Dynamic Transition from α-Helices to ß-Sheets in Polypeptide Coiled-Coil Motifs.

We carried out dynamic force manipulations in silico on a variety of coiled-coil protein fragments from myosin, chemotaxis receptor, vimentin, fibrin, and phenylalanine zippers that vary in size and topology of their α-helical packing. When stretched along the superhelical axis, all superhelices show elastic, plastic, and inelastic elongation regimes and undergo a dynamic transition from the α-helices to the ß-sheets, which marks the onset of plastic deformation. Using the Abeyaratne-Knowles formulation of phase transitions, we developed a new theoretical methodology to model mechanical and kinetic properties of protein coiled-coils under mechanical nonequilibrium conditions and to map out their energy landscapes. The theory was successfully validated by comparing the simulated and theoretical force-strain spectra. We derived the scaling laws for the elastic force and the force for α-to-ß transition, which can be used to understand natural proteins' properties as well as to rationally design novel biomaterials of required mechanical strength with desired balance between stiffness and plasticity.

Preoperative chemotherapy in patients with resectable esophageal carcinoma: a single center Phase II study.

OBJECTIVE: The role of preoperative chemotherapy in squamous cell esophageal carcinoma remains controversial. A prospective trial was initiated to investigate whether preoperative chemotherapy followed by surgery results in increased progression-free survival in patients with resectable thoracic esophageal carcinoma. METHODS: Patients with Stage IIb-IIIa/b resectable esophageal carcinoma were eligible for the study. They received two cycles of FLEP regimen chemotherapy (cisplatin, etoposide, leucovorine, 5-fluorouracil) followed by transthoracic extended 2- or 3-field esophagectomy. Two-year progression-free survival was the primary endpoint. To evaluate the potential benefit of the dual-modality approach we compared these results with the outcome of patients who were treated in our center in the same period of time and were non-randomly allocated to surgery alone. RESULTS: From 2001 to 2008, 63 patients were included in the study (bimodality group) and 58 patients into the surgery-alone group. Median follow-up was 68 (range, 4-123) months. Squamous cell carcinoma had 93% patients. Two-year progression-free survival for all patients was 45.3 and 30.7% (hazard ratio 0.71, 95% confidence interval 0.46-1.08) and median overall survival was 26.5 months and 18.0 months (hazard ratio 0.67, 95% confidence interval 0.41-1.01) in bimodality- and surgery-alone groups, respectively. Patients who underwent R0-resection after bimodality treatment had significantly better overall survival (40.9 months) than after surgery alone (19.0 months, hazard ratio 0.51, 95% confidence interval 0.30-0.81). CONCLUSIONS: Two cycles of preoperative chemotherapy did not improve progression-free survival of patients with resectable thoracic esophageal carcinoma in intent-to-treat population. However, significantly better results of bimodality approach was seen in R0-resected patients which warrants further trials with more effective chemotherapy combinations.

Structures and Biogenesis of Fallaxosides D4, D5, D6 and D7, Trisulfated Non-Holostane Triterpene Glycosides from the Sea Cucumber Cucumaria fallax.

Four new trisulfated triterpene glycosides, fallaxosides D4 (1), D5 (2), D6 (3) and D7 (4) have been isolated from the sea cucumber Cucumaria fallax (Cucumariidae, Dendrochirotida). The structures of the glycosides have been elucidated by 2D NMR spectroscopy and HRESIMS. All the glycosides have the lanostane aglycones of a rare non-holostane type with 7(8)-, 8(9)- or 9(11)-double bonds, one or two hydroxyl groups occupying unusual positions in the polycyclic nucleus and shortened or normal side chains. The pentasaccharide carbohydrate moieties of 1-4 have three sulfate groups. The cytotoxic activity of glycosides 1-4 against the ascite form of mouse Ehrlich carcinoma cells and mouse spleen lymphocytes and hemolytic activity against mouse erythrocytes have been studied.

Fallaxosides C1, C2, D1 and D2, Unusual Oligosulfated Triterpene Glycosides from the Sea Cucumber Cucumariafallax (Cucumariidae, Dendrochirotida, Holothurioidea) and Taxonomic Status of this Animal.

Four hew triterpene glycosides, fallaxosides C, (1), C2 (2), D, (3) and D2 (4) along with the known cucumarioside A3-2 (5) and koreoside A (6) have-been isolated from the sea cucumber Cucumaria fallax (Cucumariidae, Dendrochirotida). Structures of the glycosides have been elucidated by 2D NMR spectroscopy and mass spectrometry. All of the glycosides are rare non-holostane derivatives having shortened side chains and contain pentasaccharide carbohydrate moieties with two or three sulfate groups. Structures of these triterpene glycosides and their comparison with those earlier isolated from Cucuniaria spp. and Pseudocnus dubiosus leoninus allow us to suggest that the present assignment of C. fallax to the genus Pseudocnus is not correct, and this species.should be assigned to the genus Cucumaria. Cytotoxic activity of glycosides 1-5 against the ascite form of mouse Ehrlich carcinoma cells and mouse spleen lymphocytes and hemolytic activity against mouse erythrocytes have been studied. The glycosides were expectedly not active in all the tests due to the absence of an 18(20)-lactone in their aglycones and the presence of several sulfate groups. There was one exception, cucumarioside A3-2 (5), which. demonstrated a weak cytotoxicity against lymphocytes and moderate hemolytic activity.