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The poor correlation of mutational landscapes with phenotypes limits our understanding of the pathogenesis and metastasis of pancreatic ductal adenocarcinoma (PDAC). Here we show that oncogenic dosage-variation has a critical role in PDAC biology and phenotypic diversification. We find an increase in gene dosage of mutant KRAS in human PDAC precursors, which drives both early tumorigenesis and metastasis and thus rationalizes early PDAC dissemination. To overcome the limitations posed to gene dosage studies by the stromal richness of PDAC, we have developed large cell culture resources of metastatic mouse PDAC. Integration of cell culture genomes, transcriptomes and tumour phenotypes with functional studies and human data reveals additional widespread effects of oncogenic dosage variation on cell morphology and plasticity, histopathology and clinical outcome, with the highest Kras MUT levels underlying aggressive undifferentiated phenotypes. We also identify alternative oncogenic gains ( Myc , Yap1 or Nfkb2 ), which collaborate with heterozygous Kras MUT in driving tumorigenesis, but have lower metastatic potential. Mechanistically, different oncogenic gains and dosages evolve along distinct evolutionary routes, licensed by defined allelic states and/or combinations of hallmark tumour suppressor alterations ( Cdkn2a , Trp53 , Tgfβ-pathway). Thus, evolutionary constraints and contingencies direct oncogenic dosage gain and variation along defined routes to drive the early progression of PDAC and shape its downstream biology. Our study uncovers universal principles of Ras -driven oncogenesis that have potential relevance beyond pancreatic cancer. Oncogenic dosage variation along distinct evolutionary routes defines fundamental aspects of pancreatic cancer biology and phenotypic diversification. Predicting pancreatic cancer phenotypes Despite the availability of hundreds of pancreatic cancer genomes, it has been difficult to associate specific mutation patterns with distinct biological features. To address this, Roland Rad and colleagues tracked genomic alterations during the development of pancreatic cancer, aiming to link mutations to heterogeneous phenotypes. Human and mouse studies reveal that different gene dosages of an activating KRAS mutation are critical determinants of pancreatic cancer biology, including early progression, metastasis, histopathology, cellular plasticity and clinical aggressiveness. Mutant KRAS is amplified through distinct evolutionary routes during tumorigenesis that are defined by prior alterations of specific tumour suppressors and oncogenes. This study sheds light on the mechanisms underlying the phenotypic heterogeneity of pancreatic cancer and may aid advances in diagnosis, prognosis and therapy.

The next generation of genetically engineered mouse models of pancreatic cancer involving a new inducible dual-recombinase system that combines Flp- FRT and Cre- loxP . Genetically engineered mouse models (GEMMs) have dramatically improved our understanding of tumor evolution and therapeutic resistance. However, sequential genetic manipulation of gene expression and targeting of the host is almost impossible using conventional Cre- loxP –based models. We have developed an inducible dual-recombinase system by combining flippase- FRT (Flp- FRT ) and Cre- loxP recombination technologies to improve GEMMs of pancreatic cancer. This enables investigation of multistep carcinogenesis, genetic manipulation of tumor subpopulations (such as cancer stem cells), selective targeting of the tumor microenvironment and genetic validation of therapeutic targets in autochthonous tumors on a genome-wide scale. As a proof of concept, we performed tumor cell–autonomous and nonautonomous targeting, recapitulated hallmarks of human multistep carcinogenesis, validated genetic therapy by 3-phosphoinositide-dependent protein kinase inactivation as well as cancer cell depletion and show that mast cells in the tumor microenvironment, which had been thought to be key oncogenic players, are dispensable for tumor formation.

SNAIL is a key transcriptional regulator in embryonic development and cancer. Its effects in physiology and disease are believed to be linked to its role as a master regulator of epithelial-to-mesenchymal transition (EMT). Here, we report EMT-independent oncogenic SNAIL functions in cancer. Using genetic models, we systematically interrogated SNAIL effects in various oncogenic backgrounds and tissue types. SNAIL-related phenotypes displayed remarkable tissue- and genetic context-dependencies, ranging from protective effects as observed in KRAS- or WNT-driven intestinal cancers, to dramatic acceleration of tumorigenesis, as shown in KRAS-induced pancreatic cancer. Unexpectedly, SNAIL-driven oncogenesis was not associated with E-cadherin downregulation or induction of an overt EMT program. Instead, we show that SNAIL induces bypass of senescence and cell cycle progression through p16 INK4A -independent inactivation of the Retinoblastoma (RB)-restriction checkpoint. Collectively, our work identifies non-canonical EMT-independent functions of SNAIL and unravel its complex context-dependent role in cancer. SNAIL promotes tumour metastasis through inducing epithelial to mesenchymal transition (EMT). Here the authors report that SNAIL bypasses senescence and regulates cell cycle progression to promote pancreatic carcinogenesis and this is independent of EMT induction.

