Access restrictions to forest resources, rather than COVID-19 bans, drive the selection of firewood species for bonfires during Festas Juninas in northeastern Brazil.

BACKGROUND: The complex interplay of social and environmental factors shapes ecosystems, potentially leading to harmony or conflict, highlighting the importance of understanding these dynamics for coexistence. In developing countries, firewood serves as a primary energy source and plays a role in cultural-religious rituals and festivities. However, the specific patterns of woody species used for the latter remain poorly understood, including the impact of access restrictions to resources and local bans on practices. Therefore, our research focuses on examining how access restrictions to forest resources and bonfire bans due to the coronavirus disease 2019 (COVID-19) impact the cultural-religious tradition of bonfire making during Festas Juninas (June festivities) in northeastern Brazil. METHODS: Ethnobotanical fieldwork was conducted in two rural populations in northeastern Brazil between 2021 and 2022. Data were collected through semi-structured interviews, observations, and the guided tour technique. The cultural-religious tradition of bonfire making (i.e., richness of native and exotic firewood species, firewood volume, and the number of bonfires related to this practice) was compared between populations (i.e., differing in access restrictions) and years (i.e., differing in COVID-19-related bans) using Mann-Whitney U tests. RESULTS: Results revealed significant differences in the richness of native (p value = 0.001) and exotic (p value < 0.001) firewood species for bonfire making due to access restrictions to forest resources. The number of native species used was higher among the population residing in the area with unrestricted access than among those with restricted access, while a greater number of exotic species was used in the population with restricted access. The rest of the variables were not influenced by access restrictions, and no variables were influenced by COVID-19 bans. CONCLUSIONS: Our study demonstrated that access restrictions to forest resources, rather than COVID-19 bans, drive the selection of firewood species for bonfires during Festas Juninas in northeastern Brazil. In addition, as populations remain deeply entrenched in cultural-religious practices amid temporary bans imposed by health crises, there is a pressing need for culturally sensitive environmental policies. Fostering socio-ecological resilience demands a comprehensive approach that encompasses not only environmental factors but also cultural dimensions, which wield a pivotal influence on long-term sustainability.

Tumor growth for remodeling process: A 2D approach.

This paper aims to present a comprehensive framework for coupling tumor-bone remodeling processes in a 2-dimensional geometry. This is achieved by introducing a bio-inspired damage that represents the growing tumor, which subsequently affects the main populations involved in the remodeling process, namely, osteoclasts, osteoblasts, and bone tissue. The model is constructed using a set of differential equations based on the Komarova's and Ayati's models, modified to incorporate the bio-inspired damage that may result in tumor mass formation. Three distinct models were developed. The first two models are based on the Komarova's governing equations, with one demonstrating an osteolytic behavior and the second one an osteoblastic model. The third model is a variation of Ayati's model, where the bio-inspired damage is induced through the paracrine and autocrine parameters, exhibiting an osteolytic behavior. The obtained results are consistent with existing literature, leading us to believe that our in-silico experiments will serve as a cornerstone for paving the way towards targeted interventions and personalized treatment strategies, ultimately improving the quality of life for those affected by these conditions.

ALK inhibitors increase ALK expression and sensitize neuroblastoma cells to ALK.CAR-T cells.

Selection of the best tumor antigen is critical for the therapeutic success of chimeric antigen receptor (CAR) T cells in hematologic malignancies and solid tumors. The anaplastic lymphoma kinase (ALK) receptor is expressed by most neuroblastomas while virtually absent in most normal tissues. ALK is an oncogenic driver in neuroblastoma and ALK inhibitors show promising clinical activity. Here, we describe the development of ALK.CAR-T cells that show potent efficacy in monotherapy against neuroblastoma with high ALK expression without toxicity. For neuroblastoma with low ALK expression, combination with ALK inhibitors specifically potentiates ALK.CAR-T cells but not GD2.CAR-T cells. Mechanistically, ALK inhibitors impair tumor growth and upregulate the expression of ALK, thereby facilitating the activity of ALK.CAR-T cells against neuroblastoma. Thus, while neither ALK inhibitors nor ALK.CAR-T cells will likely be sufficient as monotherapy in neuroblastoma with low ALK density, their combination specifically enhances therapeutic efficacy.

The Role of Mechanical Properties and Structure of Type I Collagen Hydrogels on Colorectal Cancer Cell Migration.

