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Cancer is a public health problem throughout the world as incidence and mortality rates are increasing year after year. Although conventional therapies such as chemotherapy and radiation show favorable results against this disease, the side effects it causes throughout the body reduce the quality of life of the patient. Therefore, nanomedicine offers us new promising tools to attack cancer through the innovation of nanodrugs, to increase the therapeutic response, reduce dosage, and without generating as many side effects as conventional therapies. For the design of nanodrugs, it is essential to know the biological barriers of the organism and the cancer barriers faced by nanodrugs, such as cell membrane openings, the solubility of the drugs to be transported, and surface electric charge and the protein corona. Due to the aforementioned, the purpose of this review article is to delve into the long journey that nanodrugs undertake from the moment they are administered until they are internalized in tumor cells, taking into account some of the biological and molecular challenges that they defy to reach to its final destination, to observe a desired therapeutic response in the cancer patient. [ABSTRACT FROM AUTHOR]

The enthalpically favoured hydration of hydrophobic entities, termed hydrophobic hydration, impacts the phase behaviour of numerous amphiphiles in water. Here, we show experimental evidence that hydrophobic hydration is strongly determined by the mean energetics of the aqueous medium. We investigate the aggregation and collapse of an amphiphilic polymer, poly-N-isopropyl acrylamide (PNiPAM), in aqueous solutions containing small amounts of alcohol and find that the thermodynamic characteristics defining the phase transitions of PNiPAM evolve relative to the solvent composition at which the excess mixing enthalpy of the water/alcohol mixtures becomes minimal. Such correlation between solvent energetics and solution thermodynamics extends to other mixtures containing neutral organic solutes that are considered as kosmotropes to induce a strengthening of the hydrogen bonded water network. This denotes the energetics of water as a key parameter controlling the phase behaviour of PNiPAM and identifies the excess mixing enthalpy of water/kosmotrope mixtures as a gauge of the kosmotropic effect on hydrophobic assemblies. [ABSTRACT FROM AUTHOR]

The enthalpically favoured hydration of hydrophobic entities, termed hydrophobic hydration, impacts the phase behaviour of numerous amphiphiles in water. Here, we show experimental evidence that hydrophobic hydration is strongly determined by the mean energetics of the aqueous medium. We investigate the aggregation and collapse of an amphiphilic polymer, poly-N-isopropyl acrylamide (PNiPAM), in aqueous solutions containing small amounts of alcohol and find that the thermodynamic characteristics defining the phase transitions of PNiPAM evolve relative to the solvent composition at which the excess mixing enthalpy of the water/alcohol mixtures becomes minimal. Such correlation between solvent energetics and solution thermodynamics extends to other mixtures containing neutral organic solutes that are considered as kosmotropes to induce a strengthening of the hydrogen bonded water network. This denotes the energetics of water as a key parameter controlling the phase behaviour of PNiPAM and identifies the excess mixing enthalpy of water/kosmotrope mixtures as a gauge of the kosmotropic effect on hydrophobic assemblies. [ABSTRACT FROM AUTHOR]

In this paper we analyze the vibrational spectra of a large ensemble of non-homologous protein structures by means of a novel tool, that we coin Hierarchical Network Model (HNM). Our coarse-grained scheme accounts for the intrinsic heterogeneity of force constants displayed by protein arrangements and also incorporates side chain degrees of freedom. Our analysis shows that vibrational entropy per unit residue correlates with the content of secondary structure. Furthermore, we assess the individual contribution to vibrational entropy of the novel features of our scheme as compared with the predictions of state-of-the-art network models. This analysis highlights the importance of properly accounting for the intrinsic hierarchy in force strengths typical of the different atomic bonds that build up and stabilize protein scaffolds. Finally, we discuss possible implications of our findings in the context of protein aggregation phenomena. [ABSTRACT FROM AUTHOR]

