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Background: Soft-tissue sarcoma involving the popliteal fossa remains challenging because it is difficult to achieve wide margins with limb salvage in this location. Adjuvant therapy is frequently necessary, and limb function can be adversely affected. We reviewed our experience with these tumours.Methods: Our prospective tumour database served to identify all patients with popliteal sarcomas treated at the McGill University Health Centre and the Maisonneuve-Rosemont Hospital between 1994 and 2005. We assessed oncologic and functional outcomes as well as complications.Results: Our study included 18 patients (12 women and 6 men). The mean age was 54 (range 16-84) years. The mean duration of follow-up was 55 (range 4-126) months. Frequent histologic diagnoses were liposarcoma (n = 6), synovial sarcoma (n = 4) and leiomyosarcoma (n = 3). Tumour size varied from 2 to 21 cm (median 11 cm). American Joint Committee on Cancer staging was as follows: 4 patients had stage IIa disease, 3 patients had stage IIb, 10 patients had stage III and 1 patient had stage IV disease. Treatment consisted of limb salvage in 15 patients and amputation in 3. Fourteen patients had radiotherapy, 4 had chemotherapy, and 3 needed partial sciatic nerve resection. Margins were negative in 7 of 18 patients and microscopically positive in 11 patients. Complications included wound infections in 3 patients and thrombophlebitis in 2 patients. Of the patients undergoing limb-salvaging procedures, 1 experienced local recurrences after limb salvage (7%), and 5 experienced lung metastases (20%). Local recurrence was always associated with positive margins, whereas metastases occurred only in patients without local recurrence. The mean Musculoskeletal Tumor Society 1987 score was 33 (range 24-35). The mean Toronto Extremity Salvage Score results was 82.4 (range 63.8-100). At latest follow-up, 6 patients had died of disease, 1 was alive with disease, and 11 (61%) patients remained free of disease.Conclusion: Despite the high rate of microscopically positive margins, the local recurrence rate was 7%. Amputation did not prevent death. We found function to be good to excellent in most patients who had limb-salvaging surgery. [ABSTRACT FROM AUTHOR]

In this paper we analyze the possibility of forming host–guest inclusion complexes between β-cyclodextrin (BCD) and several anticancer active principles, characterized by different mechanism of action, by atomistic molecular dynamics simulations. The trajectories of the insertion angles, rotation of the non-polar parts of the drugs inside the macrocycle and other geometrical features give detailed information on the dynamics of the complexes. The relative binding energies in all cases indicate possibilities of formation of inclusion complexes between BCD and the anticancer drugs either in a 1:1 or in a 2:2 stoichiometry. [Copyright &y& Elsevier]