Mechanical interactions between cells and their microenvironment play an important role in determining cell fate, which is particularly relevant in metastasis, a process where cells invade tissue matrices with different mechanical properties. In vitro, type I collagen hydrogels have been commonly used for modeling the microenvironment due to its ubiquity in the human body. In this work, the combined influence of the stiffness of these hydrogels and their ultrastructure on the migration patterns of HCT-116 and HT-29 spheroids are analyzed. For this, six different types of pure type I collagen hydrogels by changing the collagen concentration and the gelation temperature are prepared. The stiffness of each sample is measured and its ultrastructure is characterized. Cell migration studies are then performed by seeding the spheroids in three different spatial conditions. It is shown that changes in the aforementioned parameters lead to differences in the mechanical stiffness of the matrices as well as the ultrastructure. These differences, in turn, lead to distinct cell migration patterns of HCT-116 and HT-29 spheroids in either of the spatial conditions tested. Based on these results, it is concluded that the stiffness and the ultrastructural organization of the matrix can actively modulate cell migration behavior in colorectal cancer spheroids.

Anatomy, molecular structures, and hyaluronic acid - Gelatin injectable hydrogels as a therapeutic alternative for hyaline cartilage recovery: A review.

Cartilage damage caused by trauma or osteoarthritis is a common joint disease that can increase the social and economic burden in society. Due to its avascular characteristics, the poor migration ability of chondrocytes, and a low number of progenitor cells, the self-healing ability of cartilage defects has been significantly limited. Hydrogels have been developed into one of the most suitable biomaterials for the regeneration of cartilage because of its characteristics such as high-water absorption, biodegradation, porosity, and biocompatibility similar to natural extracellular matrix. Therefore, the present review article presents a conceptual framework that summarizes the anatomical, molecular structure and biochemical properties of hyaline cartilage located in long bones: articular cartilage and growth plate. Moreover, the importance of preparation and application of hyaluronic acid - gelatin hydrogels for cartilage tissue engineering are included. Hydrogels possess benefits of stimulating the production of Agc1, Col2α1-IIa, and SOX9, molecules important for the synthesis and composition of the extracellular matrix of cartilage. Accordingly, they are believed to be promising biomaterials of therapeutic alternatives to treat cartilage damage.

Both network architecture and micro cracks effects on lacuno-canalicular liquid flow efficiency within the context of multiphysics approach for bone remodeling.

When physical forces are applied to bone, its mechanical adaptive behaviors change according to the microarchitecture configuration. This leads to changes in biological and physical thresholds in the remodeling cell population, involving sensor cells (osteocytes) interacting with each other and changes in osteocyte shape due to variation in lacunar shape. The resulting alterations in fluid flow leads to changes in the membrane electrical potential and shear stress. Eventual creation of microcracks, may lead in turn to modify cell activity. In contrast, the redundancy in the lacuno canalicular network (LCN) interconnectivity maintains partial flow. Our goal was to investigate the role of fluid flow in LCN by proposing a model of electro-mechanical energy spread through inhomogeneous microarchitectures. We focused on mechano-sensitivity to changes in load-induced flow impacted by neighboring micro cracks and quantifying its critical role in changing, velocity, shear stress and orientation of liquid mass transportation from one cell to another. To enhance the concept of intricacy LCN micro-structure to fluid flow, we provide a new combined effects factor considered as osteocytes sensor efficiency. We customized an influence function for each osteocyte, coupling: in one hand, the spatial distribution within remodeling influence areas, conducting a significant fluid spread, leading hydro-dynamic behavior and impacted further by presence of micro cracks and; in other hand, the fluid electro kinetic behavior. As an attempt to fill the limitations stated by many of the recent studies, we reveal in numerical simulation, some results which cannot be measured in vitro/in vivo studies. Numerical calculations were performed in order to evaluate, among many others, how liquid flow conditions changes between lacunas, how the orientation and the magnitude of the governing flow in LCN can regulate osteocytes efficiency. In addition to be regulated by osteocytes, a direct effects of fluid flow are also acting on osteoblast activity. In summary, this new approach considers mechano-sensitivity in relation to liquid flow dynamic and suggests additional pathway for Osseo integration via osteoblast regulation. However, this novel modeling approach may help improve the mapping and design bone scaffolds and/or selection of scaffold implantation regions.

