Non-cell autonomous control of apoptosis by ligand-independent Hedgehog signaling in Drosophila.

Hedgehog (Hh) signaling is important for development and homeostasis in vertebrates and invertebrates. Ligand-independent, deregulated Hh signaling caused by loss of negative regulators such as Patched causes excessive cell proliferation, leading to overgrowth in Drosophila and tumors in humans, including basal-cell carcinoma and medulloblastoma. We show that in Drosophila deregulated Hh signaling also promotes cell survival by increasing the resistance to apoptosis. Surprisingly, cells with deregulated Hh activity do not protect themselves from apoptosis; instead, they promote cell survival of neighboring wild-type cells. This non-cell autonomous effect is mediated by Hh-induced Notch signaling, which elevates the protein levels of Drosophila inhibitor of apoptosis protein-1 (Diap-1), conferring resistance to apoptosis. In summary, we demonstrate that deregulated Hh signaling not only promotes proliferation but also cell survival of neighboring cells. This non-cell autonomous control of apoptosis highlights an underappreciated function of deregulated Hh signaling, which may help to generate a supportive micro-environment for tumor development.

Enhanced sensory re-learning after nerve repair using 3D audio-visual signals and kinaesthesia--preliminary results.

Sensory re-learning methods and basics on cortical reorganization after peripheral nerve lesion are well documented. The aim of enhanced sensory re-learning using 3D audio-visual signals and kinaesthetic training is the augmentation of cognitive memory (visual and acoustic sensory memory) and cognitive function for the improvement of cerebral plasticity processes and starts as soon as possible after nerve repair. Preliminary results are shown.

Generalized approach for accelerated maximum likelihood based image restoration applied to three-dimensional fluorescence microscopy.

For deconvolution applications in three-dimensional microscopy we derived and implemented a generic, accelerated maximum likelihood image restoration algorithm. A conjugate gradient iteration scheme was used considering either Gaussian or Poisson noise models. Poisson models are better suited to low intensity fluorescent image data; typically, they show smaller restoration errors and smoother results. For the regularization, we modified the standard Tikhonov method. However, the generic design of the algorithm allows for more regularization approaches. The Hessian matrix of the restoration functional was used to determine the step size. We compared restoration error and convergence behaviour between the classical line-search and the Hessian matrix method. Under typical working conditions, the restoration error did not increase over that of the line-search and the speed of convergence did not significantly decrease allowing for a twofold increase in processing speed. To determine the regularization parameter, we modified the generalized cross-validation method. Tests that were done on both simulated and experimental fluorescence wide-field data show reliable results.

Intramolecular [4 + 2] cycloaddition reaction of six- and seven-membered cyclic N-allyl-C-arylethynyl iminium salts.

N-Allyl-2-(het)arylethynyl-3,4,5,6-tetrahydropyridinium triflates 1c,d,e and N-allyl-2-(het)aryl-4,5,6,7-tetrahydro-3H-azepinium triflates 1g,h undergo a thermal isomerization reaction leading to derivatives of [a,f]-annulated isoindolium salts 2 in good yields. Similarly, N-allyl-2-phenylethynyl-pyridinium triflate 4 is transformed into the condensed pyridinium salt 5. An intramolecular [4 + 2] cycloaddition reaction, in which the (het)arylethynyl moiety acts as the 4pi component, is considered as the key step of this transformation. In contrast, the related N-allyl-4,5-dihydro-3H-pyrrolium salts 1a,b and N-homoallyl-3,4,5,6-tetrahydropyridinium salt 1f undergo unspecific decomposition under thermal impact.

Metastatic secretory breast cancer. Non-responsiveness to chemotherapy: case report and review of the literature.

Secretory carcinoma of the breast is a rare and indolent tumour originally described in children but occurring equally in the adult population. The principal management problems following primary surgical treatment are local recurrence and axillary lymph node metastases. Distant metastases are extremely rare. We present the case of a 27-year-old woman with pulmonary metastases from a secretory breast cancer treated by mastectomy and axillary lymph node dissection 12 years previously. There was no response to chemotherapy; however, the patient remained alive and active two years from presentation with metastatic disease and one year from cessation of all cytotoxic chemotherapy. She eventually died of respiratory failure two and a half years after presentation. To our knowledge, this is only the fourth reported case of distant metastases from secretory breast cancer and the second reported case in which current active chemotherapy has been used. We review the literature and discuss the apparent chemoresistance of this tumour including the lack of membrane staining for Her2/neu. In the absence of any proven effective chemotherapy we believe that symptom control becomes the focus of management and offers patients with metastatic secretory breast cancer the greatest chance of a functional and good quality existence.

