Biological Levels Research Articles

Hydroxyacid Oxidase 1, a Glutamine Metabolism-Associated Protein, Predicts Poor Patient Outcome in Luminal Breast Cancer

Breast cancer (BC), which remains the most prevalent malignancy among women, is characterised by significant heterogeneity across its molecular subtypes. Oestrogen receptor-positive (ER+) (luminal) BC represents approximately 75% of cases, and despite advancements in treatment there remains around a 40% recurrence rate. Cellular uptake of glutamine is conducted by solute carriers (SLCs), which are significantly associated with outcome in luminal BC. In this study, differential gene expression analysis was carried out using The Cancer Genome Atlas BC dataset. This identified hydroxyacid oxidase 1 (HAO1) as significantly overexpressed in luminal BC with a high expression of SLCs. Extended analysis in the METABRIC (n = 1980) and Breast Cancer Gene-Expression Miner (n = 4421) transcriptomic databases and the Nottingham (n = 952) BC tissue cohort showed a varied survival outcome for HAO1 expression at the genomic, transcriptomic, and proteomic levels. HAO1 copy number (CN) gain (p = 0.002) and high HAO1 protein expression (p = 0.019) were associated with poor prognosis in luminal BC, whereas high HAO1 mRNA expression correlated with better survival outcomes (p = 0.023) suggesting a complex regulatory mechanism affecting HAO1 at different biological levels. Importantly, in luminal BC patients treated with endocrine therapy, high protein expression of HAO1 predicted shorter distant-metastasis free survival (p = 0.042). The knockdown of SLC1A5 and SLC7A5 significantly reduced HAO1 expression in MCF-7 and ZR-751 BC cell lines. Protein analysis confirmed significant associations between HAO1 and SLC7A5 and SLC1A5, emphasising a potential role for the enzyme in glutamine metabolism and its potential as a therapeutic target. This study underscores the prognostic significance of HAO1 in luminal BC and its relationship with patient outcomes.

Integrating Environmental Covariates into Adaptability and Stability Analyses: A Structural Equation Modeling Approach for Cotton Breeding

Breeding programs rely on genotype-by-environment interaction (GEI) to recommend cultivars for specific locations. GEI describes how different genotypes perform under varying environmental conditions. Several methods were proposed to assess adaptability and stability across environments. These methods utilize various statistical approaches like parametric and non-parametric regression, multivariate analysis techniques, and even Bayesian frameworks and artificial intelligence. The accessibility of environmental data through platforms like NASA POWER allows breeders to integrate this information into a breeding process. It has been done by using multi-omics integration models that combine data across various biological levels to create accurate predictive models. In the context of phenotypic adaptability and stability analysis, structural equation modeling (SEM) offers an interesting approach to integrating environmental covariates. This work aimed to propose a novel approach that integrates weather information into adaptability and stability analysis, combining SEM with the established Eberhart and Russell model. Additionally, a user-friendly applet, denoted ECERSEM-AdaptStab, was made available to perform the analysis. This approach utilized data from 12 cotton cultivar trials conducted across two growing seasons at 19 sites. This approach successfully integrated environmental covariates into a phenotypic adaptability and stability analysis of cotton cultivars. Specifically, the genotypes TMG 41 WS, IMA CV 690, DP 555 BGRR, BRS 286 and BRS 369 RF were recommended for favorable environments, while the genotypes TMG 43 WS, IMA 5675 B2RF, IMA 08 WS, NUOPAL, DELTA OPAL, BRS 335, and BRS 368 RF are more suitable for unfavorable environments.

Correlation of magnetic resonance imaging and computed tomography with biological factor expression and lymph node metastasis in aggressive prostate cancer.