Background: It would be helpful for the decision-making process of patients with metastatic bone disease to understand which patients are at risk for worse quality of life (QOL), pain, anxiety, and depression. Normative data, and where these stand compared with general population scores, can be useful to compare and interpret results of similar patients or patient groups, but to our knowledge, there are no such robust data.Questions/purposes: We wished (1) to assess what factors are independently associated with QOL, pain interference, anxiety, and depression in patients with metastatic bone disease, and (2) to compare these outcomes with general US population values.Methods: Between November 2011 and February 2015, 859 patients with metastatic bone disease presented to our orthopaedic oncology clinic; 202 (24%) were included as they completed the EuroQOL-5 Dimension (EQ-5DTM), PROMIS® Pain Interference, PROMIS® Anxiety, and PROMIS® Depression questionnaires as part of a quality improvement program. We did not record reasons for not responding and found no differences between survey respondents and nonrespondents in terms of age (63 versus 64 years; p = 0.916), gender (51% men versus 47% men; p = 0.228), and race (91% white versus 88% white; p = 0.306), but survey responders were more likely to be married or living with a partner (72%, versus 62%; p = 0.001). We assessed risk factors for QOL, pain interference, anxiety, and depression using multivariable linear regression analysis. We used the one-sample signed rank test to assess whether scores differed from US population averages drawn from earlier large epidemiologic studies.Results: Younger age (β regression coefficient [β], < 0.01; 95% CI, 0.00-0.01; p = 0.041), smoking (β, -0.12; 95% CI, -0.22 to -0.01; p = 0.026), pathologic fracture (β, -0.10; 95% CI, -0.18 to -0.02; p = 0.012), and being unemployed (β, -0.09; 95% CI, -0.17 to -0.02; p = 0.017) were associated with worse QOL. Current smoking status was associated with more pain interference (β, 6.0; 95% CI, 1.6-11; p = 0.008). Poor-prognosis cancers (β, 3.8; 95% CI, 0.37-7.2; p = 0.030), and pathologic fracture (β, 6.3; 95% CI, 2.5-7.2; p = 0.001) were associated with more anxiety. Being single (β, 5.9; 95% CI, 0.83-11; p = 0.023), and pathologic fracture (β, 4.4; 95% CI, 0.8-8.0; p = 0.017) were associated with depression. QOL scores (0.68 versus 0.85; p < 0.001), pain interference scores (65 versus 50; p < 0.001), and anxiety scores (53 versus 50; p = 0.011) were worse for patients with bone metastases compared with general US population values, whereas depression scores were comparable (48 versus 50; p = 0.171).Conclusions: Impending pathologic fractures should be treated promptly to prevent deterioration in QOL, anxiety, and depression. Our normative data can be used to compare and interpret results of similar patients or patient groups. Future studies could focus on specific cancers metastasizing to the bone, to further understand which patients are at risk for worse patient-reported outcomes.Level Of Evidence: Level III, prognostic study. [ABSTRACT FROM AUTHOR]

This paper presents an extensive study about atrazine behavior in saturated sands by the aid of molecular simulation techniques. Systems have been described in a simplified way to predict adhesion and diffusion phenomena, and to give useful insights at the atomistic level. Diffusion coefficients, binding energies, and concentration profiles have been determined as a function of interlayer distances and atrazine concentration. Combined Monte Carlo, Molecular Mechanics, and Molecular Dynamics techniques have been used. In silico results have been compared with available experimental data for validation, and with similar in silico experiments, finding a good agreement. Results confirm a moderate atrazine adhesion onto silica framework and a more favorable tendency to bind with water. Atrazine diffusion has been found to be influenced by concentration and interlayer distance. Encouraging results show how these techniques can be generalized and made applicable for soil contamination modelling at the atomistic level in a more extensive way. [ABSTRACT FROM AUTHOR]

A set of grand canonical Monte Carlo molecular simulations has been performed over zeolite MFI (Zeolite Socony Mobil-five) and disordered, activated carbon structures, to determine adsorption isotherms and thermodynamic characteristics of a gaseous mixture adsorbed into porous structures, activated carbon, all-silica MFI and hydrophilic FAU (Faujasite)-NaY zeolites. Simulations have been carried out over a multi-component mixture, in order to mimic a more realistic gaseous emission, when benzene has to be removed. Validation of the model has been obtained by comparison with available experimental data. Different conditions, as temperature and total pressure of the stream have been taken into account. Results give a ranking for the most appropriate process conditions, and for the best materials to be employed for the separation process. Data fitting with the Sips thermodynamic model has also been provided for benzene isotherms. Our procedure is simple and may be adapted to different temperature and pressure conditions, adsorbate or adsorbent characteristics, and gas composition. [ABSTRACT FROM AUTHOR]

In our previous work, racemic β-carbomethoxy-γ-lactams were subjected to enzymatic hydrolysis in the presence of α-chymotrypsin. The hydrolysis of three N-substituted lactams proved to be highly enantioselective, whereas an unsubstituted lactam was recovered in racemic form. Thus, in this paper we applied several molecular modeling protocols to explain the substrate specificity and the enantioselectivity of this enzyme. The adopted procedures involved accurate docking experiments of both enantiomers of each lactam to the protein active site, whose 3-D structure was obtained from X-ray crystallographic data, followed by extensive conformational and energetic analysis of the computer-generated complexes. The results obtained fully account for the experimental evidences on the enantioselective hydrolysis of these interesting, potential drugs by α-chymotrypsin. [Copyright &y& Elsevier]

