Inhibition of tumor angiogenesis by antibodies, synthetic small molecules and natural products

Cancer remains one of the major causes of death worldwide. The switch to pathological angiogenesis is a key process in the promotion of cancer and consequently provides several new and promising targets to anticancer therapy. Thus, antagonizing angiogenesis cuts off the tumor's oxygen and nutrition supply. This review focuses on angiogenesis inhibitors as option for cancer treatment. Modes of action, adverse effects, mechanisms of resistance as well as new developments are highlighted. One approach in angiogenesis inhibition is intermitting the further VEGF (vascular endothelial growth factor) signal pathway with monoclonal antibodies. Bevacizumab is a highly specific recombinant humanized monoclonal IgG antibody targeting VEGF-A. An efficient antitumor therapy demands more specific antibodies that affect other signal molecules besides VEGF-A, which is in the focus of current research. In addition to antagonizing VEGF, there are also small molecules that inhibit receptor tyrosine kinases (RTKs). Many RTK inhibitors have been described, which exhibit different specificity profiles. The question, whether highly specific antagonists are necessary remains open, because other affected RTKs may also represent growth factor receptors that are essential for tumor growth. Therefore their inhibition may also contribute to anticancer activity. Secondary plant metabolites represent templates for the development of new small molecules. The identification of new drugs from plants has a long and successful history. There is convincing evidence for the beneficial effect of phytochemicals on cancer-related pathways, particularly with regard to anti-angiogenesis. Plant phenolics are the most important category of phytochemicals, including flavanoids. Prominent phytochemicals affecting different pathways of angiogenesis are green tea polyphenols (epigallocatechin gallate) and soy bean isoflavones (genistein).     

Biased wrist and finger coordination in Parkinsonian patients during performance of graphical tasks

Handwriting impairments in Parkinson's disease (PD) have been associated with micrographia, i.e. diminished letter size. However, dyscoordination of the wrist and fingers may also contribute to handwriting deterioration in PD. To investigate this hypothesis, right-handed PD patients and controls were tested in performance of three types of cyclic wrist and finger movements: drawing of two lines and a circle. The line drawing was performed with either simultaneous flexion and extension of the wrist and fingers (equivalent pattern resulting in a right-tilted line) or with wrist flexion/extension accompanied with finger extension/flexion (nonequivalent pattern resulting in a left-tilted line). Circle drawing required a specific phase difference between wrist and finger motions. Movements were performed with an inkless pen on a digitizer-tablet at two frequency levels. Consistent deformations of the circle into right-tilted ovals and lower variability in equivalent compared with nonequivalent lines revealed preference to produce right-tilted shapes. This preference became more apparent with increased movement speed and it was amplified in PD patients. Analysis revealed that the circle deformation emerged mainly due to reduction in relative phase, while wrist and finger amplitudes remained unchanged. The results suggest that PD causes deficit characterized by strong tendency to produce certain coordination patterns between wrist and finger motions. This deficit may significantly contribute to handwriting impairments in PD by reducing the dexterity in the production of the variety of shapes of the cursive letters. Furthermore, the deficiency revealed in wrist and finger coordination may represent a more general deficit affecting control of various multi-joint movements in PD.     

Emotion recognition following human pulvinar damage

Pulvinar activation has been observed while viewing fearful expressions, but the necessity of this activation to their recognition has not been previously assessed. We measured the processing of emotional facial expressions in a rare patient with complete unilateral loss of the pulvinar. With brief presentations, patient CJ was incapable of recognizing fearful expressions in his contralesional field. Three other patients, with damage limited to the anterior and to the lateral pulvinar, showed no deficits in recognition. In conjunction with anatomical studies of the monkey pulvinar, these results suggest that fear recognition is mediated by the human medial pulvinar. We outline the possible role of the pulvinar in fear recognition, considering both the pulvinar's direct and indirect cortical connections with the amygdala, and we suggest that the integrative role of the pulvinar may be primary. Our results suggest that the cortex in isolation from the entire pulvinar is incapable of recognizing fearful expressions.     