A coupled mathematical model between bone remodeling and tumors: a study of different scenarios using Komarova's model.

This paper aims to construct a general framework of coupling tumor-bone remodeling processes in order to produce plausible outcomes of the effects of tumors on the number of osteoclasts, osteoblasts, and the frequency of the bone turnover cycle. In this document, Komarova's model has been extended to include the effect of tumors on the bone remodeling processes. Thus, we explored three alternatives for coupling tumor presence into Komarova's model: first, using a "damage" parameter that depends on the tumor cell concentration. A second model follows the original structure of Komarova, including the tumor presence in those equations powered up to a new parameter, called the paracrine effect of the tumor on osteoclasts and osteoblasts; the last model is replicated from Ayati and collaborators in which the impact of the tumor is included into the paracrine parameters. Through the models, we studied their stability and considered some examples that can reproduce the tumor effects seen in clinic and experimentally. Therefore, this paper has three parts: the exposition of the three models, the results and discussion (where we explore some aspects and examples of the solution of the models), and the conclusion.

Influence of growth plate morphology on bone trabecular groups, a framework computational approach.

The morphology of the growth plate undergoes various transformations during each stage of development, affecting its shape, width, density, and other characteristics. This significantly impacts the distribution of stress in the epiphysis of long bones. To the best of our knowledge, this study represents the first attempt to examine the relationship between growth plate morphology and trabecular bone patterns. Our analysis was conducted using a finite element model and we analyzed two medical cases: trabecular patterns in the femoral epiphysis and the calcaneus bone. Our findings revealed a correlation between the formation of main trabecular groups and growth plate morphology. We investigated how an increased density in high-shear stress zones, which are typically located at the periphery of the growth plate, may occur to prevent failure by shear. This is evident in cases such as slipped capital femoral epiphysis or sever's disease, different simulations align with the clinical data available in the literature from a qualitative and quantitative point of view. Our results suggest that further research should focus on understanding the impact of growth plate morphology on bone remodeling and exploring potential preventive measures for different bone disorders.

A unified framework of cell population dynamics and mechanical stimulus using a discrete approach in bone remodelling.

Multiphysics models have become a key tool in understanding the way different phenomenon are related in bone remodeling and various approaches have been proposed, yet, to the best of the author's knowledge there is no model able to link a cell population model with a mechanical stimulus model using a discrete approach, which allows for an easy implementation. This article couples two classical models, the cell population model from Komarova and the Nackenhorst model in a 2D domain, where correlations between the mechanical loading and the cell population dynamics can be established, furthermore the effect of different paracrine and autocrine regulators is seen on the overall density of a portion of trabecular bone. A discretization is performed using frame 1D finite elements, representing the trabecular structure. The Nackenhorst model is implemented by using the finite element method to calculate the strain energy as the main mechanical stimulus that determines the bone mass density evolution in time. This density is normalized to be added to the bone mass percentage proposed by the Komarova model, where coupling terms have been added as well that guarantee a stable response. In the simulations, the equations were solved employing the finite element method with a user subroutine implemented in ABAQUS (2017) and by applying a direct formulation. The methodology presented can model the cell dynamics occurring in bone remodelling in accordance with the asynchronous nature of this process, yet allowing to differentiate zones with higher density, the main trabecular groups are obtained for the proximal femur. Finally, the model is tested in pathological cases, such as osteoporosis and osteopetrosis, yielding results similar to the pathology behavior. Furthermore, the discrete modelling technique is shown to be of use in this particular application.

Anti-KIT antibody, barzolvolimab, reduces skin mast cells and disease activity in chronic inducible urticaria.

BACKGROUND: Chronic inducible urticaria (CIndU) is characterized by mast cell (MC)-mediated wheals in response to triggers: cold in cold urticaria (ColdU) and friction in symptomatic dermographism (SD). KIT receptor activation by stem cell factor (SCF) is essential for MC function. Barzolvolimab (CDX-0159) is a humanized antibody that inhibits KIT activation by SCF and was well tolerated in healthy volunteers with dose-dependent plasma tryptase suppression indicative of systemic mast cell ablation. METHODS: This is an open-label, trial in patients with antihistamine refractory ColdU or SD, receiving one IV dose of barzolvolimab (3 mg/kg), with a 12-week follow-up. Primary endpoint was safety/tolerability; pharmacodynamic (PD)/clinical endpoints included serum tryptase, plasma SCF, skin MC histology, provocation tests, urticaria control test (UCT), and dermatology life quality index (DLQI). RESULTS: Analysis populations were safety (n = 21) and pharmacodynamics/clinical activity (n = 20). Barzolvolimab was well tolerated; most adverse events were mild and resolved. Treatment resulted in significant depletion of skin MCs, decreased tryptase (

Multi-scale mechanobiological model for skeletal muscle hypertrophy.

