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The investigation of metabolic fluxes and metabolite distributions within cells by means of tracer molecules is a valuable tool to unravel the complexity of biological systems. Technological advances in mass spectrometry (MS) technology such as atmospheric pressure chemical ionization (APCI) coupled with high resolution (HR), not only allows for highly sensitive analyses but also broadens the usefulness of tracer-based experiments, as interesting signals can be annotated de novo when not yet present in a compound library. However, several effects in the APCI ion source, i.e., fragmentation and rearrangement, lead to superimposed mass isotopologue distributions (MID) within the mass spectra, which need to be corrected during data evaluation as they will impair enrichment calculation otherwise. Here, we present and evaluate a novel software tool to automatically perform such corrections. We discuss the different effects, explain the implemented algorithm, and show its application on several experimental datasets. This adjustable tool is available as an R package from CRAN.
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MACC1 is a prognostic and predictive metastasis biomarker for more than 20 solid cancer entities. However, its role in cancer metabolism is not sufficiently explored. Here, we report on how MACC1 impacts the use of glucose, glutamine, lactate, pyruvate and fatty acids and show the comprehensive analysis of MACC1-driven metabolic networks. We analyzed concentration-dependent changes in nutrient use, nutrient depletion, metabolic tracing employing 13C-labeled substrates, and in vivo studies. We found that MACC1 permits numerous effects on cancer metabolism. Most of those effects increased nutrient uptake. Furthermore, MACC1 alters metabolic pathways by affecting metabolite production or turnover from metabolic substrates. MACC1 supports use of glucose, glutamine and pyruvate via their increased depletion or altered distribution within metabolic pathways. In summary, we demonstrate that MACC1 is an important regulator of metabolism in cancer cells.
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N-Myc is a transcription factor that is aberrantly expressed in many tumor types and is often correlated with poor patient prognosis. Recently, several lines of evidence pointed to the fact that oncogenic activation of Myc family proteins is concomitant with reprogramming of tumor cells to cope with an enhanced need for metabolites during cell growth. These adaptions are driven by the ability of Myc proteins to act as transcriptional amplifiers in a tissue-of-origin specific manner. Here, we describe the effects of N-Myc overexpression on metabolic reprogramming in neuroblastoma cells. Ectopic expression of N-Myc induced a glycolytic switch that was concomitant with enhanced sensitivity towards 2-deoxyglucose, an inhibitor of glycolysis. Moreover, global metabolic profiling revealed extensive alterations in the cellular metabolome resulting from overexpression of N-Myc. Limited supply with either of the two main carbon sources, glucose or glutamine, resulted in distinct shifts in steady-state metabolite levels and significant changes in glutathione metabolism. Interestingly, interference with glutamine-glutamate conversion preferentially blocked proliferation of N-Myc overexpressing cells, when glutamine levels were reduced. Thus, our study uncovered N-Myc induction and nutrient levels as important metabolic master switches in neuroblastoma cells and identified critical nodes that restrict tumor cell proliferation.
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Proteína Proto-Oncogénica N-Myc/fisiología , Neuroblastoma/patología , Línea Celular Tumoral , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Glucosamina/metabolismo , Glucosa/metabolismo , Humanos , Neuroblastoma/genética , Neuroblastoma/metabolismo , Neuroblastoma/terapiaRESUMEN
BACKGROUND: The aim of this study was to investigate the efficacy of orthodontic treatment using the Invisalign® system. Particularly, we analyzed the influence of auxiliaries (Attachment/Power Ridge) as well as the staging (movement per aligner) on treatment efficacy. METHODS: We reviewed the tooth movements of 30 consecutive patients who required orthodontic treatment with Invisalign®. In all patients, one of the following tooth movements was performed: (1) Incisor Torque >10°, (2) Premolar derotation >10° (3) Molar distalization >1.5 mm. The groups (1)-(3) were subdivided: in the first subgroup (a) the movements were supported with the use of an attachment, while in the subgroup (b) no auxiliaries were used (except incisor torque, in which Power Ridges were used). All tooth movements were performed in a split-mouth design. To analyze the clinical efficacy, pre-treatment and final plaster cast models were laser-scanned and the achieved tooth movement was determined by way of a surface/surface matching algorithm. The results were compared with the amount of tooth movement predicted by ClinCheck®. RESULTS: The overall mean efficacy was 59% (SD = 0.2). The mean accuracy for upper incisor torque was 42% (SD = 0.2). Premolar derotation showed the lowest accuracy with approximately 40% (SD = 0.3). Distalization of an upper molar was the most effective movement, with efficacy approximately 87% (SD = 0.2). CONCLUSION: Incisor torque, premolar derotation and molar distalization can be performed using Invisalign® aligners. The staging (movement/aligner) and the total amount of planned movement have an significant impact on treatment efficacy.
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Diente Premolar/patología , Incisivo/patología , Diente Molar/patología , Diseño de Aparato Ortodóncico , Técnicas de Movimiento Dental/instrumentación , Adolescente , Adulto , Anciano , Femenino , Estudios de Seguimiento , Holografía/instrumentación , Humanos , Procesamiento de Imagen Asistido por Computador/métodos , Imagenología Tridimensional/métodos , Rayos Láser , Masculino , Maloclusión/patología , Maloclusión/terapia , Persona de Mediana Edad , Modelos Dentales , Estudios Retrospectivos , Rotación , Torque , Resultado del Tratamiento , Interfaz Usuario-Computador , Adulto JovenRESUMEN
INTRODUCTION: The exact force systems as well as their progressions generated by removable thermoplastic appliances have not been investigated. Thus, the purposes of this experimental study were to quantify the forces and moments delivered by a single aligner and a series of aligners (Invisalign; Align Technology, Santa Clara, Calif) and to investigate the influence of attachments and power ridges on the force transfer. METHODS: We studied 970 aligners of the Invisalign system (60 series of aligners). The aligners came from 30 consecutive patients, of which 3 tooth movements (incisor torque, premolar derotation, molar distalization) with 20 movements each were analyzed. The 3 movement groups were subdivided so that 10 movements were supported with an attachment and 10 were not. The patients' ClinCheck (Align Technology, Santa Clara, Calif) was planned so that the movements to be investigated were performed in isolation in the respective quadrant. Resin replicas of the patients' intraoral situation before the start of the investigated movement were taken and mounted in a biomechanical measurement system. An aligner was put on the model, the force systems were measured, and the calculated movements were experimentally performed until no further forces or moments were generated. Subsequently, the next aligners were installed, and the measurements were repeated. RESULTS: The initial mean moments were about 7.3 N·mm for maxillary incisor torque and about 1.0 N for distalization. Significant differences in the generated moments were measured in the premolar derotation group, whether they were supported with an attachment (8.8 N·mm) or not (1.2 N·mm). All measurements showed an exponential force change. CONCLUSIONS: Apart from a few maximal initial force systems, the forces and moments generated by aligners of the Invisalign system are within the range of orthodontic forces. The force change is exponential while a patient is wearing removable thermoplastic appliances.