Modulation of mitochondrial function by extracellular acidosis in tumor cells and normal fibroblasts: Role of signaling pathways.

In many tumors pronounced extracellular acidosis resulting from glycolytic metabolism is found. Since several environmental stress factors affect the mitochondrial activity the aim of the study was to analyze the impact of acidosis on cellular oxygen consumption and which signaling pathways may be involved in the regulation. In two tumor cell lines and normal fibroblasts cellular oxygen consumption rate (OCR) and mitochondrial function were measured after 3 h at pH 6.

The Role of microRNAs in Gene Expression and Signaling Response of Tumor Cells to an Acidic Environment.

Many tumors are characterized by marked extracellular acidosis due to increased glycolytic metabolism, which affects gene expression and thereby tumor biological behavior. At the same time, acidosis leads to altered expression of several microRNAs (, , , ). The aim of this study was to analyze whether the acidosis-induced changes in cytokines and tumor-related genes are mediated via pH-sensitive microRNAs.

Development and evaluation of a software system for medical students to teach and practice anamnestic interviews with virtual patient avatars.

Background And Objectives: Taking a medical history is a core competence of the diagnostic process. At the beginning of their study medical students need to learn and practice the necessary techniques, initially focusing on good structuring and completeness. For this purpose, an interactive software system (ViPATalk) was developed in which the student can train to pose questions to virtual patient avatars in free conversation.

Correlation between Circulating miR-16, miR-29a, miR-144 and miR-150, and the Radiotherapy Response and Survival of Non-Small-Cell Lung Cancer Patients.

Despite the success of current therapy concepts, patients with advanced non-small-cell lung cancer (NSCLC) still have a very poor prognosis. Therefore, biological markers are urgently needed, which allow the assessment of prognosis, or prediction of the success of therapy or resistance in this disease. Circulating microRNAs (miRs) have potential as biomarkers for the prognosis and prediction of response to therapy in cancer patients.

Role of acidosis-sensitive microRNAs in gene expression and functional parameters of tumors in vitro and in vivo.

Background: The acidic extracellular environment of tumors has been shown to affect the malignant progression of tumor cells by modulating proliferation, cell death or metastatic potential. The aim of the study was to analyze whether acidosis-dependent miRNAs play a role in the signaling cascade from low pH through changes in gene expression to functional properties of tumors in vitro and in vivo.

Methods: In two experimental tumor lines the expression of 13 genes was tested under acidic conditions in combination with overexpression or downregulation of 4 pH-sensitive miRNAs (miR-7, 183, 203, 215).

Impact of the acidic environment on gene expression and functional parameters of tumors in vitro and in vivo.

Background: The low extracellular pH (pH) of tumors resulting from glycolytic metabolism is a stress factor for the cells independent from concomitant hypoxia. The aim of the study was to analyze the impact of acidic pH on gene expression on mRNA and protein level in two experimental tumor lines in vitro and in vivo and were compared to hypoxic conditions as well as combined acidosis+hypoxia.

Methods: Gene expression was analyzed in AT1 prostate and Walker-256 mammary carcinoma of the rat by Next Generation Sequencing (NGS), qPCR and Western blot.

A hydraulic model of cardiovascular physiology and pathophysiology embedded into a computer-based teaching system for student training in laboratory courses.

Functional understanding of the different parts of the cardiovascular system is essential for an insight into pathomechanisms of numerous diseases. During training cardiovascular physiology, students and early-stage medical personnel should understand the role of different functional parameters for systolic and diastolic blood pressure, as well as for blood flow. The impact of isolated parameters can only be studied in models.

Causes and Consequences of A Glutamine Induced Normoxic HIF1 Activity for the Tumor Metabolism.

The transcription factor hypoxia-inducible factor 1 (HIF1) is the crucial regulator of genes that are involved in metabolism under hypoxic conditions, but information regarding the transcriptional activity of HIF1 in normoxic metabolism is limited. Different tumor cells were treated under normoxic and hypoxic conditions with various drugs that affect cellular metabolism. HIF1α was silenced by siRNA in normoxic/hypoxic tumor cells, before RNA sequencing and bioinformatics analyses were performed while using the breast cancer cell line MDA-MB-231 as a model.

