Author Correction:Conservation of copy number profiles during engraftment and passaging of patient-derived cancer xenografts (Nature Genetics, (2021), 53, 1, (86-99), 10.1038/s41588-020-00750-6)

This paper was originally published without open access. As of the date of this correction, the paper is available online as an open-access paper under a Creative Commons Attribution 4.0 International License. *Lists of authors and their affiliations appear online

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Abstract. The most interesting and challenging applications of rapid prototyping technologies are in the field of medicine. RP medical models have found application for planning treatment for complex surgery procedures, training, surgical simulation, diagnosis, design and manufacturing of implants as well as medical tools. This paper explores and presents the procedure for making medical models using RP, medical rapid prototyping technologies application in different fields of medicine and the future trends in this area. Key words: Rapid Prototyping (RP), Computer Tomography (CT), DICOM, Segmentation, Medical Modeling, 3D Medical Model INTRODUCTION As it is well known, the term "rapid prototyping" refers to a number of different but related technologies that can be used for building very complex physical models and prototype parts directly from 3D CAD model. Among these technologies are stereolithography (SLA), selective laser sintering (SLS), fused deposition modeling (FDM), laminated object manufacturing (LOM), inkjet-based systems and three dimensional printing (3DP). RP technologies can use wide range of materials (from paper, plastic to metal and nowadays biomaterials) which gives possibility for their application in different fields. RP (including Rapid Tooling) has primary been developed for manufacturing industry in order to speed up the development of new products. They have showed a great impact in this area (prototypes, concept models, form, fit, and function testing, tooling patterns, final products -direct parts). Preliminary research results show significant potential in application of RP technologies in many different fields including medicine. This paper covers possibilities of using RP technologies as a multi-discipline area in the field of medicine. Using RP in medicine is a quite complex task which implies a multidisciplinary approach and very good knowledge of engineering as well as medicine; it also demands many human resources and tight collaboration between doctors and engineers. After years of development rapid prototyping technologies are now being applied in medicine for manufacturing dimensionally accurate human anatomy models from high resolution medical image data. The procedure for making medical models using RP technologies is also presented in this paper. RP MEDICAL MODEL PRODUCTION The procedure for making 3D medical models using RP technologies implies few steps: • 3D digital image; • Data transfer, processing and segmentation; • Evaluation of design; • RP medical model production; • RP medical model validation. 3D Digital Image 3D digital image can be obtained by using computer tomography -CT scanner or MRI data (see Data Transfer, Processing and Segmentation After saving CT or MRI image data, they should be transferred to RP or RE laboratory. The next step is processing these data, which is a very complex and important step, that the quality of the final medical model depends on. Medical Applications of Rapid Prototyping 81 For this step engineers need software package (Mimics, 3D Doctor) in which they can make segmentation of this anatomy image, achieve high resolution 3D rendering in different colors, make 3D virtual model and finally make possible to convert CT or MRI scanned image data from DICOM to .STL (Stereolithography) file format, which is universally accepted RP file format (see The virtual model of internal structures of human's body, which is needed for final production of 3D physical model, requests very good segmentation with a good resolution and small dimensions of pixels. This demands good knowledge in this field which should help engineers to exclude all structures which are not the subject of interest in the scanned image and choose the right region of interest ROI (separate bone from tissue, include just part of a bone, exclude anomalous structures, noise or other problems which can be faced). Depending on complexity of the problem this step usually demands collaboration of RE engineers with radiologists and surgeons who will help to achieve good segmentation, resolution and a finally accurate 3D virtual model. Fig. 2 Commercial Software Packages for Image Segmentation Evaluation of Design This step depends on a case-to-case basis. Sometimes the created model is directly used as an input for RP machine (biomodels). For making surgical tools, incorporating other objects (fixation devices, implants), bone replacements, producing patterns for making fixtures or templates or other complex problems in different fields of medicine, this virtual model in IGES or STL format is processed using some CAD package (Pro Engineer, Catia). This is necessary for evaluation of design, quality of the made model, checking possible errors or other important steps which depends on the concrete case. Surgeons have a very important roll in validation of the created virtual model. It is even more important in some cases of errors which are made because of the misunderstanding of anatomical structures by engineers or because of some disturbances in the scanned images. After this step 3D virtual model is ready for production. RP Medical Model Production This step implies choosing the right RP technology according to the purpose of model itself as well as demanding accuracy, surface finish, visual appearance of internal structures, number of desired colors in the model, strength, material, mechanical properties, etc. Finally 3D virtual model in STL format should be inputted into the RP commercial software for production of 3D physical model (see The quality of physical model is influenced, in the first place, by quality of input STL file but also by orientation of the model in RP machine and by