This paper focused on probing the correlation of magnetic resonance imaging (MRI) and computed tomography (CT) manifestations with biological factor expression and lymph node metastasis (LNM) in aggressive prostate cancer (PCa). A total of 136 PCa patients underwent surgical treatment, and received CT and MRI examinations before surgery, whereby the apparent diffusion coefficient (ADC) values of quantitative MRI (qMRI) parameters were obtained. Patients were categorized into the non-aggressive PCa group and aggressive PCa group according to the postoperative pathological results and Gleason scores. The expression of biological factors [prostate-specific antigen (PSA), proliferating cell nuclear antigen (PCNA), p27, and ki-67] in both groups was tested. CT and MRI manifestations of aggressive PCa patients were analyzed. The qMRI parameters, biological factors levels and LNM were compared in two groups; the relationships between CT and MRI manifestations, qMRI parameters and positive expression of biological factors and LNM were probed in two groups. In the aggressive PCa group, MRI and CT presented different degrees of abnormal prostate changes. In the aggressive PCa group, PSA and p27 expression and ADC values were lower, and PCNA and ki-67, and LNM rates were higher. Patients' LNM rate was higher than that of ≤ 2 cm when the tumor diameter was > 2 cm. ADC values were positively correlated with PSA and p27 positive expression, and negatively correlated with PCNA, ki-67 and LNM in the aggressive PCa group. MRI and CT manifestations of aggressive PCa had certain characteristics; MRI manifestations and qMRI possessed a correlation with biological factors and LNM; ADC could be employed to assess the aggressiveness of PCa.

Untargeted Metabolomics Analysis Using FTIR and LC-HRMS for Differentiating Sonchus arvensis Plant Parts and Evaluating Their Biological Activity.

The composition and concentration of compounds in medicinal plants vary based on several factors, including the specific part of the plant being used. These variations in composition and concentration lead to differences in biological activity levels. In this study, we aimed to assess the phytochemical profile of Sonchus arvensis and to investigate the biological activity of different plant parts (roots, stems, and leaves) using ametabolomics approach. We analyzed the plant extracts for total phenolic and flavonoid levels, antioxidant activity, and xanthine oxidase inhibition. We also conducted metabolite profiling using Fourier-transform infrared spectroscopy and liquid chromatography-high resolution mass spectrometry. A total of 17 metabolites were identified (13 in leaves, 10 in stems, and 9 in roots). Principal component analysis effectively differentiated S. arvensis extracts based on differences in plant parts. These findings indicate that the quantity and diversity of metabolites present in the roots, stems, and leaves influence the biological activity of S. arvensis.

Self-creation of Older People in the Perspective of Developing Wisdom and Adaptation to Changing Roles in the Family and Society

Old age is a stage of life during which a person must confront the changes that occur both in the reality around them and in themself. Those are changes at the biological, psychological and social levels. Adapting to old age and the roles it brings becomes a difficult and demanding task. One of the most important developmental tasks of an elderly person is developing wisdom that can support and facilitate the process of adaptation to old age. Entering the period of late adulthood is therefore a special opportunity for further development and self-creative action of the individual leading to the creation of a mature identity of an old person. The aim of this text is to provide insight into the meaning and manifestations of this self-creative involvement, with particular emphasis on its importance in the process of adaptation to changing roles in old age and building wisdom.

Linking individual experiments and multiscale models to simulate physiological perturbations on aquatic food webs

Numerous threats affect aquatic ecosystems at different biological organizational levels from individuals to ecosystems. Stresses occurring on the metabolism and physiological functions of individuals can have repercussions on the individual behavior, its ability to survive and reproduce, also known as the individual fitness, which may then influence the demography and spatial distribution of populations, and ultimately modify trophic flows and ecosystem functioning. In a context of a globally changing environment, predicting the life history traits and fitness of individuals can be relevantly performed with the association of laboratory experiments with Dynamic Energy Budget (DEB) theory, while modeling species interactions have proven to be an efficient tool to understand aquatic food webs using mass-balanced models such as linear inverse models (LIMs) or Chance and Necessity (CaN) models. However, while predictive results obtained on individuals can be provided with a thorough mechanistic interpretation, the propagation of the effects is most often limited to the closest biological hierarchical level, i.e., the population, and rarely to the food-web level. Furthermore, there is a need to understand how to avoid misleading approaches and interpretations due to the simplicity of experiments. For the moment, no clear methodology has stood out yet to do so. In this study, we provide a new methodology based on a combination of models (i.e., DEB, LIM, and CaN) aiming at upscaling information from laboratory experiments on individuals to ecosystems to address multiple ecological issues. This framework has a potential to enhance our understanding of higher-scale consequences of the effect of stressors measured at the sub-individual scale. This combination of models was chosen for the convergence of their framework but also their ability to consider a substantial portion of the projected uncertainty. The description of this methodology can help experimenters and modelers to jointly address a specific question involving upscaling from individual to ecosystem, proposes approaches, and gives tips on the pitfalls to avoid along the upscaling process.