Correction to: Tumor pH and metastasis: a malignant process beyond hypoxia.

The authors have noticed a typographical error in the published article. The term "epithelial-to-mesenchymal transition" should have been used instead of the term "endothelial-to-mesenchymal transition" throughout the manuscript.

Extracellular Acidosis Modulates the Expression of Epithelial-Mesenchymal Transition (EMT) Markers and Adhesion of Epithelial and Tumor Cells.

Epithelial-to-mesenchymal transition (EMT) is an important process of tumor progression associated with increased metastatic potential. EMT can be activated by external triggers such as cytokines or metabolic parameters (e.g.

Cellular and radiobiological effects of carbonic anhydrase IX in human breast cancer cells.

Hypoxia‑induced carbonic anhydrase IX (CAIX) is involved in intracellular and extracellular pH regulation, which is critical for tumor growth and metastasis. CAIX is overexpressed in breast cancer and is associated with the poor survival of patients after radiotherapy. Therefore, we evaluated the cellular and radiobiological effects of CAIX inhibition in human breast cancer cells.

Tumor pH and metastasis: a malignant process beyond hypoxia.

Tumors often show, compared to normal tissues, a markedly decreased extracellular pH resulting from anaerobic or aerobic glycolysis in combination with a reduced removal of acidic metabolites. Several studies indicate that acidosis induces (independently from hypoxia) hematogenous and lymphatic spread of tumor cells worsening the long-term prognosis of tumor patients. This review gives an overview on the impact of low pH on different steps of metastasis including (a) local tumor cell invasion and angiogenesis, (b) intravasation of tumor cells and detachment into the circulation, and (c) adherence of circulating tumor cells, transmigration and invasion in the new host tissue.

Acidic extracellular environment affects miRNA expression in tumors in vitro and in vivo.

Hypoxia can control the expression of miRNAs in tumors which play an important role for the control of the malignant behavior. The aim of the study was to analyze whether extracellular acidosis, a common feature of tumors, also has an impact on the miRNA expression in isolated cells as well as in solid tumors. MiRNA expression was analyzed in two rat tumor cell lines (AT1 prostate and Walker-256 mammary carcinomas) by NGS and qPCR.

Hyperbaric oxygenation and glucose/amino acids substitution in human severe placental insufficiency.

In the first case, the AA and glucose were infused through a perinatal port system into the umbilical vein at 30 weeks' gestation due to severe IUGR. The patient received daily hyperbaric oxygenation (HBO, 100% O ) with 1.4 atmospheres absolute for 50 min for 7 days.

Long-term biodistribution study of HPMA-ran-LMA copolymers in vivo by means of I-labeling.

Background: For the evaluation of macromolecular drug delivery systems suitable pre-clinical monitoring of potential nanocarrier systems is needed. In this regard, both short-term as well as long-term in vivo tracking is crucial to understand structure-property relationships of polymer carrier systems and their resulting pharmacokinetic profile. Based on former studies revealing favorable in vivo characteristics for F-labeled random (ran) copolymers consisting of N-(2-hydroxypropyl)methacrylamide (HPMA) and lauryl methacrylate (LMA) - including prolonged plasma half-life as well as enhanced tumor accumulation - the presented work focuses on their long-term investigation in the living organism.

Correction to: Oxygen Transport to Tissue XL.

The chapters "Changes in Cytochrome-C-Oxidase Account for Changes in Attenuation of Near-Infrared Light in the Healthy Infant Brain" and "Fibreless Multiwavelength NIRS System for Imaging Localised Changes in Cerebral Oxidised Cytochrome C Oxidase" are made as open access as per the author's request in this revised version of the book.

Tumor Acidosis and Hypoxia Differently Modulate the Inflammatory Program: Measurements In Vitro and In Vivo.

Inflammatory mediators produced by the tumor cells are of importance for immune response but also for malignant progression. The aim of the study was to analyze the expression of monocyte chemoattractant protein-1, interleukin-6 (IL-6), tumor necrosis factor-α, inducible isoform of nitric oxide synthase (iNOS), cyclooxygenase-2, and osteopontin in vitro in two different tumor cell lines under hypoxia (pO≈1.5 mmHg) and/or acidosis (pH=6.

