MondoA drives malignancy in B-ALL through enhanced adaptation to metabolic stress.

peer reviewedCancer cells are in most instances characterized by rapid proliferation and uncontrolled cell division. Hence, they must adapt to proliferation-induced metabolic stress through intrinsic or acquired antimetabolic stress responses to maintain homeostasis and survival. One mechanism to achieve this is reprogramming gene expression in a metabolism-dependent manner. MondoA (also known as Myc-associated factor X-like protein X-interacting protein [MLXIP]), a member of the MYC interactome, has been described as an example of such a metabolic sensor. However, the role of MondoA in malignancy is not fully understood and the underlying mechanism in metabolic responses remains elusive. By assessing patient data sets, we found that MondoA overexpression is associated with worse survival in pediatric common acute lymphoblastic leukemia (ALL; B-precursor ALL [B-ALL]). Using clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) and RNA-interference approaches, we observed that MondoA depletion reduces the transformational capacity of B-ALL cells in vitro and dramatically inhibits malignant potential in an in vivo mouse model. Interestingly, reduced expression of MondoA in patient data sets correlated with enrichment in metabolic pathways. The loss of MondoA correlated with increased tricarboxylic acid cycle activity. Mechanistically, MondoA senses metabolic stress in B-ALL cells by restricting oxidative phosphorylation through reduced pyruvate dehydrogenase activity. Glutamine starvation conditions greatly enhance this effect and highlight the inability to mitigate metabolic stress upon loss of MondoA in B-ALL. Our findings give novel insight into the function of MondoA in pediatric B-ALL and support the notion that MondoA inhibition in this entity offers a therapeutic opportunity and should be further explored

Concept for Intuitive Control of Omni-Directional Industrial Trucks with Arbitrary Wheels Configuration

Die Steuerung von Flurförderzeugen mit ihren vielfältigen Fahrwerkskonfigurationen erfolgt auf ebenso unterschiedliche Arten entweder von Menschenhand oder maschinell über Schnittstellen, die fahrzeugspezifisch und bei flächenbeweglichen Fahrzeugen oft wenig intuitiv sind. Das Ziel einer einheitlichen Beschreibungsform zur Vorgabe der Bewegungsart und Geschwindigkeit führt zur Definition dreier unabhängiger, intuitiv erfassbarer und physikalisch greifbarer Parameter. Ein Fokus liegt auf der Vermeidung von Singularitäten, so dass sich immer stetige Vorgabegrößen für die Antriebe ergeben. Eine effiziente Rechenstruktur am Beispiel eines Fahrwerks mit beliebig vielen Fahr-Lenk-Modulen verdeutlicht das Konzept, welches die Vereinheitlichung solcher Schnittstellen anregen soll.Industrial trucks with their manifold wheel configurations are controlled in many different ways either manually or automatically. The employed interfaces are vehicle specific and often not very intuitive. To reach the goal of a uniform description for the target type of motion and velocity, three independent, intuitive to grasp and physically meaningful parameters are defined. A focus on avoiding singularities leads to continuous control variables for the involved drives under all conditions. Based on an example chassis with an arbitrary number of combined steering and drive modules, an efficient way of calculation illustrates this concept, which aims to harmonize such control interfaces

Application of the Omni-Curve-Parameters to Determine the Actuator Set-points and Universally Assess the Possible Motions of Different Traveling Gears

Die Omni-Kurven-Parameter (OKP) bilden eine Basis zur universellen Ansteuerung beliebiger Fahrwerke. Die darin bisher nicht definierten Kenngrößen werden hier systematisch bestimmt und die Methode auf unter-schiedliche Beispiel-Fahrwerke angewendet. Auf die daraus gewonnenen Gleichungen stützt sich die weitere Untersuchung zu den Auswirkungen begrenzter Stellgrößen auf die Steuerung mittels OKP. Zur maschinell verwertbaren Beschreibung der teils komplexen Zusammenhänge dienen dreidimensionale Darstellungen des erlaubten Konfigurationsraums. Diese eignen sich sowohl zur internen Fahrzeugsteuerung, als auch für eine vorgelagerte Pfadplanung insbesondere bei FTF.Omni-Curve-Parameters (OCP) provide a basis for universally controlling arbitrary types of undercarriages. While systematically determining the yet undefined characteristic metrics therein, the method is now applied to various examples of traveling gears. Based on the developed equations, an analysis concerning the implications of limits in the actuating variables for piloting via OCP follows. A machine-usable description of the partly complex correlations is facilitated by three-dimensional representations of the permissible configuration space. These are suitable for use in the internal vehicle control system, as well as for prior path planning, especially in the context of AGVs