Factors influencing metal concentrations in hair and nails during longitudinal follow-up of apprentice welders

ABSTRACT The aim of this study was to determine factors influencing observed increased metal biomarkers of exposure levels in a group of 116 Quebec apprentice welders during a longitudinal follow-up of exposure. Analysis of 14 metals was carried out in hair, fingernail, and toenail samples taken from participants over the course of their welding curriculum at 6 different times. Personal and socio-demographic characteristics, lifestyle habits, and other potential confounding factors were documented by questionnaire. Multivariate linear mixed-effect models were used to assess main predictors of metal concentrations in each biological matrix including increasing time of exposure throughout the curriculum (defined as the repeated measure “time” variable”). Significant associations between repeated measure “time” variable and metal levels in hair, fingernails, and toenails were found for chromium, iron, manganese and nickel. Significant associations with “time” were also noted for arsenic levels in hair and fingernails, and for barium, cobalt and vanadium levels in fingernails and toenails. The repeated measure “time” variable, hence increasing time of exposure throughout the curriculum, was the predominant predictor of elevated biological metal levels. Reduced spaces and simultaneous activities such as oxyfuel-cutting and welding in the same welding room were suspected to contribute to higher metal levels. Age, ethnicity, and annual household income exerted an effect on metal levels and considered as confounders in the models. Variations observed in metal levels between hair and nails of apprentice welders also emphasized the relevance and importance of performing multi-matrix and multi-element biomonitoring to assess temporal variations in biological metal concentrations during welding curriculum.

The effects of different densities of Asparagopsis armata (Harvey, 1855) seaweed on the clam Ruditapes philippinarum (A. Adams & Reeve, 1850): Insights from a laboratory assessment

Several invasive species can occupy the same geographic area. Interaction between species depends on several factors, and the results of such interactions can be highly diverse. Asparagopsis armata is a red invasive seaweed whose exudates contain a cocktail of toxic halogenated compounds. In this study, the impact of high and low levels of A. armata on the bivalve Ruditapes philippinarum was assessed in a laboratory experiment. Both are prominent invasive species in Europe and could share the same habitats. The effects of the algae were measured at different biological levels, framed by an integrated approach: bioturbation as a proxy for organismal activity and behaviour within the sediment, and several subcellular biomarkers related to oxidative stress and damage, energy metabolism, detoxification, and neurotransmission. While bioturbation denounced the effects of exudates on the bivalve, with a decrease in most parameters when exposed to the different amounts of algae, only marginal responses were found for biomarkers, suggesting a possible temporal decoupling between the behavioural response and the intrinsic biochemical environment. These results denote that despite the recognized potential of biomarkers to address a myriad of situations, a proxy for higher levels of biological organization, such as behaviour, for its integration of lower-level effects, is a robust tool to address complex and lesser-known mixtures of stressors.