Extreme genomic variation in a natural population

Whole-genome sequence data from samples of natural populations provide fertile grounds for analyses of intraspecific variation and tests of population genetic theory. We show that the urochordate Ciona savignyi, one of the species of ocean-dwelling broadcast spawners commonly known as sea squirts, exhibits the highest rates of single-nucleotide and structural polymorphism ever comprehensively quantified in a multicellular organism. We demonstrate that the cause for the extreme heterozygosity is a large effective population size, and, consistent with prediction by the neutral theory, we find evidence of strong purifying selection. These results constitute in-depth insight into the dynamics of highly polymorphic genomes and provide important empirical support of population genetic theory as it pertains to population size, heterozygosity, and natural selection.     

Hemispheric asymmetries in feature integration during visual word recognition

Although the definitive source of the left hemisphere's superiority for visual word recognition remains illusive, some argue that the left (LH) and right (RH) hemispheres engage different strategies during early perceptual processes involved in stimulus encoding. In particular, it is proposed that the LH treats a word as a unitary perceptual group whereas the RH processes the letters comprising a word as a series of individual perceptual units. The present study investigated support for this processing distinction by examining hemispheric strategies for temporal integration using Prinzmetal and Millis-Wright's (1984) feature-binding paradigm. A total of 20 participants identified the colour and identity of a target letter, presented within a three-letter word (e.g., ART) or nonword (e.g., HRF), directed to their left or right visual field. Errors were classified on the basis of whether they involved substitution of a colour present within the stimulus but at a different location (ON error), or the substitution of a colour not present within the stimulus (OFF error). As anticipated, for word stimuli there was a higher proportion of OFF errors associated with trials directed to the RH, consistent with the notion that the LH treats words as single perceptual units and is hence biased toward miscombination of perceptual information present within the stimulus. The pattern of ON errors across stimulus type provided clear evidence of RH sequential encoding effects, with the number of errors increasing markedly across the ordinal position of the letters comprising the stimulus string. As such, these data provide new evidence that the LH's advantage for visual word recognition arises, at least in part, from the ability to encode verbal stimuli as single perceptual units.     

Three-dimensional proton MR spectroscopy of human prostate at 3 T without endorectal coil: feasibility

PURPOSE: To evaluate sensitivity and specificity of proton magnetic resonance (MR) spectroscopy of the prostate with external surface coil elements at 3 T for differentiation of cancer from healthy tissue within an acceptable measurement time, by using histopathologic findings as the reference standard. MATERIALS AND METHODS: The study was approved by the institutional review board; informed consent was obtained. Forty-five men (age range, 51-70 years) underwent 3-T MR imaging with external radiofrequency surface coils for signal reception. MR spectroscopy was performed with acquisition-weighted three-dimensional water- and lipid-suppressed point-resolved spectroscopy pulse sequence. Voxels were classified into healthy peripheral zone, central gland, and periurethral zone and cancer tissue. Cancer voxels were classified according to cancer size and certainty in matching histopathologic findings with MR images. After visual inspection of automated fitting of classified voxels, the choline plus creatine-to-citrate (Cho + Cr/Cit) ratio was calculated for all tissues. Area under the receiver operating characteristic curves (A(z)) values were used to assess accuracy of discrimination of cancer from healthy tissues. P < .05 indicated a significant difference. RESULTS: After exclusion of four patients with no voxels that passed visual inspection of the automated fit, a median of 82% of the classified voxels per patient was used in the analysis. Mean Cho + Cr/Cit ratios for healthy tissues were 0.22 +/- 0.12 (standard deviation) for peripheral zone, 0.34 +/- 0.14 for central gland, and 0.36 +/- 0.20 for periurethral area; all were significantly different from that of cancer (P < .001). A(z) for discrimination of probable and definite cancer tissue from healthy tissue for the peripheral zone (0.84) was significantly higher than that for the central gland (0.69) (P < .05). CONCLUSION: Three-dimensional proton MR spectroscopy of the prostate, with a combination of only external radiofrequency surface coils at 3 T, can be used to discriminate cancer from healthy tissue.