Frozen section analysis of sentinel lymph nodes in patients with breast cancer does not impair the probability to detect lymph node metastases

Intra-operative frozen section analysis (FS analysis) of sentinel lymph nodes (SLNs) in patients with breast cancer can prevent a second operation for axillary lymph node dissection. In contrast, loss of tissue during FS analysis may impair the probability to detect lymph node metastases. To determine the effect of tissue loss on the probability of detection of metastases, dimensions and tissue loss resulting from intra-operative frozen section analysis were measured for 21 SLNs. In a mathematical model, the influence of tissue loss on the probability to detect metastases was calculated in relation to SLN size for various pathology protocols: an American, a widely used European, the extensive ‘Milan’ and the Dutch protocol. For median-sized SLN 11 × 8 × 5 mm (length × width × height), FS analysis led to a median loss of 680 μm (13.6%) of the height of the SLN. Irrespective of SLN size or used pathology protocol, the probability of detecting 2 mm metastases remained unchanged or even increased (0–12.8%). Moreover, the probability to detect 0.2 mm metastases increased for the majority of tested combinations of SLN size, tissue loss and used protocol. Only when combining maximum tissue loss and smallest SLN size in the Dutch protocol, or when applying the extensive Milan protocol on a median-sized SLN, the probability to detect 0.2 mm metastases decreased by 2.7% and 14.3%, respectively. Contrary to ‘common knowledge’, doing FS analysis of SLNs does not impair the probability to detect lymph node metastases

Temperature Affects the Tripartite Interactions between Bacteriophage WO, Wolbachia, and Cytoplasmic Incompatibility

Wolbachia infections are a model for understanding intracellular, bacterial symbioses. While the symbiosis is often studied from a binary perspective of host and bacteria, it is increasingly apparent that additional trophic levels can influence the symbiosis. For example, Wolbachia in arthropods harbor a widespread temperate bacteriophage, termed WO, that forms virions and rampantly transfers between coinfections. Here we test the hypothesis that temperatures at the extreme edges of an insect's habitable range alter bacteriophage WO inducibility and in turn, Wolbachia densities and the penetrance of cytoplasmic incompatibility. We report four key findings using the model wasp, Nasonia vitripennis: First, both cold treatment at 18 C and heat treatment at 30 C reduce Wolbachia densities by as much as 74% relative to wasps reared at 25 C. Second, in all cases where Wolbachia densities decline due to temperature changes, phage WO densities increase and inversely associate with Wolbachia densities. Heat has a marked effect on phage WO, yielding phage densities that are 552% higher than the room temperature control. Third, there is a significant affect of insect family on phage WO and endoysmbiont densities. Fourth, at extreme temperatures, there was a temperature-mediated adjustment to the density threshold at which Wolbachia cause complete cytoplasmic incompatibility. Taken together, these results demonstrate that temperature simultaneously affects phage WO densities, endosymbiont densities, and the penetrance of cytoplasmic incompatibility. While temperature shock enhances bacteriophage inducibility and the ensuing bacterial mortality in a wide range of medically and industrially-important bacteria, this is the first investigation of the associations in an obligate intracellular bacteria. Implications to a SOS global sensing feedback mechanism in Wolbachia are discussed

GUCY2C Opposes Systemic Genotoxic Tumorigenesis by Regulating AKT-Dependent Intestinal Barrier Integrity

The barrier separating mucosal and systemic compartments comprises epithelial cells, annealed by tight junctions, limiting permeability. GUCY2C recently emerged as an intestinal tumor suppressor coordinating AKT1-dependent crypt-villus homeostasis. Here, the contribution of GUCY2C to barrier integrity opposing colitis and systemic tumorigenesis is defined. Mice deficient in GUCY2C (Gucy2c−/−) exhibited barrier hyperpermeability associated with reduced junctional proteins. Conversely, activation of GUCY2C in mice reduced barrier permeability associated with increased junctional proteins. Further, silencing GUCY2C exacerbated, while activation reduced, chemical barrier disruption and colitis. Moreover, eliminating GUCY2C amplified, while activation reduced, systemic oxidative DNA damage. This genotoxicity was associated with increased spontaneous and carcinogen-induced systemic tumorigenesis in Gucy2c−/− mice. GUCY2C regulated barrier integrity by repressing AKT1, associated with increased junction proteins occludin and claudin 4 in mice and Caco2 cells in vitro. Thus, GUCY2C defends the intestinal barrier, opposing colitis and systemic genotoxicity and tumorigenesis. The therapeutic potential of this observation is underscored by the emerging clinical development of oral GUCY2C ligands, which can be used for chemoprophylaxis in inflammatory bowel disease and cancer