choosing the right parameters for building the model in the same machine. RP Medical Model Validation When the RP medical model is manufactured it should be validated by surgeons. If there are no errors the model is ready for application. RP APPLICATIONS AND MATERIALS No single rapid prototyping technology is dominant in medical applications and they can be used in the most fields of medicine. This paper will summarize the most common application of these technologies. RP Applications • Design and development of medical devices and instrumentation. This is the field where applications of RP show the best results. It specially applies to hearing aids but also to other surgical aid tools. • Great improvements to the fields of prosthetics and implantation. RP techniques are very useful in making prostheses and implants for years. The ability to quickly fit prosthesis to a patient's unique proportions is a great advantage. The techniques are also used for making hip sockets, knee joints and spinal implants for quite some Medical Applications of Rapid Prototyping 83 time. Both the release of and the improvement of the properties of used materials have had a significant influence on the quality of prostheses and implants made by RP. One interesting example is maxillofacial prostheses of an ear which is obtained by creating a wax cast by laser sintering of a plaster cast of existing ear. Due to RP technologies it is very easy to manufacture custom implants. The made model could be used as a negative or a master model of the custom implant. Many researchers explored new applications of RP in this field. • Planning and explaining complex surgical operations. This is very important role of RP technologies in medicine which enable presurgery planning. The use of 3D medical models helps the surgeon to plan and perform complex surgical procedures and simulations and gives him an opportunity to study the bony structures of the patient before the surgery, to increase surgical precision, to reduce time of procedures and risk during surgery as well as costs (thus making surgery more efficient). The possibility to mark different structures in different colors (due to segmentation technique) in a 3D physical model can be very useful for surgery planning and better understanding of the problem as well as for teaching purpose. This is especially important in cancer surgery where tumor tissue can be clearly distinguished from healthy tissue by different color. Surgical planning is most often done with stereolithography (SLA) where the made model has high accuracy, transparency but limited number of colors and 3DP (for more colored models, presentation of FEA results). • Teaching purposes. RP models can be used as teaching aids for students in the classroom as well as for researchers. These models can be made in many colors and provide a better illustration of anatomy, allow viewing of internal structures and much better understanding of some problems or procedures which should be taken in concrete case. They are also used as teaching simulators. • Design and manufacturing biocompatible and bioactive implants and tissue engineering. RP technologies gave significant contribution in the field of tissue engineering through the use of biomaterials including the direct manufacture of bioactive implants. Tissue engineering is a combination of living cells and a support structure called scaffolds. RP systems like fused deposition modeling (FDM), 3D printing (3-DP) and selective laser sintering (SLS) have been proved to be convenient for making porous structures for use in tissue engineering. In this field it is essential to be able to fabricate three-dimensional scaffolds of various geometric shapes, in order to repair defects caused by accidents, surgery, or birth. FDM, SLS and 3DP can be used to fabricate a functional scaffold directly but RP systems can also be used for manufacturing a sacrificial mould to fabricate tissue-engineering scaffolds. Materials There are varieties of materials which can be used for medical applications of RP. Which material should be selected depends on the purpose of made model (planning procedures, implants, prostheses, surgical tools, tissue scaffold …), demanded properties of material for concrete application and the possibilities of the chosen RP technique. Materials must show biological compatibility. Recent and Future Trends Resent research has led to the development of the RP process building and improving upon artificial bone implants which are strong enough to support a new bone yet, at the same time, porous enough to be absorbed and replaced by the body. This will help in using RP for replacing severely injured bones. It is a very significant discovery in medicine and the first step on the way to making other complex human organs. There are also many unexplored possibilities of using RP in different fields of medicine. Further development in RP in tissue engineering requires the design of new materials, optimal scaffold design and the input of such kind of knowledge of cell physiology that would make it possible in the future to print whole replacement organs or whole bodies by machines. There are also many new trends of applying RP in orthopedics, oral and maxillofacial surgery and other fields of medicine. CONCLUSION RP technologies are definitely widely spread in different fields of medicine and show a great potential in medical applications. Various uses of RP within surgical planning, simulation, training, production of models of hard tissue, prosthesis and implants, biomechanics, tissue engineering and many other cases open up a new chapter in medicine. Due to RP technologies doctors and especially surgeons are privileged to do some things which previous generations could only have imagined. However this is just a little step ahead. There are many unsolved medical problems and many expectations from RP in this field. Development in speed, cost, accuracy, materials (especially biomaterials) and tight collaboration between radiologists, surgeons and engineers is necessary and so are constant improvements from RP vendors. This will help RP technologies to give their maximum in such an important field like medicine