High resolution 1H NMR investigations of the reactivities of alpha-keto acid anions with hydrogen peroxide.

The chemical reactivity of various alpha-keto acid anions (beta-hydroxypyruvate, beta-phenylpyruvate, 2-ketobutyrate and 2-ketoglutarate) with hydrogen peroxide (H2O2) was investigated at physiological pH (7.4) and a temperature of 25 degrees C. The initial concentration of the alpha-keto acid anions was kept constant at 1.00 mM whilst that of added H2O2 was varied from 0.25 to 1.00 mM, and the rate and extent of these reactions was evaluated using 1H NMR spectroscopy. At all H2O2 concentrations utilised, the order of reactivity of the alpha-keto acid anions was beta-hydroxypyruvate > beta-phenylpyruvate > 2-ketobutyrate > 2-ketoglutarate. The results obtained are in agreement with a proposed mechanism for these reactions, involving nucleophilic attack of the mono-deprotonated peroxide species (HO2-) at the C-2 carbonyl group carbon centre. The antioxidant capacity of such alpha-keto acids is discussed in terms of their potential use as therapeutic agents in clinical conditions where H2O2 has been shown to play a critical role in the disease process, i.e., those involving 'oxidative stress'.

Multicomponent investigations of the hydrogen peroxide- and hydroxyl radical-scavenging antioxidant capacities of biofluids: the roles of endogenous pyruvate and lactate. Relevance to inflammatory joint diseases.

High field proton (1H) nuclear magnetic resonance (NMR) analysis of biofluids (health human blood sera and inflammatory knee-joint synovial fluids) has been employed to evaluate the hydrogen peroxide (H2O2)- and hydroxyl radical (0OH)- scavenging antioxidant capacities of a range of polar, low-molecular-mass endogenous metabolites therein. Data obtained indicate that consumption of H2O2 by pyruvate (generating acetate and CO2 via an oxidative decarboxylation reaction) and 0OH radical by lactate (generating pyruvate, and subsequently acetate and CO2) may serve to protect alternative biofluid components (e.g., macromolecules) against reactive oxygen species-mediated oxidative damage in vivo. The mechanistic, physiological and potential therapeutic implications of these results are discussed with special reference to inflammatory joint diseases.

Structures of sulfated oligosaccharides isolated from the respiratory mucins of a non-secretor (O, Le(a + b -)) patient suffering from chronic bronchitis.

Mucin glycopeptides were prepared from the respiratory mucus of a non-secretor, chronic bronchitic patient with blood group O, Le(a + b-). Oligosaccharides were released by alkaline borohydride treatment and purified by anion-exchange chromatography, size-exclusion chromatography and high performance anion-exchange chromatography. Structural studies employed 400-MHz 1H-NMR spectroscopy and matrix assisted laser desorption/ionization mass spectrometry (MALDI-MS). Nine monosulfated oligosaccharides ranging in size from tetra- to hexasaccharide, were fully characterized in this study. The sulfate group occurs either on the C-3 of a terminal galactose residue or on the C-6 of a N-acetylglucosamine residue. In keeping with the non-secretor status of the patient, no structure with an (alpha 1-2)-linked fucose residue was found. Five of the structures had fucose present in (alpha 1-3)-linkage in the X determinant, while only one oligosaccharide (compound 7b) was seen with fucose (alpha 1-4)-linked in the Le(a) determinant. Eight structures isolated from the mucins of the non-secretor patient had not been found previously in the respiratory mucins; they are listed below.

Precise diode method for recording contact potential changes caused by gas adsorption.

A low-temperature recording diode is described which allows the determination of adsorption-induced contact potential differences with an accuracy of better than 0.5 mV. Some experimental work function results of the hydrogen adsorption on platinum (111) and (997) single-crystal faces are presented which demonstrate the usefulness of the method.