This paper presents the results of experiments conducted on a batch of additively manufactured customized prosthetic sockets for upper limbs, made of thermoplastics and designed automatically on the basis of a 3D-scanned limb of a 3-year-old patient. The aim of this work was to compare sockets made of two different materials—rigid PLA and elastic TPE. Two distinct socket designs with various mounting systems were prepared. To find a reliable set of parameters for cheap and stable manufacturing of usable prostheses using 3D printers, realizing the fused deposition modeling (FDM) process, sets of sockets were manufactured with various process parameters. This paper presents the methodology of the design, the plan of the experiments and the obtained results in terms of process stability, fit and assessment by patient, as well as strength of the obtained sockets and their measured surface roughness. The results are promising, as most of the obtained products fulfil the strength criteria, although not all of them meet the fitting and use comfort criteria. As a result, recommendations of materials and process parameters were determined. These parameters were included in a prototype of the automated design and production system developed by the authors, and prostheses for several other patients were manufactured.

The paper presents results of research conducted on a batch of additively manufactured individualized openwork wrist–hand orthoses made of thermoplastics and designed automatically based on 3D-scanned geometry of a given patient. The aim of the work was to establish an automated design process and find a reliable set of parameters for rapid and affordable manufacturing of usable orthoses on popular 3D printers, with little or no supervision of the process. The paper presents motivations, methodology of automated design, plan of manufacturing and testing, the obtained results in terms of process stability, fit and assessment by patient and strength of the obtained orthoses. Almost 100 manufacturing processes of ready-to-use orthosis parts were carried out in a controlled environment and their results were analyzed thoroughly. The results are promising, as most of the obtained products fulfil the strength criteria, although not all of them meet the economic criteria. As a result, a recommended set of process parameters was determined. These parameters were included in a prototype of the automated design and in a production system developed by the authors.

The methods of additive manufacturing of anatomical models are widely used in medical practice, including physician support, education and planning of treatment procedures. The aim of the review was to identify the area of additive manufacturing and the application of anatomical models, imitating both soft and hard tissue. The paper outlines the most commonly used methodologies, from medical imaging to obtaining a functional physical model. The materials used to imitate specific organs and tissues, and the related technologies used to produce, them are included. The study covers publications in English, published by the end of 2022 and included in the Scopus. The obtained results emphasise the growing popularity of the issue, especially in the areas related to the attempt to imitate soft tissues with the use of low-cost 3D printing and plastic casting techniques.

This paper presents results from experimental studies that assess the utilization of virtual, augmented, and mixed reality (VR, AR, MR) at different stages of developing personalized 3D printed upper limb prostheses for adult patients. The prostheses are designed automatically using the AutoMedPrint system, leveraging 3D scans as described in various prior publications. Various stages of development of the prosthesis are made as applications of different extended reality technologies. An assembly instruction is implemented as an immersive VR application, a configurator is designed as AR application and a configurator and try-on application is prepared and deployed in MR. The applications are tested by an international group of experts during a scheduled experiment. The experts then participate to surveys and comparatively evaluate the potential of all the XR technologies. The paper presents the development of these applications, provides a detailed account of the experimental process, including the rankings of XR technologies for different applications throughout the lifecycle of a prosthetic device.

This paper presents the outcomes of investigations conducted on the development procedure of a personalized prosthetic device for an adult patient. The individualization is achieved through 3D scanning, followed by semi-automated design using the AutoMedPrint system, and low-cost fused deposition modelling (FDM) technology for 3D printing. The prosthesis is aimed for use during bicycle riding and other sport activities. During the conducted experiments outlined in this manuscript, the prosthesis is equipped with force and movement sensors. The purpose is to collect data on its functionality across different scenarios and dynamic activities, aiming to assess potential harm, refine the design, and serve as an initial step before activating the prosthesis end effector. This article describes the methodology in detail, including the process of designing, producing, and programming, as well as laboratory and field test results (including testing performed with and without a patient). Overall, the design and prototype are implemented successfully. A discussion about the need for particular improvements in both the mechanical and electrical areas is finally presented.

The paper presents results of studies on an innovative approach to mass customization of prostheses, namely automated design and rapid manufacturing (3D printing), on the basis of 3D scanning of upper limb of a given patient. Two different products are presented – a simple mechanical prosthesis and a cosmetic prosthesis. In both cases, intelligent CAD models, with adaptive geometry – changing automatically to the data from 3D scanning – were prepared. The digital models were built and tested using data of real patients. A special algorithm of 3D scanning data processing was prepared and implemented, as well as a set of algorithms of automated data processing for 3D printing processes. The test models were manufactured using low-cost 3D printing technology. The verification was successful – possibility of preparing customized prostheses was reached, using automated design.

This article presents the process of development, testing, and use of wrist–hand orthosis in the hand therapy of a teen patient with congenital paresis disease. A regular 3D-printed anatomically adjusted orthosis is modified with a set of sensors, to work as motion and interaction controller in virtual reality (VR). As the patient with this condition cannot operate VR controllers due to wrist and hand defects, the corrective orthosis was converted to a VR controller, by introducing custom-made electronics and commercially available motion trackers, linking them to the orthosis. A VR game scenario, with typical input from the VR controllers replaced by input from the custom-made controllers is then designed. The VR game scenario is prepared with involvement of physiotherapists, to incorporate the most important exercises for patients with the same condition. The scenario is tested with a group of human patients and assessed by an expert physiotherapist, for determining its efficiency, as well as to determine a set of necessary improvements for future development of the orthosis.