Preventing acute neurotoxicity of CNS therapeutic oligonucleotides with the addition of Ca2+ and Mg2+ in the formulation

Oligonucleotide therapeutics (ASOs and siRNAs) have been explored for modulation of gene expression in the central nervous system (CNS), with several drugs approved and many in clinical evaluation. Administration of highly concentrated oligonucleotides to the CNS can induce acute neurotoxicity. We demonstrate that delivery of concentrated oligonucleotides to the CSF in awake mice induces acute toxicity, observable within seconds of injection. Electroencephalography (EEG) and electromyography (EMG) in awake mice demonstrated seizures. Using ion chromatography, we show that siRNAs can tightly bind Ca2+ and Mg2+ up to molar equivalents of the phosphodiester (PO)/phosphorothioate (PS) bonds independently of the structure or phosphorothioate content. Optimization of the formulation by adding high concentrations (above biological levels) of divalent cations (Ca2+ alone, Mg2+ alone, or Ca2+ and Mg2+) prevents seizures with no impact on the distribution or efficacy of the oligonucleotide. The data here establishes the importance of adding Ca2+ and Mg2+ to the formulation for the safety of CNS administration of therapeutic oligonucleotides.

A Novel Phytocolorant, Neoxanthin, as a Potent Chemopreventive: Current Progress and Future Prospects.

Cancer is a general term for a group of similar diseases. It is a combined process that results from an accumulation of abnormalities at different biological levels, which involves changes at both genetic and biochemical levels in the cells. Several modifiable risk factors for each type of cancer include heredity, age, and institutional screening guidelines, including colonoscopy, mammograms, prostate-specific antigen testing, etc., which an individual cannot modify. Although a wide range of resources is available for cancer drugs and developmental studies, the cases are supposed to increase by about 70% in the next two decades due to environmental factors commonly driven by the way of living. The drugs used in cancer prevention are not entirely safe, have potential side effects and are generally unsuitable owing to substantial monetary costs. Interventions during the initiation and progression of cancer can prevent, diminish, or stop the transformation of healthy cells on the way to malignancy. Diet modifications are one of the most promising lifestyle changes that can decrease the threat of cancer development by nearly 40%. Neoxanthin is a xanthophyll pigment found in many microalgae and macroalgae, having significant anti-cancer, antioxidant and chemo-preventive activity. In this review, we have focused on the anti-cancer activity of neoxanthin on different cell lines and its cancer-preventive activity concerning obesity and oxidative stress. In addition to this, the preclinical studies and future perspectives are also discussed in this review.

Melatonin ameliorates chronic sleep deprivation against memory encoding vulnerability: Involvement of synapse regulation via the mitochondrial-dependent redox homeostasis-induced autophagy inhibition

Voluntary sleep curtailment is increasingly more rampant in modern society and compromises healthy cognition, including memory, to varying degrees. However, whether memory encoding is impaired after chronic sleep deprivation (CSD) and the underlying molecular mechanisms involved remain unclear. Here, using the mice, we tested the impact of CSD on the encoding abilities of social recognition-dependent memory and object recognition-dependent memory. We found that memory encoding was indeed vulnerable to CSD, while memory retrieval remained unaffected. The hippocampal neurons of mice with memory encoding deficits exhibited significant synapse damage and hyperactive autophagy, which dissipates during regular sleep cycles. This excessive autophagy appeared to be triggered by damage to mitochondrial DNA (mtDNA), resulting from oxidative stress within the mitochondria. The relief at the behavioral and molecular biological levels can be achieved with intraperitoneal injections of the antioxidant compound melatonin. Moreover, our in vitro experiments using HT-22 cells demonstrated that oxidative stress induced by hydrogen peroxide led to oxidative damage, including mtDNA damage, and activation of autophagy. Melatonin treatment effectively countered these effects, restoring redox homeostasis and reducing excessive autophagic activity. Notably, this protective effect was not observed when melatonin was administered as a pre-treatment. Together, our findings reveal the vulnerability of memory encoding during chronic sleep curtailment, which is caused by oxidative stress and consequent enhancement of autophagy, suggest a potential therapeutic strategy for addressing these effects following prolonged wakefulness through melatonin intervention, and reiterate the significance of adequate sleep for memory formation and retention.

Can microplastic contamination affect the wing morphology and wingbeat frequency of Aedes aegypti (Diptera: Culicidae) mosquitoes?

