Snake Cytotoxins Bind to Membranes via Interactions with Phosphatidylserine Head Groups of Lipids

The major representatives of Elapidae snake venom, cytotoxins (CTs), share similar three-fingered fold and exert diverse range of biological activities against various cell types. CT-induced cell death starts from the membrane recognition process, whose molecular details remain unclear. It is known, however, that the presence of anionic lipids in cell membranes is one of the important factors determining CT-membrane binding. In this work, we therefore investigated specific interactions between one of the most abundant of such lipids, phosphatidylserine (PS), and CT 4 of Naja kaouthia using a combined, experimental and modeling, approach. It was shown that incorporation of PS into zwitterionic liposomes greatly increased the membrane-damaging activity of CT 4 measured by the release of the liposome-entrapped calcein fluorescent dye. The CT-induced leakage rate depends on the PS concentration with a maximum at approximately 20% PS. Interestingly, the effects observed for PS were much more pronounced than those measured for another anionic lipid, sulfatide. To delineate the potential PS binding sites on CT 4 and estimate their relative affinities, a series of computer simulations was performed for the systems containing the head group of PS and different spatial models of CT 4 in aqueous solution and in an implicit membrane. This was done using an original hybrid computational protocol implementing docking, Monte Carlo and molecular dynamics simulations. As a result, at least three putative PS-binding sites with different affinities to PS molecule were delineated. Being located in different parts of the CT molecule, these anion-binding sites can potentially facilitate and modulate the multi-step process of the toxin insertion into lipid bilayers. This feature together with the diverse binding affinities of the sites to a wide variety of anionic targets on the membrane surface appears to be functionally meaningful and may adjust CT action against different types of cells

Mapping Protein Interactions between Dengue Virus and Its Human and Insect Hosts

Dengue virus (DENV) represents a major disease burden in tropical and subtropical regions of the world, and has shown an increase in the number of cases in recent years. DENV is transmitted to humans through the bite of an infected mosquito, typically Aedes aegypti, after which it begins the infection and replication lifecycle within human cells. To perform the molecular functions required for invasion, replication, and spread of the virus, proteins encoded by DENV must interact with and alter the behavior of protein networks in both of these hosts. In this work, we used a computational method based on protein structures to predict interactions between DENV and its human and insect hosts. We predict numerous interactions, with many involved in known cell death, stress, and immune system pathways. Further investigation of these predicted protein-protein interactions should provide targets to combat the clinical manifestations of this disease in humans as well as points of intervention focused within the mosquito vector

FOXC2 Expression is Associated with Tumor Proliferation and Invasion Potential in Oral Tongue Squamous Cell Carcinoma

Forkhead box protein C2 (FOXC2) is a gene encoding a transcription factor that controls the generation of mesodermal tissue including vascular and lymphatic tissues. FOXC2 has previously been associated with EMT and tumor angiogenesis in various cancers. Moreover, a relationship between the expression of FOXC2 and poor prognosis has been reported in various cancers. We herein examined the clinicopathological significance of FOXC2 in oral tongue squamous cell carcinoma (OTSCC) and attempted to clarify the function of FOXC2 in OTSCC cell lines in vitro. The overexpression of FOXC2 was more frequent in cancers with higher grades according to the pattern of invasion (grade 4 vs. 1?3; p < 0.05). A correlation was observed between the expression of FOXC2 and that of VEGF-A and -C (VEGF-A; p < 0.05, VEGF-C; p < 0.001). The high-FOXC2 expression group had a significantly poorer prognosis than that of the low-expression group (p < 0.001). Multivariate analysis indicated that the overexpression of FOXC2 may also be an independent prognostic factor, similar to N classification (N0 vs 1/2; p < 0.05), stage classification (stage I/II vs III/IV; p < 0.05), pattern of invasion (grade 1-3vs 4; p < 0.05), local recurrence (local recurrence (+) vs (?); p < 0.01), and the overexpression of FOXC2 (FOXC2 overexpression (?) vs.(+); p < 0.05). In the OTSCC cell line analysis, the expression of FOXC2 was also associated with proliferation and invasion potential. These results strongly suggest that the overexpression of FOXC2 may be a potent predictor of survival in OTSCC patients

Cervical lymph node metastasis in adenoid cystic carcinoma of the larynx: a collective international review

Adenoid cystic carcinoma (AdCC) of the head and neck is a well-recognized pathologic entity that rarely occurs in the larynx. Although the 5-year locoregional control rates are high, distant metastasis has a tendency to appear more than 5 years post treatment. Because AdCC of the larynx is uncommon, it is difficult to standardize a treatment protocol. One of the controversial points is the decision whether or not to perform an elective neck dissection on these patients. Because there is contradictory information about this issue, we have critically reviewed the literature from 1912 to 2015 on all reported cases of AdCC of the larynx in order to clarify this issue. During the most recent period of our review (1991-2015) with a more exact diagnosis of the tumor histology, 142 cases were observed of AdCC of the larynx, of which 91 patients had data pertaining to lymph node status. Eleven of the 91 patients (12.1%) had nodal metastasis and, based on this low proportion of patients, routine elective neck dissection is therefore not recommended

Contemporary management of cancer of the oral cavity

Oral cancer represents a common entity comprising a third of all head and neck malignant tumors. The options for curative treatment of oral cavity cancer have not changed significantly in the last three decades; however, the work up, the approach to surveillance, and the options for reconstruction have evolved significantly. Because of the profound functional and cosmetic importance of the oral cavity, management of oral cavity cancers requires a thorough understanding of disease progression, approaches to management and options for reconstruction. The purpose of this review is to discuss the most current management options for oral cavity cancers

The evolution of a highly variable sex chromosome in Gehyra purpurascens (Gekkonidae)

A karyotypic survey of the gekkonid lizard Gehyra purpurascens revealed a distinctive sex chromosome system. G-banding showed that the Z Chromosome of males is derived from a tandem fusion of two acrocentric chromosomes of a presumed ancestral Gehyra with 2n=44. Through the application of G-; N- and C-banding, a total of six morphs of the W chromosome were identified. These differ by paracentric and pericentric inversions and, in one case, by a centric shift. The possible reasons for such extensive variation in the W chromosome are considered, and it is suggested that increased mutability of the W chromosome may be a causal factor. In contrast to earlier speculations, this example demonstrates that sex chromosomes can evolve without significant changes in the amount of C-band heterochromatin.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47361/1/412_2004_Article_BF00292447.pd