The fecal microbiome of ALS patients

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative motor neuron disease accompanied by both systemic and central nervous system-specific inflammation as well as deregulated energy metabolism. These potential pathogenetic factors have recently been found to mutually interact with the gut microbiota, raising the hypothesis of a link between microbiome alterations and ALS pathogenesis. The aim of our study was to assess whether ALS is associated with an altered composition of the fecal microbiota. We compared the fecal microbiota of 25 ALS patients with 32 age-and gender-matched healthy persons using 16S rRNA gene sequencing analysis. Confounding factors and secondary disease effects on the microbiome were minimized by selection of patients without dysphagia, gastrostomy, noninvasive ventilation, or reduced body mass index. Comparing the 2 carefully matched groups, the diversity and the abundance of the bacterial taxa on the different taxonomic levels as well as PICRUSt-predicted metagenomes were almost indistinguishable. Significant differences between ALS patients and healthy controls were only observed with regard to the overall number of microbial species (operational taxonomic units) and in the abundance of uncultured Rumino-coccaceae. Conclusively, ALS patients do not exhibit a substantial alteration of the gut microbiota composition. (C) 2017 Elsevier Inc. All rights reserved

Finding the Optimal Surgical Incision Pattern—A Biomechanical Study

The closure of wounds and subsequent optimal wound healing is essential to any successful surgical intervention. Especially on parts of the body with limited possibilities for local reconstruction, optimal distribution of load is essential. The aim of the present study was therefore to examine three different incision patterns, conventional straight, Lazy-S and Zigzag, with regard to their biomechanical stability and mode of failure on a porcine skin model. Our results demonstrate the superior biomechanical stability of Lazy-S and Zigzag incision patterns with perpendicular suture placement. This holds true, in particular, for Zigzag incisions, which showed the highest values for all parameters assessed. Moreover, the observed superior stability of Lazy-S and Zigzag incision patterns was diminished when sutures were placed in tensile direction. The conventional straight incision represents the standard access for a large number of surgical procedures. However, we were able to demonstrate the superior biomechanical stability of alternative incision patterns, in particular the Zigzag incision. This is most likely caused by an improved distribution of tensile force across the wound due to the perpendicular placement of sutures. Moreover, this technique offers additional advantages, such as a better overview of the operated area as well as several cosmetic improvements. We therefore advocate that the surgeon should consider the use of a Zigzag incision over a conventional straight incision pattern

Dynamic 18F-FET PET/CT to differentiate recurrent primary brain tumor and brain metastases from radiation necrosis after single-session robotic radiosurgery

Objective Cyberknife robotic radiosurgery (RRS) provides single-session high-dose radiotherapy of brain tumors with a steep dose gradient and precise real-time image-guided motion correction. Although RRS appears to cause more radiation necrosis (RN), the radiometabolic changes after RRS have not been fully clarified. 18F-FET-PET/CT is used to differentiate recurrent tumor (RT) from RN after radiosurgery when MRI findings are indecisive. We explored the usefulness of dynamic parameters derived from 18F-FET PET in differentiating RT from RN after Cyberknife treatment in a single-center study population. Methods We retrospectively identified brain tumor patients with static and dynamic 18F-FET-PET/CT for suspected RN after Cyberknife. Static (tumor-to-background ratio) and dynamic PET parameters (time-activity curve, time-to-peak) were quantified. Analyses were performed for all lesions taken together (TOTAL) and for brain metastases only (METS). Diagnostic accuracy of PET parameters (using mean tumor-to-background ratio >1.95 and time-to-peak of 20 min for RT as cut-offs) and their respective improvement of diagnostic probability were analyzed. Results Fourteen patients with 28 brain tumors were included in quantitative analysis. Time-activity curves alone provided the highest sensitivities (TOTAL: 95%, METS: 100%) at the cost of specificity (TOTAL: 50%, METS: 57%). Combined mean tumor-to-background ratio and time-activity curve had the highest specificities (TOTAL: 63%, METS: 71%) and led to the highest increase in diagnosis probability of up to 16% p. – versus 5% p. when only static parameters were used. Conclusions This preliminary study shows that combined dynamic and static 18F-FET PET/CT parameters can be used in differentiating RT from RN after RRS