Microplastics (MPs) are increasingly widespread in the environment, which raises questions about their potential effects at different biological levels. It is essential to assess the impacts on biodiversity, and it is also crucial to understand whether the presence of MPs can interfere with the biological traits of species of relevance in public health. Considering that the life-history traits of mosquitoes, such as size and the wingbeat frequency (WBF), are related to its vector competence, here, we study the effects of 106 particles L-1 (as expected concentration of MPs on the environment, using the polyethylene type) on WBF, as well as wing morphology, testing the Culicidae species found across all continents, Aedes aegypti, as an indicator. Results show that larvae survival and development were not affected by the tested concentration of MP. Geometric morphometrics showed some asymmetry in female mosquito wings, which were also smaller for individuals reared in MP suspension. As for WBF, results did not indicate any significant differences between females. Male mosquitoes, however, showed alterations in WBF and wing morphology, suggesting possible sex-specific reactions to microplastic exposure. Also, the combination of morphological parameters analyzed as covariates (wing centroid size and body weight) did not significantly affect WBF for both female and male mosquitoes. Overall, this study shows an inaugural investigation of the effects of MP on wing size and WBF on Ae. aegypti, shedding light on these parameters tested for a current pollution issue and its impact on a virus vector.

Analysis of Biological Stress Response as the Impact of Workplace Bullying on Performance Perception

This study aims to determine the extent to which workplace bullying is related to employees' performance perception at health centers and its impact on biological stress. The research was conducted on all employees at eight health centers in Regency X, randomly selected. Workplace bullying was measured using the Negative Acts Questionnaire Revised (NAQ-R), translated into Indonesian. Performance perception was measured using the Performance Perception Questionnaire. Biological stress was assessed through cortisol levels in saliva. Among the 240 participants, the majority (60%) rarely experienced workplace bullying, with an average score of 41.00 (SD=6.532). Most participants (67.1%) had a high perception of performance, with an average score of 67.12 (SD=9.747). Pearson's test results showed a value of 0.038 with a coefficient of -0.207, indicating a significant correlation between workplace bullying and performance perception. The findings also indicate that biological stress levels, measured through cortisol, correlate with lower performance perceptions. Workplace bullying contributes 4.285% to performance perception. This study provides preliminary evidence that workplace bullying can affect employee performance through biological stress mechanisms, highlighting the importance of interventions to reduce workplace bullying to improve employee well-being and performance

Early life factors that affect obesity and the need for complex solutions.

The prevalence of obesity increases with age but is apparent even in early life. Early childhood is a critical period for development that is known to influence future health. Even so, the focus on obesity in this phase, and the factors that affect the development of obesity, has only emerged over the past two decades. Furthermore, there is a paucity of iterative work in this area that would move the field forward. Obesity is a complex condition involving the interplay of multiple influences at different levels: the individual and biological level, the sociocultural level, and the environmental and system levels. This Review provides a brief overview of the evidence for these factors with a focus on aspects specific to early life. By spotlighting the complex web of interactions between the broad range of influences, both causal and risk markers, we highlight the complex nature of the condition. Much work in the early life field remains observational and many of the intervention studies are limited by a focus on single influences and a disjointed approach to solutions. Yet the complexity of obesity necessitates coordinated multi-focused solutions and joined-up action across the first 2,000days from conception, and beyond.

A cultural comparison of children’s emotion knowledge: Data from two cultures

Knowing about emotions is vital for children’s school adjustment, well-being, and future social relationships. Whereas experiencing emotions is a universal psychological process at the biological level, how emotions are categorized and communicated is shaped by culture. Most studies have investigated cultural differences in emotion (knowledge) in Western and Eastern cultures. To compare emotion knowledge within Western countries, N = 585 children from Germany and N = 100 children from Israel in the two age groups preschool (42–71 months) and primary school (72–89 months) were interviewed with the Adaptive Test of Emotion Knowledge for Three- to Nine-Year-Olds (ATEM 3-9). Generalized linear models (GLMs) indicate that children from Israel showed higher levels of emotion knowledge in the total score and in all seven components of emotion knowledge than their agemates from Germany. These results highlight the importance of differences in family structure and values within Western countries. It is important to determine the various factors and the socialization in the family and in educational institutions that influence emotion knowledge in Germany and Israel.

