Erythropoietin receptor regulates tumor mitochondrial biogenesis through iNOS and pAKT

Erythropoietin receptor (EPOR) is widely expressed in healthy and malignant tissues. In certain malignancies, EPOR stimulates tumor growth. In healthy tissues, EPOR controls processes other than erythropoiesis, including mitochondrial metabolism. We hypothesized that EPOR also controls the mitochondrial metabolism in cancer cells. To test this hypothesis, we generated EPOR-knockdown cancer cells to grow tumor xenografts in mice and analyzed tumor cellular respiration via high-resolution respirometry. Furthermore, we analyzed cellular respiratory control, mitochondrial content, and regulators of mitochondrial biogenesis in vivo and in vitro in different cancer cell lines. Our results show that EPOR controls tumor growth and mitochondrial biogenesis in tumors by controlling the levels of both, pAKT and inducible NO synthase (iNOS). Furthermore, we observed that the expression of EPOR is associated with the expression of the mitochondrial marker VDAC1 in tissue arrays of lung cancer patients, suggesting that EPOR indeed helps to regulate mitochondrial biogenesis in tumors of cancer patients. Thus, our data imply that EPOR not only stimulates tumor growth but also regulates tumor metabolism and is a target for direct intervention against progression

Iron- and erythropoietin-resistant anemia in a spontaneous breast cancer mouse model

Anemia of cancer (AoC) with its multifactorial etiology and complex pathology is a poor prognostic indicator for cancer patients. One of the main causes of AoC is cancer-associated inflammation that activates mechanisms, commonly observed in anemia of inflammation, where functional iron deficiency and iron-restricted erythropoiesis is induced by increased hepcidin levels in response to IL-6 elevation. So far only a few AoC mouse models have been described, and most of them did not fully recapitulate the interplay of anemia, increased hepcidin levels and functional iron deficiency in human patients. To test if the selection and the complexity of AoC mouse models dictates the pathology or if AoC in mice per se develops independently of iron deficiency, we characterized AoC in Trp53floxWapCre mice that spontaneously develop breast cancer. These mice developed AoC associated with high IL-6 levels and iron deficiency. However, hepcidin levels were not increased and hypoferremia coincided with anemia rather than causing it. Instead, an early shift in the commitment of common myeloid progenitors from the erythroid to the myeloid lineage resulted in increased myelopoiesis and in the excessive production of neutrophils that accumulate in necrotic tumor regions. This process could neither be prevented by iron nor erythropoietin (EPO) treatment. Trp53floxWapCre mice are the first mouse model where EPO-resistant anemia is described and may serve as a disease model to test therapeutic approaches for a subpopulation of human cancer patients with normal or corrected iron levels that do not respond to EPO

The impact of platelet-derived growth factor on closure of chronic tympanic membrane perforations: a randomized, double-blind, placebo-controlled study

Objective: Patients with tympanic membrane (TM) perforations often suffer from infections, and repetitive topical treatment may be required. These infections can be prevented by permanent closure of the TM perforation. Different surgical treatment options have been described, but non-invasive techniques may be preferred as they carry less risk than surgery. One non-invasive approach is to induce wound healing by application of growth factors. The effect and clinical utility of applying topical platelet derived growth factor (PDGF) for decrease of size and closure of chronic TM perforations is evaluated. Study design: Prospective, randomized, placebo controlled, double blind study Setting: Tertiary referral center. Patients: Twenty patients suffering with chronic suppurative otitis media without cholesteatoma for more than 3 months. Intervention: Topical treatment with PDGF or placebo applied weekly to the TM for 6 weeks. Main outcome measures: Success rate, defined as a reduction of perforation size of 50% or more to determine relative changes of the perforation size; effect of initial size and location of TM perforation on success rate, and air and bone conduction thresholds to determine air-bone gap (ABG) measured before treatment. Results: Randomization made matching pre-treatment perforation size of the two study groups impossible, and the initial rate perforation/TM was significantly smaller in the PDGF group. No difference between the two groups was found for perforation/TM < 10%. However, success rate did not differ significantly between the two groups (Power=0.8), and the effect of PDGF was found to be small (-2%, +-49% STD). Initial size and position of the TM perforation were not significant factors determining success. Mean ABG for the frequencies of 0.5, 1, 2, and 4 kHz was 22.5 dB. Conclusion: The topical application of PDGF as an office treatment for chronic otitis media is not a favourable alternative to surgery

Simulating Facial Surgery Using Finite Element Models

This paper describes a prototype system for surgical planning and prediction of human facial shape after craniofacial and maxillofacial surgery for patients with facial deformities. For this purpose it combines, unifies, and extends various methods from geometric modeling, finite element analysis, and image processing to render highly realistic 3D images of the post surgical situation. The basic concept of the system is to join advanced geometric modeling and animation systems such as Alias with a special purpose finite element model of the human face developed under AVS . In contrast to existing facial models we acquire facial surface and soft tissue data both from photogrammetric and CT scans of the individual. After initial data preprocessing, reconstruction, and registration, a finite element model of the facial surface and soft tissue is provided which is based on triangular finite elements. Stiffness parameters of the soft tissue are computed using segmentations of the underlying..