Skeletal muscle adaptation is correlated to training exercise by triggering different signaling pathways that target many functions; in particular, the IGF1-AKT pathway controls protein synthesis and degradation. These two functions regulate the adaptation in size and strength of muscles. Computational models for muscle adaptation have focused on: the biochemical description of signaling pathways or the mechanical description of muscle function at organ scale; however, an interrelation between these two models should be considered to understand how an adaptation in muscle size affects the protein synthesis rate. In this research, a dynamical model for the IGF1-AKT signaling pathway is linked to a continuum-mechanical model describing the active and passive mechanical response of a muscle; this model is used to study the impact of the adaptive muscle geometry on the protein synthesis at the fiber scale. This new computational model links the signaling pathway to the mechanical response by introducing a growth tensor, and links the mechanical response to the signaling pathway through the evolution of the protein synthesis rate. The predicted increase in cross sectional area (CSA) due to an 8 weeks training protocol excellently agreed with experimental data. Further, our results show that muscle growth rate decreases, if the correlation between protein synthesis and CSA is negative. The outcome of this study suggests that multi-scale models coupling continuum mechanical properties and molecular functions may improve muscular therapies and training protocols.

Tissue-specific modifier alleles determine Mertk loss-of-function traits.

Knockout (KO) mouse models play critical roles in elucidating biological processes behind disease-associated or disease-resistant traits. As a presumed consequence of gene KO, mice display certain phenotypes. Based on insight into the molecular role of said gene in a biological process, it is inferred that the particular biological process causally underlies the trait. This approach has been crucial towards understanding the basis of pathological and/or advantageous traits associated with Mertk KO mice. Mertk KO mice suffer from severe, early-onset retinal degeneration. MERTK, expressed in retinal pigment epithelia, is a receptor tyrosine kinase with a critical role in phagocytosis of apoptotic cells or cellular debris. Therefore, early-onset, severe retinal degeneration was described to be a direct consequence of failed MERTK-mediated phagocytosis of photoreceptor outer segments by retinal pigment epithelia. Here, we report that the loss of Mertk alone is not sufficient for retinal degeneration. The widely used Mertk KO mouse carries multiple coincidental changes in its genome that affect the expression of a number of genes, including the Mertk paralog Tyro3. Retinal degeneration manifests only when the function of Tyro3 is concomitantly lost. Furthermore, Mertk KO mice display improved anti-tumor immunity. MERTK is expressed in macrophages. Therefore, enhanced anti-tumor immunity was inferred to result from the failure of macrophages to dispose of cancer cell corpses, resulting in a pro-inflammatory tumor microenvironment. The resistance against two syngeneic mouse tumor models observed in Mertk KO mice is not, however, phenocopied by the loss of Mertk alone. Neither Tyro3 nor macrophage phagocytosis by alternate genetic redundancy accounts for the absence of anti-tumor immunity. Collectively, our results indicate that context-dependent epistasis of independent modifier alleles determines Mertk KO traits.

Monomethyl auristatin antibody and peptide drug conjugates for trimodal cancer chemo-radio-immunotherapy.

Locally advanced cancers remain therapeutically challenging to eradicate. The most successful treatments continue to combine decades old non-targeted chemotherapies with radiotherapy that unfortunately increase normal tissue damage in the irradiated field and have systemic toxicities precluding further treatment intensification. Therefore, alternative molecularly guided systemic therapies are needed to improve patient outcomes when applied with radiotherapy. In this work, we report a trimodal precision cytotoxic chemo-radio-immunotherapy paradigm using spatially targeted auristatin warheads. Tumor-directed antibodies and peptides conjugated to radiosensitizing monomethyl auristatin E (MMAE) specifically produce CD8 T cell dependent durable tumor control of irradiated tumors and immunologic memory. In combination with ionizing radiation, MMAE sculpts the tumor immune infiltrate to potentiate immune checkpoint inhibition. Here, we report therapeutic synergies of targeted cytotoxic auristatin radiosensitization to stimulate anti-tumor immune responses providing a rationale for clinical translational of auristatin antibody drug conjugates with radio-immunotherapy combinations to improve tumor control.