Non-equilibrium physics of multi-species assembly applied to fibrils inhibition in biomolecular condensates and growth of online distrust

Self-assembly is a key process in living systems—from the microscopic biological level (e.g. assembly of proteins into fibrils within biomolecular condensates in a human cell) through to the macroscopic societal level (e.g. assembly of humans into common-interest communities across online social media platforms). The components in such systems (e.g. macromolecules, humans) are highly diverse, and so are the self-assembled structures that they form. However, there is no simple theory of how such structures assemble from a multi-species pool of components. Here we provide a very simple model which trades myriad chemical and human details for a transparent analysis, and yields results in good agreement with recent empirical data. It reveals a new inhibitory role for biomolecular condensates in the formation of dangerous amyloid fibrils, as well as a kinetic explanation of why so many diverse distrust movements are now emerging across social media. The nonlinear dependencies that we uncover suggest new real-world control strategies for such multi-species assembly.

An Innovative Approach to Optimize First-In-Human Minimal Anticipated Biological Effect Level Based Starting Dose in Oncology Trials for Bispecific T-Cell Engagers: Experience from A Solid Tumor Bispecific T-Cell Engager.

Bispecific T-cell engagers (Bi-TCEs) have revolutionized the treatment and management of both hematological and solid tumor indications with opportunities to become best-in-class therapeutics for cancer. However, defining the dose and dosing regimen for the first-in-human (FIH) studies of Bi-TCEs can be challenging, as a high starting dose can expose subjects to serious toxicity while a low starting dose based on traditional minimal anticipated biological effect level (MABEL) approach could lead to lengthy dose escalations that exposes seriously ill patients to sub-therapeutic dosing. Leveraging our in-depth and broad clinical development experience across three generations of Bi-TCEs across both liquid and solid tumor indications, we developed an innovative modified MABEL approach for starting dose selection that integrates knowledge based on the target biology, indication, toxicology, in vitro, in vivo pharmacological evaluations, and translational pharmacokinetic/pharmacodynamic (PK/PD) modeling, together with anticipated safety profile. Compared to the traditional MABEL approach in which high effector to target (E:T) cell ratios are typically used, our innovative approach utilized an optimized E:T cell ratio that better reflects the tumor microenvironment. This modified MABEL approach was successfully applied to FIH dose selection for a half-life extended (HLE) Bi-TCE for gastric cancer. This modified MABEL approach enabled a 10-fold higher starting dose that was deemed safe and well tolerated and saved at least two dose-escalation cohorts before reaching the projected efficacious dose. This approach was successfully accepted by global regulatory agencies and can be applied for Bi-TCEs across both hematological and solid tumor indications for accelerating the clinical development for Bi-TCEs.

Interplay of UV-filter pollution and temperature rise scenarios on Mytilus galloprovincialis health: Unveiling sperm quality and adult physiology, biochemistry, and histology insights

Addressing the impacts of emerging contaminants within the context of climate change is crucial for understanding ecosystem health decline. Among these, the organic UV-filters 4-methylbenzylidenecamphor (4-MBC) and benzophenone-3 (BP-3) are widely used in cosmetics and personal care products. Their unique physico-chemical properties, along with their growing commercialization and consumption, have made them ubiquitous in aquatic environments through both direct and indirect releases, raising significant concerns about their potential threats to inhabiting biota. Additionally, increasing surface water temperatures exacerbate ecological risks, making it imperative to understand the implications for non-target species at different biological levels. This study investigated the short- and long-term effects of UV-filters 4-MBC or BP-3, at ecologically relevant concentrations, combined with current and predicted warming scenarios, on the performance and male reproductive health of Mytilus galloprovincialis mussel populations. Using biomarkers across sub-cellular, cellular, tissue, and individual levels, the study revealed significant physiological and biochemical impairments in both sperm cells and adults exposed to UV-filters. Temperature emerged as the primary driver influencing mussel responses and modulating the impacts of 4-MBC/BP-3, emphasizing their sensitivity to temperatures outside the optimal range and interactive effects between stressors. Specifically, sperm motility declined with increasing UV-filter concentrations, while temperature alone influenced ROS production, leading to compromised mitochondrial activity and DNA damage in the presence of combined stressors, indicative of potential reproductive impairments. Adults exhibited high UV-filter bioconcentration potential in whole tissues, compromised physiological status, morphophysiological changes in digestive glands, oxidative stress, and alterations in metabolic capacity, antioxidant defences, and biotransformation mechanisms, correlating with UV-filter exposure and temperature increase. Among the UV-filters tested, 4-MBC was the most detrimental, especially when combined with warming. Overall, this study underscores the vulnerability of M. galloprovincialis to cumulative stressors and highlights the importance of employing a multi-biomarker approach to assess and mitigate the impacts of stressors on coastal ecosystems.