Assessing Glomerular Filtration in Small Animals Using [Ga]DTPA and [Ga]EDTA with PET Imaging.

Purpose: Determining the glomerular filtration rate (GFR) is essential for clinical medicine but also for pre-clinical animal studies. Functional imaging using positron emission tomography (PET) allows repetitive almost non-invasive measurements. The aim of the study was the development and evaluation of easily synthesizable PET tracers for GFR measurements in small animals.

Endocytotic uptake of HPMA-based polymers by different cancer cells: impact of extracellular acidosis and hypoxia.

Background: Polymeric nanoparticles allow to selectively transport chemotherapeutic drugs to the tumor tissue. These nanocarriers have to be taken up into the cells to release the drug. In addition, tumors often show pathological metabolic characteristics (hypoxia and acidosis) which might affect the polymer endocytosis.

Inhibition of Carbonic Anhydrase IX by Ureidosulfonamide Inhibitor U104 Reduces Prostate Cancer Cell Growth, But Does Not Modulate Daunorubicin or Cisplatin Cytotoxicity.

Carbonic anhydrase (CA) IX has emerged as a promising target for cancer therapy. It is highly upregulated in hypoxic regions and mediates pH regulation critical for tumor cell survival as well as extracellular acidification of the tumor microenvironment, which promotes tumor aggressiveness via various mechanisms, such as augmenting metastatic potential. Therefore, the aim of this study was to analyze the complex interdependency between CA IX and the tumor microenvironment in prostate tumor cells with regard to potential therapeutic implications.

Using numeric simulation in an online e-learning environment to teach functional physiological contexts.

Background And Objectives: Mathematical models are suitable to simulate complex biological processes by a set of non-linear differential equations. These simulation models can be used as an e-learning tool in medical education. However, in many cases these mathematical systems have to be treated numerically which is computationally intensive.

Temporal changes in tumor oxygenation and perfusion upon normo- and hyperbaric inspiratory hyperoxia.

Background: Inspiratory hyperoxia under hyperbaric conditions has been shown to effectively reduce tumor hypoxia and to improve radiosensitivity. However, applying irradiation (RT) under hyperbaric conditions is technically difficult in the clinical setting since RT after decompression may be effective only if tumor pO2 remains elevated for a certain period of time. The aim of the present study was to analyze the time course of tumor oxygenation and perfusion during and after hyperbaric hyperoxia.

Acidosis differently modulates the inflammatory program in monocytes and macrophages.

Inflammation, ischemia or the microenvironment of solid tumors is often accompanied by a reduction of extracellular pH (acidosis) that stresses the cells and acts on cellular signaling and transcription. The effect of acidosis on the expression of various inflammatory markers, on functional parameters (migration, phagocytic activity) and on signaling pathways involved was studied in monocytic cells and macrophages. In monocytic cell lines acidosis led to a reduction in expression of most of the inflammatory mediators, namely IL-1ß, IL-6, TNF-α, MCP-1, COX-2 and osteopontin.

Injectable LiNc-BuO loaded microspheres as in vivo EPR oxygen sensors after co-implantation with tumor cells.

Electron paramagnetic resonance (EPR) oximetry is a technique which allows accurate and repeatable oxygen measurements. We encapsulated a highly oxygen sensitive particulate EPR spin probe into microparticles to improve its dispersibility and, hence, facilitate the administration. These biocompatible, non-toxic microspheres contained 5-10 % (w/w) spin probe and had an oxygen sensitivity of 0.

Spatial oxygenation profiles in tumors during normo- and hyperbaric hyperoxia.

Background: Inspiratory hyperoxia reduces tumor hypoxia, which is responsible for limited radiosensitivity of tumors. However, very little is known about the heterogeneity of intratumoral oxygenation during this supportive treatment. The study analyzes whether local hypoxia is still present during normobaric and hyperbaric inspiratory hyperoxia and whether the addition of CO2 to the inspiratory gas affects the spatial pO2 distribution.