Phase II Trial of CDX-3379 and Cetuximab in Recurrent/Metastatic, HPV-Negative, Cetuximab-Resistant Head and Neck Cancer.

In phase I development, CDX-3379, an anti-ErbB3 monoclonal antibody, showed promising molecular and antitumor activity in head and neck squamous cell carcinoma (HNSCC), alone or in combination with cetuximab. Preliminary biomarker data raised the hypothesis of enhanced response in tumors harboring FAT1 mutations. This phase II, multicenter trial used a Simon 2-stage design to investigate the efficacy of CDX-3379 and cetuximab in 30 patients with recurrent/metastatic, HPV-negative, cetuximab-resistant HNSCC. The primary endpoint was objective response rate (ORR). Secondary endpoints included ORR in patients with somatic FAT1 mutations, progression-free survival (PFS), overall survival (OS), and safety. Thirty patients were enrolled from March 2018 to September 2020. The ORR in genomically unselected patients was 2/30 (6.7%; 95% confidence interval [CI], 0.8-22.1). Median PFS and OS were 2.2 (95% CI: 1.3-3.6) and 6.6 months (95% CI: 2.7-7.5), respectively. Tissue was available in 27 patients including one of two responders. ORR was 1/10 (complete response; 10%; 95% CI 0.30-44.5) in the FAT1-mutated versus 0/17 (0%; 95% CI: 0-19.5) in the FAT1-wildtype cohorts. Sixteen patients (53%) experienced treatment-related adverse events (AEs) ≥ grade 3. The most common AEs were diarrhea (83%) and acneiform dermatitis (53%). Dose modification was required in 21 patients (70%). The modest ORR coupled with excessive, dose-limiting toxicity of this combination precludes further clinical development. Dual ErbB3-EGFR inhibition remains of scientific interest in HPV-negative HNSCC. Should more tolerable combinations be identified, development in an earlier line of therapy and prospective evaluation of the FAT1 hypothesis warrant consideration.

Agonistic CD27 antibody potency is determined by epitope-dependent receptor clustering augmented through Fc-engineering.

Agonistic CD27 monoclonal antibodies (mAb) have demonstrated impressive anti-tumour efficacy in multiple preclinical models but modest clinical responses. This might reflect current reagents delivering suboptimal CD27 agonism. Here, using a novel panel of CD27 mAb including a clinical candidate, we investigate the determinants of CD27 mAb agonism. Epitope mapping and in silico docking analysis show that mAb binding to membrane-distal and external-facing residues are stronger agonists. However, poor epitope-dependent agonism could partially be overcome by Fc-engineering, using mAb isotypes that promote receptor clustering, such as human immunoglobulin G1 (hIgG1, h1) with enhanced affinity to Fc gamma receptor (FcγR) IIb, or hIgG2 (h2). This study provides the critical knowledge required for the development of agonistic CD27 mAb that are potentially more clinically efficacious.

Anti-KIT monoclonal antibody CDX-0159 induces profound and durable mast cell suppression in a healthy volunteer study.

BACKGROUND: Mast cells (MC) are powerful inflammatory immune sentinel cells that drive numerous allergic, inflammatory, and pruritic disorders when activated. MC-targeted therapies are approved in several disorders, yet many patients have limited benefit suggesting the need for approaches that more broadly inhibit MC activity. MCs require the KIT receptor and its ligand stem cell factor (SCF) for differentiation, maturation, and survival. Here we describe CDX-0159, an anti-KIT monoclonal antibody that potently suppresses MCs in human healthy volunteers. METHODS: CDX-0159-mediated KIT inhibition was tested in vitro using KIT-expressing immortalized cells and primary human mast cells. CDX-0159 safety and pharmacokinetics were evaluated in a 13-week good laboratory practice (GLP)-compliant cynomolgus macaque study. A single ascending dose (0.3, 1, 3, and 9 mg/kg), double-blinded placebo-controlled phase 1a human healthy volunteer study (n = 32) was conducted to evaluate the safety, pharmacokinetics, and pharmacodynamics of CDX-0159. RESULTS: CDX-0159 inhibits SCF-dependent KIT activation in vitro. Fc modifications in CDX-0159 led to elimination of effector function and reduced serum clearance. In cynomolgus macaques, multiple high doses were safely administered without a significant impact on hematology, a potential concern for KIT inhibitors. A single dose of CDX-0159 in healthy human subjects was generally well tolerated and demonstrated long antibody exposure. Importantly, CDX-0159 led to dose-dependent, profound suppression of plasma tryptase, a MC-specific protease associated with tissue MC burden, indicative of systemic MC suppression or ablation. CONCLUSION: CDX-0159 administration leads to systemic mast cell ablation and may represent a safe and novel approach to treat mast cell-driven disorders.