NEK1 haploinsufficiency worsens DNA damage, but not defective ciliogenesis, in C9ORF72 patient-derived iPSC-motoneurons.

The hexanucleotide G4C2 repeat expansion (HRE) in C9ORF72 gene is the major cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), leading to both loss- and gain-of-function pathomechanisms. The wide clinical heterogeneity among C9ORF72 patients suggests potential modifying genetic and epigenetic factors. Notably, C9ORF72 HRE often co-occurs with other rare variants in ALS/FTD-associated genes, such as NEK1, which encodes for a kinase involved in multiple cell pathways, including DNA damage response and ciliogenesis. In this study, we generated induced pluripotent stem cells (iPSCs) and differentiated motoneurons (iPSC-MNs) from an ALS patient carrying both C9ORF72 HRE and a NEK1 loss-of-function mutation to investigate the biological effect of NEK1 haploinsufficiency on C9ORF72 pathology in a condition of oligogenicity. Double mutant C9ORF72/NEK1 cells showed increased pathological C9ORF72 RNA foci in iPSCs and higher DNA damage levels in iPSC-MNs compared to single mutant C9ORF72 cells, but no effect on DNA damage response. When we analysed the primary cilium, we observed a defective ciliogenesis in C9ORF72 iPSC-MNs which was not worsened by NEK1 haploinsufficiency in the double mutant iPSC-MNs. Altogether, our study shows that NEK1 haploinsufficiency influences differently DNA damage and cilia length, potentially acting as a modifier at biological level in an in vitro ALS patient-derived disease model of C9ORF72 pathology.

Beyond MABEL: An Integrative Approach to First in Human Dose Selection of Immunomodulators by the Health and Environmental Sciences Institute (HESI) Immuno-Safety Technical Committee (ITC).

Administration of a new drug candidate in a first-in-human (FIH) clinical trial is a particularly challenging phase in drug development and is especially true for immunomodulators, which are a diverse and complex class of drugs with a broad range of mechanisms of action and associated safety risks. Risk is generally greater for immunostimulators, in which safety concerns are associated with acute toxicity, compared to immunosuppressors, where the risks are related to chronic effects. Current methodologies for FIH dose selection for immunostimulators are focused primarily on identifying the minimum anticipated biological effect level (MABEL), which has often resulted in sub-therapeutic doses, leading to long and costly escalation phases. The Health and Environmental Sciences Institute (HESI) - Immuno-Safety Technical Committee (ITC) organized a project to address this issue through two complementary approaches: (i) an industry survey on FIH dose selection strategies and (ii) detailed case studies for immunomodulators in oncology and non-oncology indications. Key messages from the industry survey responses highlighted a preference toward more dynamic PK/PD approaches as in vitro assays are seemingly not representative of true physiological conditions for immunomodulators. These principles are highlighted in case studies. To address the above themes, we have proposed a revised decision tree, which expands on the guidance by the IQ MABEL Working Group (Leach et al. 2021). This approach facilitates a more refined recommendation of FIH dose selection for immunomodulators, allowing for a nuanced consideration of their mechanisms of action (MOAs) and the associated risk-to-benefit ratio, among other factors.