be used to design an intervention that is engaging and meets end-user needs. In addition, we point to novel applications of UCD to complement new directions in SITB research.ResultsIn this paper, we offer a 2-pronged approach to meet these challenges. First, in terms of addressing access to effective interventions, digital interventions hold promise to extend the reach of evidence-based treatments outside of brick-and-mortar health care settings. Second, to address challenges related to treatment targets and engagement, we propose involving individuals with lived experience in the design and research process.ConclusionsUCD offers a well-developed and systematic process to center the unique needs, preferences, and perceived barriers of individuals with lived SITB experience in the development and evaluation of digital interventions.

Life cycle assessment for identification of critical aspects in emerging technologies for the extraction of phenolic compounds from spruce bark

Polyphenolic compounds in bark are resources of great interest to produce renewable chemicals and several different technologies are available or under early development for the extraction of these types of compounds. Since critical environmental effects of a product are often set during the design phase, it is important to use life cycle assessment (LCA) to identify the steps resulting in the largest environmental burdens and the overall performance of the various technologies at an early stage during technology development. In addition, for a better understanding of the environmental impact of the future system, it is needed to consider an up-scaled process already in early process development. In the current study, LCAs of three different technologies; hot water extraction (HWE), ultrasound assisted extraction (UAE), and supercritical fluid extraction (SFE) for the extraction of phenolic compounds from spruce bark were compared in a large-scale production scenario. The study includes industrially relevant heat sources and heating technologies, downstream separations, solvent recovery, and heat recovery within the processes. The LCA shows that the simpler HWE process has a lower environmental impact per amount of phenolic compound extracted than UAE and SFE unless the extraction yields of the latter are more than about 5 times that of HWE. The reason for this result is mainly the environmental burden caused by the consumption of ethanol in the UAE and SFE processes, which accounts for more than 70% of the total environmental burden in most impact categories. Even if bioethanol produced with a particularly low carbon footprint would be used, the impact from ethanol use in the extractions would be considerable. UAE and SFE were also more dependent on the use of electricity. In the base case scenario, electricity produced with a low share of fossil resources was used, and electricity was in this case not one of the main contributors to the environmental impact of the processes. However, if the production of electricity is largely fossil-based, it comes out as a significant factor. Furthermore, the heat recovery in an up-scaled process is very important and accounts for a reduction of 35–60% net heat demand. As a complement to LCAs, future studies of promising polyphenolic compound production systems should also include economic aspects and performance.

A Review of Prostate Organogenesis and a Role for iPSC-Derived Prostate Organoids to Study Prostate Development and Disease.

The prostate is vulnerable to two major age-associated diseases, cancer and benign enlargement, which account for significant morbidity and mortality for men across the globe. Prostate cancer is the most common cancer reported in men, with over 1.2 million new cases diagnosed and 350,000 deaths recorded annually worldwide. Benign prostatic hyperplasia (BPH), characterised by the continuous enlargement of the adult prostate, symptomatically afflicts around 50% of men worldwide. A better understanding of the biological processes underpinning these diseases is needed to generate new treatment approaches. Developmental studies of the prostate have shed some light on the processes essential for prostate organogenesis, with many of these up- or downregulated genes expressions also observed in prostate cancer and/or BPH progression. These insights into human disease have been inferred through comparative biological studies relying primarily on rodent models. However, directly observing mechanisms of human prostate development has been more challenging due to limitations in accessing human foetal material. Induced pluripotent stem cells (iPSCs) could provide a suitable alternative as they can mimic embryonic cells, and iPSC-derived prostate organoids present a significant opportunity to study early human prostate developmental processes. In this review, we discuss the current understanding of prostate development and its relevance to prostate-associated diseases. Additionally, we detail the potential of iPSC-derived prostate organoids for studying human prostate development and disease.