Embryo-fetal developmental toxicity study design for pharmaceuticals

Assessment of potential developmental and reproductive toxicity of human pharmaceuticals is currently guided by the International Conference on Harmonization (ICH) S5(R2) document (available at http://www.ich.org). The studies that assess developmental hazard are generally conducted in rodents and rabbits. Based on the authors' collective experience, adequate designs (including range-finding studies) and the presentation of data for these studies are described in detail. In addition, the suggested initiation and then total duration of these studies in relation to clinical studies that enroll women of childbearing potential are described. Optional parameters that may be included in the studies are discussed, as are study designs that combine assessments of fertility and developmental toxicity. New methods that may replace or enhance current procedures are outlined. The details described herein will assist all laboratories performing these studies, individuals who need to plan for the studies, and regulatory agencies that ultimately review these studies

Proteomic analysis of colorectal cancer reveals alterations in metabolic pathways

10.1074/mcp.M500432-MCP200Molecular and Cellular Proteomics561119-113

Terminology of developmental abnormalities in common laboratory mammals (Version 2)

This update (Version 2) of the Terminology of Developmental Abnormalities in Common Laboratory Mammals (Version 1) incorporates improvements and enhancements to both content and organization of the terminology to enable greater flexibility in its application, while maintaining a consistent approach to the description of findings. The revisions are the result of an international collaboration among interested organizations, advised by individual experts and the outcomes of several workshops. The terminology remains organized into tables under the broad categories of external, visceral, and skeletal observations, following the manner in which data are typically collected and recorded in developmental toxicity studies. This arrangement of the tables, as well as other information provided in appendices, is intended to facilitate the process of specimen evaluation at the laboratory bench level. Only the commonly used laboratory mammals (i.e. rats, mice, rabbits) are addressed in the current terminology tables. The inclusion of other species that are used in developmental toxicity testing, such as primates, is considered outside the scope of the present update. Similarly, categorization of findings as, for example, 'malformation' or 'variation' remains unaddressed, in accordance with the overall principle that the focus of this document is descriptive terminology and not diagnosis or interpretation. The skeletal terms have been augmented to accommodate cartilage findings

Cross-talk between tight and anchoring junctions-lesson from the testis

Spermatogenesis takes place in the seminiferous tubules in adult testes such as rats, in which developing germ cells must traverse the seminiferous epithelium while spermatogonia (2n, diploid) undergo mitotic and meiotic divisions, and differentiate into elongated spermatids (1n, haploid). It is conceivable that this event involves extensive junction restructuring particularly at the blood-testis barrier (BTB, a structure that segregates the seminiferous epithelium into the basal and the adluminal compartments) that occurs at stages VII-VIII of the seminiferous epithelial cycle. As such, cross-talk between tight (TJ) and anchoring junctions [e.g., basal ectoplasmic specialization (basal ES), adherens junction (AJ), desmosome-like junction (DJ)] at the BTB must occur to coordinate the transient opening of the BTB to facilitate preleptotene spermatocyte migration. Interestingly, while there are extensively restructuring at the BTB during the epithelial cycle, the immunological barrier function of the BTB must be maintained without disruption even transiently. Recent studies using the androgen suppression and Adjudin models have shown that anchoring junction restructuring that leads to germ cell loss from the seminiferous epithelium also promotes the production of AJ (e.g., basal ES) proteins (such as N-cadherins, catenins) at the BTB site. We postulate the testis is using a similar mechanism during spermatogenesis at stage VIII of the epithelial cycle that these induced basal ES proteins, likely form a "patch" surrounding the BTB, transiently maintain the BTB integrity while TJ is "opened", such as induced by TGF-b3 or TNFa, to facilitate preleptotene spermatocyte migration. However, in other stages of the epithelial cycle other than VII and VIII when the BTB remains "closed" (for ∼10 days), anchoring junctions (e.g., AJ, DJ, and apical ES) restructuring continues to facilitate germ cell movement. Interestingly, the mechanism(s) that governs this communication between TJ and anchoring junction (e.g., basal ES and AJ) in the testis has remained obscure until recently. Herein, we provide a critical review based on the recently available data regarding the cross-talk between TJ and anchoring junction to allow simultaneous maintenance of the BTB and germ cell movement across the seminiferous epithelium. © 2008 Landes Bioscience and Springer Science+Business Media.link_to_subscribed_fulltex