A simple and effective 1D-element discrete-based method for computational bone remodeling.

In-silico models applied to bone remodeling are widely used to investigate bone mechanics, bone diseases, bone-implant interactions, and also the effect of treatments of bone pathologies. This article proposes a new methodology to solve the bone remodeling problem using one-dimensional (1D) elements to discretize trabecular structures more efficiently for 2D and 3D domains. An Euler integration scheme is coupled with the momentum equations to obtain the evolution of material density at each step. For the simulations, the equations were solved by using the finite element method, and two benchmark tests were solved varying mesh parameters. Proximal femur and calcaneus bone were selected as study cases given the vast research available on the topology of these bones, and compared with the anatomical features of trabecular bone reported in the literature. The presented methodology has proven to be efficient in optimizing topologies of lattice structures; It can predict the trend of formation patterns of the main trabecular groups from two different cancellous bones (femur and calcaneus) using domains set up by discrete elements as a starting point. Preliminary results confirm that the proposed approach is suitable and useful in bone remodeling problems leading to a considerable computational cost reduction. Characteristics similar to those encountered in topological optimization algorithms were identified in the benchmark tests as well, showing the viability of the proposed approach in other applications such as bio-inspired design.

Prediction of EMG Activation Profiles from Gait Kinematics and Kinetics during Multiple Terrains.

Continuous myoelectric prediction of intended limb dynamics has the ability to provide transparent control of a prosthesis by the user. However, the impact on these models of adding a human user into the control loop is less clear. Here, the ability of a User Response Model (URM) to continuously predict EMG activity from gait kinematics and kinetics collected during three mobility tasks (level-ground walking, stair ascent, and stair descent) was examined. Multiple-input, multiple-output NARX-based URMs were developed with two outputs (ankle plantarflexor and dorsiflexor) and variable inputs (ankle kinetics, and shank and/or ankle kinematics). Accuracy in predicting the tibialis anterior and medial gastrocnemius EMG was comparable across URMs regardless of the number of inputs. Stair descent had the lowest accuracy among the mobility tasks. No significant differences in normalized root-mean-square error and cross-correlation were found between URMs with five and nine inputs. A URM that continuously predicts EMG activity from gait kinetics and kinematics could be used to simulate human-in-the-loop myoelectric control of a transtibial prosthesis and examine the stability of the system to changes in the environment or due to control errors.

Structural basis for ligand reception by anaplastic lymphoma kinase.

The proto-oncogene ALK encodes anaplastic lymphoma kinase, a receptor tyrosine kinase that is expressed primarily in the developing nervous system. After development, ALK activity is associated with learning and memory1 and controls energy expenditure, and inhibition of ALK can prevent diet-induced obesity2. Aberrant ALK signalling causes numerous cancers3. In particular, full-length ALK is an important driver in paediatric neuroblastoma4,5, in which it is either mutated6 or activated by ligand7. Here we report crystal structures of the extracellular glycine-rich domain (GRD) of ALK, which regulates receptor activity by binding to activating peptides8,9. Fusing the ALK GRD to its ligand enabled us to capture a dimeric receptor complex that reveals how ALK responds to its regulatory ligands. We show that repetitive glycines in the GRD form rigid helices that separate the major ligand-binding site from a distal polyglycine extension loop (PXL) that mediates ALK dimerization. The PXL of one receptor acts as a sensor for the complex by interacting with a ligand-bound second receptor. ALK activation can be abolished through PXL mutation or with PXL-targeting antibodies. Together, these results explain how ALK uses its atypical architecture for its regulation, and suggest new therapeutic opportunities for ALK-expressing cancers such as paediatric neuroblastoma.