Biological, diagnostic and therapeutic relevance of the MET receptor signaling in head and neck cancer.

Head and neck cancer constitutes the 6th most common malignancy worldwide and affects the crucial anatomical structures and physiological functions of the upper aerodigestive tract. Classical therapeutic strategies such as surgery and radiotherapy carry substantial toxicity and functional impairment. Moreover, the loco-regional control rates as well as overall survival still need to be improved in subgroups of patients. The scatter-factor/hepatocyte growth factor receptor tyrosine kinase MET is an established effector in the promotion, maintenance and progression of malignant transformation in a wide range of human malignancies, and has been gaining considerable interest in head and neck cancer over the last 15 years. Aberrant MET activation due to overexpression, mutations, tumor-stroma paracrine loops, and cooperative/redundant signaling has been shown to play prominent roles in epithelial-to-mesenchymal transition, angiogenesis, and responses to anti-cancer therapeutic modalities. Accumulating preclinical and translational evidence highly supports the increasing interest of MET as a biomarker for lymph node and distant metastases, as well as a potential marker of stratification for responses to ionizing radiation. The relevance of MET as a therapeutic molecular target in head and neck cancer described in preclinical studies remains largely under-evaluated in clinical trials, and therefore inconclusive. Also in the context of anti-cancer targeted therapy, a large body of preclinical data suggests a central role for MET in treatment resistance towards multiple therapeutic modalities in malignancies of the head and neck region. These findings, as well as the potential use of combination therapies including MET inhibitors in these tumors, need to be further explored.

Assessment of post-stroke fatigue: the fatigue scale for motor and cognitive functions

Post-stroke fatigue (PSF) is an important but still controversial issue since knowledge on its nature is still humble. The aim of the present study was to characterize PSF beyond the subacute phase.

Intestinal microbes affect phenotypes and functions of invariant natural killer T cells in mice

Invariant natural killer T (iNKT) cells undergo canonical, Vα14-Jα18 rearrangement of the T-cell receptor (TCR) in mice; this form of the TCR recognizes glycolipids presented by CD1d. iNKT cells mediate many different immune reactions. Their constitutive activated and memory phenotype and rapid initiation of effector functions after stimulation indicate previous antigen-specific stimulation. However, little is known about this process. We investigated whether symbiotic microbes can determine the activated phenotype and function of iNKT cells.

First serial assessment at 6 months and 2 years of the second generation of absorb everolimus-eluting bioresorbable vascular scaffold: a multi-imaging modality study

Nonserial observations have shown this bioresorbable scaffold to have no signs of area reduction at 6 months and recovery of vasomotion at 1 year. Serial observations at 6 months and 2 years have to confirm the absence of late restenosis or unfavorable imaging outcomes.

Cognitive and behavioral aspects of executive functions in children born very preterm

This study investigated whether children aged between 8 and 12 years born very preterm (VPT) and/or at very low birth weight (VLBW) performed lower than same-aged term-born controls in cognitive and behavioral aspects of three executive functions: inhibition, working memory, and shifting. Special attention was given to sex differences. Fifty-two VPT/VLBW children (26 girls, 50%) born in the cohort of 1998-2003 and 36 same-aged term-born children (18 girls, 50%) were recruited. As cognitive measures, children completed tasks of inhibition (Color-Word Interference Test, D-KEFS; Delis, Kaplan, & Kramer, 2001 ), working memory (digit span backwards, HAWIK-IV; Petermann & Petermann, 2008 ), and shifting (Trail Making Test, number-letter-switching, D-KEFS; Delis et al., 2001 ). As behavioral measures, mothers completed the Behavior Rating Inventory of Executive Function (BRIEF; Gioia, Isquith, Guy, & Kenworthy, 2000 ). Scales of interest were inhibit, working memory, and shift. Analyses of the cognitive aspects of executive functions revealed that VPT/VLBW children performed significantly lower than controls in the shifting task but not in the working memory and inhibition tasks. Analyses of behavioral aspects of executive functions revealed that VPT/VLBW children displayed more problems than the controls in working memory in everyday life but not in inhibition and shifting. No sex differences could be detected either in cognitive or behavioral aspects of executive functions. To conclude, cognitive and behavioral measures of executive functions were not congruent in VPT/VLBW children. In clinical practice, the combination of cognitive and behavioral instruments is required to disclose children's executive difficulties.