Adolescent Brain Development and the Risk for Alcohol and Other Drug Problems

Dynamic changes in neurochemistry, fiber architecture, and tissue composition occur in the adolescent brain. The course of these maturational processes is being charted with greater specificity, owing to advances in neuroimaging and indicate grey matter volume reductions and protracted development of white matter in regions known to support complex cognition and behavior. Though fronto-subcortical circuitry development is notable during adolescence, asynchronous maturation of prefrontal and limbic systems may render youth more vulnerable to risky behaviors such as substance use. Indeed, binge-pattern alcohol consumption and comorbid marijuana use are common among adolescents, and are associated with neural consequences. This review summarizes the unique characteristics of adolescent brain development, particularly aspects that predispose individuals to reward seeking and risky choices during this phase of life, and discusses the influence of substance use on neuromaturation. Together, findings in this arena underscore the importance of refined research and programming efforts in adolescent health and interventional needs

Heritable determinants of male fertilization success in the nematode Caenorhabditis elegans

<p>Abstract</p> <p>Background</p> <p>Sperm competition is a driving force in the evolution of male sperm characteristics in many species. In the nematode <it>Caenorhabditis elegans</it>, larger male sperm evolve under experimentally increased sperm competition and larger male sperm outcompete smaller hermaphrodite sperm for fertilization within the hermaphrodite reproductive tract. To further elucidate the relative importance of sperm-related traits that contribute to differential reproductive success among males, we quantified within- and among-strain variation in sperm traits (size, rate of production, number transferred, competitive ability) for seven male genetic backgrounds known previously to differ with respect to some sperm traits. We also quantified male mating ability in assays for rates of courtship and successful copulation, and then assessed the roles of these pre- and post-mating traits in first- and second-male fertilization success.</p> <p>Results</p> <p>We document significant variation in courtship ability, mating ability, sperm size and sperm production rate. Sperm size and production rate were strong indicators of early fertilization success for males that mated second, but male genetic backgrounds conferring faster sperm production make smaller sperm, despite virgin males of all genetic backgrounds transferring indistinguishable numbers of sperm to mating partners.</p> <p>Conclusions</p> <p>We have demonstrated that sperm size and the rate of sperm production represent dominant factors in determining male fertilization success and that <it>C. elegans </it>harbors substantial heritable variation for traits contributing to male reproductive success. <it>C. elegans </it>provides a powerful, tractable system for studying sexual selection and for dissecting the genetic basis and evolution of reproduction-related traits.</p

Correlation between investment in sexual traits and valve sexual dimorphism in Cyprideis species (Ostracoda)

Assessing the long-term macroevolutionary consequences of sexual selection has been hampered by the difficulty of studying this process in the fossil record. Cytheroid ostracodes offer an excellent system to explore sexual selection in the fossil record because their readily fossilized carapaces are sexually dimorphic. Specifically, males are relatively more elongate than females in this superfamily. This sexual shape difference is thought to arise so that males carapaces can accommodate their very large copulatory apparatus, which can account for up to one-third of body volume. Here we test this widely held explanation for sexual dimorphism in cytheroid ostracodes by correlating investment in male genitalia, a trait in which sexual selection is seen as the main evolutionary driver, with sexual dimorphism of carapace in the genus Cyprideis. We analyzed specimens collected in the field (C. salebrosa, USA; C. torosa, UK) and from collections of the National Museum of Natural History, Washington, DC (C. mexicana). We digitized valve outlines in lateral view to obtain measures of size (valve area) and shape (elongation, measured as length to height ratio), and obtained several dimensions from two components of the hemipenis: the muscular basal capsule, which functions as a sperm pump, and the section that includes the intromittent organ (terminal extension). In addition to the assessment of this primary sexual trait, we also quantified two dimensions of the male secondary sexual trait-where the transformed right walking leg functions as a clasping organ during mating. We also measured linear dimensions from four limbs as indicators of overall (soft-part) body size, and assessed allometry of the soft anatomy. We observed significant correlations in males between valve size, but not elongation, and distinct structural parts of the hemipenis, even after accounting for their shared correlation with overall body size. We also found weak but significant positive correlation between valve elongation and the degree of sexual dimorphism of the walking leg, but only in C. torosa. The correlation between the hemipenis parts, especially basal capsule size and male valve size dimorphism suggests that sexual selection on sperm size, quantity, and/or efficiency of transfer may drive sexual size dimorphism in these species, although we cannot exclude other aspects of sexual and natural selection