Visualization of protein folding funnels in lattice models

Protein folding occurs in a very high dimensional phase space with an exponentially large number of states, and according to the energy landscape theory it exhibits a topology resembling a funnel. In this statistical approach, the folding mechanism is unveiled by describing the local minima in an effective one-dimensional representation. Other approaches based on potential energy landscapes address the hierarchical structure of local energy minima through disconnectivity graphs. In this paper, we introduce a metric to describe the distance between any two conformations, which also allows us to go beyond the one-dimensional representation and visualize the folding funnel in 2D and 3D. In this way it is possible to assess the folding process in detail, e.g., by identifying the connectivity between conformations and establishing the paths to reach the native state, in addition to regions where trapping may occur. Unlike the disconnectivity maps method, which is based on the kinetic connections between states, our methodology is based on structural similarities inferred from the new metric. The method was developed in a 27-mer protein lattice model, folded into a 3×3×3 cube. Five sequences were studied and distinct funnels were generated in an analysis restricted to conformations from the transition-state to the native configuration. Consistent with the expected results from the energy landscape theory, folding routes can be visualized to probe different regions of the phase space, as well as determine the difficulty in folding of the distinct sequences. Changes in the landscape due to mutations were visualized, with the comparison between wild and mutated local minima in a single map, which serves to identify different trapping regions. The extension of this approach to more realistic models and its use in combination with other approaches are discussed.FAPESPCNPqCAPESnBioNet network (Brazil

Population Pharmacokinetic Study of a Test Dose Busulfan Patients Undergoing Hematopoietic Stem Cell Transplantation

UNIFESP (Universidade Federal de São Paulo), BrazilOnco-Hematology Unit, Instituto da Criança - HC - FMUSP, Sao Paulo, BrazilHospital Israelita Albert Einstein, BrazilHematology and Bone Marrow Transplantation Dept, Hospital Israelita Albert Einstein, BrazilHematology and Bone Marrow Transplantation Dept, UNIFESP (Universidade Federal de Sao Paulo), BrazilPediatric Bone Marrow Transplantation Center, Instituto de Oncologia Pediatrica, São Paulo, BrazilHematology and Bone Marrow Transplantation Dept, Hospital Israelita Albert Einstein, Sao Paulo, BrazilInstituto de Oncologia Pediátrica, São Paulo, BrazilClinical Research Center, Instituto de Oncologia Pediátrica, São Paulo, BrazilDepartment of Medicine - Bone Marrow Transplant Program, Case Western Reserve University, ClevelandUNIFESP (Universidade Federal de São Paulo), BrazilHematology and Bone Marrow Transplantation Dept, UNIFESP (Universidade Federal de Sao Paulo), BrazilWeb of Scienc

Gastric stump cancer after distal gastrectomy for benign disease: clinicopathological features and surgical outcomes.

The purpose of the present study was to analyze clinicopathologic features and long-term prognosis of gastric stump cancer (GSC) arising in the remnant stomach 5 years or later after partial gastrectomy for benign disease. METHODS: We reviewed the results of 176 patients resected with curative intent for GSC at 8 Italian centers belonging to the Italian Research Group for Gastric Cancer (GIRCG). The median (range) follow-up time for surviving patients was 71.2 (6-207) months. RESULTS: One hundred forty-six patients were men, the mean age at the time of diagnosis was 69.2 years, and the great majority (167 cases) underwent Billroth II reconstruction. R0 resection was achieved in 158 (90 %) patients, and in 94 (53 %) lymph node dissection was 65D2. Postoperative mortality and complication rates were 6.2 and 43.2 %, respectively. T1 tumor was diagnosed in 45 (25 %) cases. Lymph node metastases were evident in 86 patients (49 %). Thirteen patients had involvement of the jejunal mesentery nodes (pJN+); five cases were T2-T3 and eight cases were T4. Overall 5-year survival rate was 53.1 %. Five-year survival rates were 68.1, 37.8, and 33.1 % for pT1, pT2-3, and pT4 tumors, respectively (P = 0.001). Five-year survival rate was 56.5 % for node-negative tumors (pN0), 32.3 % for tumors with nodal metastases without involvement of jejunal mesentery nodes (pN+), and 17.1 % for tumors with involvement of jejunal mesentery nodes (pJN+) (P = 0.002). CONCLUSIONS: Our study suggests that an aggressive surgical approach can achieve a satisfactory outcome in GSC