Structural and functional diversity of connexin genes in the mouse and human genome

Gap junctions are clustered channels between contacting cells through which direct intercellular communication via diffusion of ions and metabolites can occur. Two hemichannels, each built up of six connexin protein subunits in the plasma membrane of adjacent cells, can dock to each other to form conduits between cells. We have recently screened mouse and human genomic data bases and have found 19 connexin (Cx) genes in the mouse genome and 20 connexin genes in the human genome. One mouse connexin gene and two human connexin genes do not appear to have orthologs in the other genome. With three exceptions, the characterized connexin genes comprise two exons whereby the complete reading frame is located on the second exon. Targeted ablation of eleven mouse connexin genes revealed basic insights into the functional diversity of the connexin gene family. In addition, the phenotypes of human genetic disorders caused by mutated connexin genes further complement our understanding of connexin functions in the human organism. In this review we compare currently identified connexin genes in both the mouse and human genome and discuss the functions of gap junctions deduced from targeted mouse mutants and human genetic disorders.

The alpha and beta subunits of the metalloprotease meprin are expressed in separate layers of human epidermis, revealing different functions in keratinocyte proliferation and differentiation

The zinc endopeptidase meprin (EC 3.4.24.18) is expressed in brush border membranes of intestine and kidney tubules, intestinal leukocytes, and certain cancer cells, suggesting a role in epithelial differentiation and cell migration. Here we show by RT-PCR and immunoblotting that meprin is also expressed in human skin. As visualized by immunohistochemistry, the two meprin subunits are localized in separate cell layers of the human epidermis. Meprin alpha is expressed in the stratum basale, whereas meprin beta is found in cells of the stratum granulosum just beneath the stratum corneum. In hyperproliferative epidermis such as in psoriasis vulgaris, meprin alpha showed a marked shift of expression from the basal to the uppermost layers of the epidermis. The expression patterns suggest distinct functions for the two subunits in skin. This assumption is supported by diverse effects of recombinant meprin alpha and beta on human adult low-calcium high-temperature keratinocytes. Here, beta induced a dramatic change in cell morphology and reduced the cell number, indicating a function in terminal differentiation, whereas meprin alpha did not affect cell viability, and may play a role in basal keratinocyte proliferation.

Trypanosomes and mammalian sperm: one of a kind?

Flagellar-mediated motility is an indispensable function for cell types as evolutionarily distant as mammalian sperm and kinetoplastid parasites, a large group of flagellated protozoa that includes several important human pathogens. Despite the obvious importance of flagellar motility, little is known about the signalling processes that direct the frequency and wave shape of the flagellar beat, or those that provide the motile cell with the necessary environmental cues that enable it to aim its movement. Similarly, the energetics of the flagellar beat and the problem of a sufficient ATP supply along the entire length of the beating flagellum remain to be explored. Recent proteome projects studying the flagella of mammalian sperm and kinetoplastid parasites have provided important information and have indicated a surprising degree of similarities between the flagella of these two cell types.

Strengthening of laterality of verbal and visuospatial functions during childhood and adolescence

Cognitive functions in the child's brain develop in the context of complex adaptive processes, determined by genetic and environmental factors. Little is known about the cerebral representation of cognitive functions during development. In particular, knowledge about the development of right hemispheric (RH) functions is scarce. Considering the dynamics of brain development, localization and lateralization of cognitive functions must be expected to change with age. Twenty healthy subjects (8.6-20.5 years) were examined with fMRI and neuropsychological tests. All participants completed two fMRI tasks known to activate left hemispheric (LH) regions (language tasks) and two tasks known to involve predominantly RH areas (visual search tasks). A laterality index (LI) was computed to determine the asymmetry of activation. Group analysis revealed unilateral activation of the LH language circuitry during language tasks while visual search tasks induced a more widespread RH activation pattern in frontal, superior temporal, and occipital areas. Laterality of language increased between the ages of 8-20 in frontal (r = 0.392, P = 0.049) and temporal (r = 0.387, P = 0.051) areas. The asymmetry of visual search functions increased in frontal (r = -0.525, P = 0.009) and parietal (r = -0.439, P = 0.027) regions. A positive correlation was found between Verbal-IQ and the LI during a language task (r = 0.585, P = 0.028), while visuospatial skills correlated with LIs of visual search (r = -0.621, P = 0.018). To summarize, cognitive development is accompanied by changes in the functional representation of neuronal circuitries, with a strengthening of lateralization not only for LH but also for RH functions. Our data show that age and performance, independently, account for the increases of laterality with age.