Imatinib-acquired resistance related to the presence of secondary point mutations has become a frequent event in gastrointestinal stromal tumors. Here, transient transfection experiments with plasmids carrying two different KIT-acquired point mutations were performed along with immunoprecipitation of total protein extracts, derived from imatinib-treated and untreated cells. The molecular mechanics/Poisson Boltzmann surface area computational techniques were applied to study the interactions of the wild-type and mutated receptors with imatinib at the molecular level. Biochemical analyses showed KIT phosphorylation in cells transfected with vectors carrying the specific mutant genes. Imatinib treatment demonstrated that T670I was insensitive to the drug at all the applied concentrations, whereas V654A was inhibited by 6 μM of imatinib. The modeling of the mutated receptors revealed that both substitutions affect imatinib-binding site, but to a different extent: T670I substantially modifies the binding pocket, whereas V654A induces only relatively confined structural changes. We demonstrated that T670I and V654A cause indeed imatinib-acquired resistance and that the former is more resistant to imatinib than the latter. The application of molecular simulations allowed us to quantify the interactions between the mutated receptors and imatinib, and to propose a molecular rationale for this type of drug resistance.Oncogene (2006) 25, 6140–6146. doi:10.1038/sj.onc.1209639; published online 5 June 2006 [ABSTRACT FROM AUTHOR]

The application of a computational approach, based on molecular dynamics (MD) simulations and quantum mechanical-free energy (QM-FE) calculations, to explain the different substrate specificity and enantioselectivity of α-chymotrypsin (α-CT) in the hydrolysis of methyl cis- and trans-5-oxo-2-pentylpirrolidine-3-carboxylates is described. By applying a combination of molecular mechanics energy derived from MD simulations in explicit solvent, and solvation free energy derived from a continuum solvation model, we have calculated reasonable absolute free energies of binding (ΔGbind) for each α-CT/enantiomer complex formation, and elucidated the balanced nature of the factors contributing to ΔGbind. Furthermore, our calculations based on QM-FE techniques have yielded an insight into the major issues affecting the observed enantioselectivity in the hydrolysis of substrate ester bonds by α-chymotrypsin. [Copyright &y& Elsevier]

Several authors have reported an association between mutations of the cystic fibrosis transmembrane conductance regulator gene (CFTR) and chronic pancreatitis. CFTR gene transcription and protein efficiency are influenced by two polymorphic loci, (TG)m and M470V, other than the T5 allele, whose role is already well-established. The TG11/T5 haplotype is commonly found in healthy subjects, while the TG12/T5/V470 and TG13/T5/V470 haplotypes are present in congenital bilateral absence of the vas deferens (CBAVD) patients. While the T5 allele is a mutation that is over-represented in patients with chronic pancreatitis, no data are available concerning the possible allelic preference at the other two polymorphic loci, (TG)m and M470V, in these patients. For this reason, we screened 39 patients with chronic pancreatitis for the most common CFTR mutations found so far in the Italian population; in addition, we examined the length of the polypyrimidine (poly-T) tract in intron 8, the (TG)m length and the M or V codon at position 470. CFTR mutations were found in 3 patients. Poly-T variant typing identified genotype T5/T7 in 5 patients and T5/T9 in 1 patient. Direct sequencing of intron 8 in patients with the T5 variant revealed the TG12/T5/V470∥TG11/T7/V470 genotype in 5 patients and TG10/T9∥TG11/T5 genotype in 1 patient. In patients with chronic pancreatitis, the T5 allele is frequently associated with TG12 and V470, a haplotype already reported in CBAVD cases and quite uncommon in healthy subjects. [ABSTRACT FROM AUTHOR]