SELENIUM EFFECT UPON THE RATS' HEMATOPOIESIS IN THE SUBACUTE BENZENE INTOXICATION

The antioxidants (selenium, vitamins C and E) stabilize the cell membrane andprotect the cells from the action of free radicals. On the other hand, the antioxidantsreduce the effects of chemical and physical agenls. Bcsidcs, selenium has animportant role in Transporting electrons in the mitochondria and il is necessary for iheglulathione peroxidase function in the protection from apoplhosis. Benzene is auniversal solvent and has a wide application in chemical industry. Its toxicity ismanifested in the damages done to the central nervous syslem, liver, kidneys andhematopoiesis system. Tn this experiment the Wistar rats were used that wereclassified in three experimental groups regarding the quantity of the receivedselenium. Each group comprised ten animals of both sexes and after two weeks'treatment by selenium of 4,8 and 16 mcg, the animals had received benzene byinlraperiloneal administration in the dose of 1,2 ml/kg of the body weight. Thecounting of the shaped blood elements was done after the selenium pretreatment andafter the benzene intoxication. The obtained results poinl to increased number of alithe blood elements after the selenium pretreatment while after benzene adminislrationthere was a drastic drop of the number of erylhrocyles and leukocytes alongwith moderate lhrombocylopenia. After the sacrifice, Ihe hematopoiesis organs weretaken. The hislological findings of the bone marrow show the emergence ofdisturbances, especially of the red sort cells as well as an obvious fat degeneration which is particularly conspicuous in the second and third groups of animals. Therewas also some damage done to the spleen, especially of its red pulp along with thepresence of a greater number of fresh erythrocytes in the second and third groups.Only the changes were more drastic in the third group. The obtained results show thatselenium in higher concentrations increases the number of erytrocytes andleukocytes which proves that it stimulates highly-proliferating cells of the bonemarrow. However, after the intoxication by a sub lethal benzene dose there was a dropof the cells of red and white color but these values are within the normal limits. Thispoints to the fact that the emergence of death is not in any direct correlation with thedisturbances in the hematopoiesis, but death was caused by the damage done to someother vital organs. Despite the fact that selenium prevents the cells' damage, in thisčaše its protective effect manifested itself only when it was given in small doses sincethere was no death in this group of animals

Physicochemically modified peat by thermal and oxidation processes as an active material for purification of wastewaters from certain hazardous pollutants

The physicochemical modification of peat through thermal and oxidation processes was carried out, in order to obtain new, inexpensive and active material for purification of different types of waters. During the modification, surface chemical compounds of Shilov type were formed. Batch adsorption properties and suitability of physicochemically modified peat (PCMP) for odor removal were tested in aqueous solutions of H2S and colloidal sulphur. Additionally, PCMP was tested in the removal of As(V) which is hazardous ingredient in contaminated waters. Possible mechanisms of pollutants binding include interactions, which lead to formation of adducts and clathrates. All these processes are elucidated in detail. The results showed that the obtained material can be used for the removal of sulphide, colloidal sulphur and As(V) from different types of waters

Systematic Establishment of Robustness and Standards in Patient-Derived Xenograft Experiments and Analysis.

Patient-derived xenografts (PDX) are tumor-in-mouse models for cancer. PDX collections, such as the NCI PDXNet, are powerful resources for preclinical therapeutic testing. However, variations in experimental and analysis procedures have limited interpretability. To determine the robustness of PDX studies, the PDXNet tested temozolomide drug response for three prevalidated PDX models (sensitive, resistant, and intermediate) across four blinded PDX Development and Trial Centers using independently selected standard operating procedures. Each PDTC was able to correctly identify the sensitive, resistant, and intermediate models, and statistical evaluations were concordant across all groups. We also developed and benchmarked optimized PDX informatics pipelines, and these yielded robust assessments across xenograft biological replicates. These studies show that PDX drug responses and sequence results are reproducible across diverse experimental protocols. In addition, we share the range of experimental procedures that maintained robustness, as well as standardized cloud-based workflows for PDX exome-sequencing and RNA-sequencing analyses and for evaluating growth. SIGNIFICANCE: The PDXNet Consortium shows that PDX drug responses and sequencing results are reproducible across diverse experimental protocols, establishing the potential for multisite preclinical studies to translate into clinical trials

Conservation of copy number profiles during engraftment and passaging of patient-derived cancer xenografts.

Patient-derived xenografts (PDXs) are resected human tumors engrafted into mice for preclinical studies and therapeutic testing. It has been proposed that the mouse host affects tumor evolution during PDX engraftment and propagation, affecting the accuracy of PDX modeling of human cancer. Here, we exhaustively analyze copy number alterations (CNAs) in 1,451 PDX and matched patient tumor (PT) samples from 509 PDX models. CNA inferences based on DNA sequencing and microarray data displayed substantially higher resolution and dynamic range than gene expression-based inferences, and they also showed strong CNA conservation from PTs through late-passage PDXs. CNA recurrence analysis of 130 colorectal and breast PT/PDX-early/PDX-late trios confirmed high-resolution CNA retention. We observed no significant enrichment of cancer-related genes in PDX-specific CNAs across models. Moreover, CNA differences between patient and PDX tumors were comparable to variations in multiregion samples within patients. Our study demonstrates the lack of systematic copy number evolution driven by the PDX mouse host