We prospectively collected data on all patients with stage IB1 cervical cancer, who underwent total laparoscopic radical hysterectomy with the use of a modified uterine manipulator. From January 2000 to December 2005, 54 patients met the study criteria. The mean age was 41.8 ± 7.47 years. Average BMI (kg/m2) was 27.38 ± 3.13. Squamous carcinoma and adenocarcinoma were found in 88.88% and 11.11% of the cases, respectively. The average surgical time was 265 ± 70.8 min. The mean estimated blood loss was 276.11 ± 123.03 ml. The average patient lymph node count was 19.64 ± 5.08. Positive malignant lymph nodes were identified in 11.11% of the cases. Surgical margins were free of disease in all patients. The mean hospital stay was 1.5 ± 1 days. There was no mortality. Total laparoscopic radical hysterectomy can be considered a safe alternative to laparotomy. The use of a uterine manipulator does not pose an increased surgical risk and allows for a simpler and more feasible procedure. [ABSTRACT FROM AUTHOR]

Small-world networks embedded in Euclidean space represent useful cartoon models for a number of real systems such as electronic circuits, communication systems, the large-scale brain architecture and others. Since the small-world behavior relies on the presence of long-range connections that are likely to have a cost which is a growing function of the length, we explore whether it is possible to choose suitable probability distributions for the shortcut lengths so as to preserve the small-world feature and, at the same time, to minimize the network cost. The flow distribution for such networks, and their robustness, are also investigated. [ABSTRACT FROM AUTHOR]

The kinetics of biomolecular isomerization processes, such as protein folding, is governed by a free-energy surface of high dimensionality and complexity. As an alternative to projections into one or two dimensions, the free-energy surface can be mapped into a weighted network where nodes and links are configurations and direct transitions among them, respectively. In this work, the free-energy basins and barriers of the alanine dipeptide are determined quantitatively using an algorithm to partition the network into clusters (i.e., states) according to the equilibrium transitions sampled by molecular dynamics. The network-based approach allows for the analysis of the thermodynamics and kinetics of biomolecule isomerization without reliance on arbitrarily chosen order parameters. Moreover, it is shown on low-dimensional models, which can be treated analytically, as well as for the alanine dipeptide, that the broad-tailed weight distribution observed in their networks originates from free-energy basins with mainly enthalpic character. [ABSTRACT FROM AUTHOR]

The encounter between anisotropic agents in diffusion-controlled reactions is a topic of very general relevance in chemistry and biology. Here we introduce a simplified model of encounter of an isotropic molecule with a pair of partially reacting agents and apply it to the encounter reaction between an antibody and its antigen. We reduce the problem to the solution of dual series relations, which can be solved iteratively, yielding the exact solution for the encounter rate constant at any desired order of accuracy. We quantify the encounter effectiveness by means of a simple indicator and show that the two binding centers systematically behave in an anticooperative fashion. However, we demonstrate that a reduction of the binding active sites allows the composite molecule to recover binding effectiveness, in spite of the overall reduction of the rate constant. In addition, we provide a simple formula that enables one to calculate the anticooperativity as a function of the size of the binding site for any values of the separation between the two active lobes and of the antigen size. Finally, some biological implications of our results are discussed. [ABSTRACT FROM AUTHOR]

Erosion by flowing water is one of the major forces shaping the surface of Earth. Studies in the last decade have shown, in particular, that the drainage region of rivers, where water is collected, exhibits scale invariant features characterized by exponents that are the same for rivers around the world. Here we show that from the data obtained by the MOLA altimeter of the Mars Global Surveyor one can perform the same analysis for mountain sides on Mars. We then show that in some regions fluid erosion might have played a role in the present martian landscape. [ABSTRACT FROM AUTHOR]

The increased availability of data on real networks has favoured an explosion of activity in the elaboration of models able to reproduce both qualitatively and quantitatively the measured properties. What has been less explored is the reliability of the data, and whether the measurement technique biases them. Here we show that tree-like explorations (similar in principle to traceroute) can indeed change the measured exponents of a scale-free network. [ABSTRACT FROM AUTHOR]

Measuring the biophysical properties of macromolecular complexes at work is a major challenge of modern biology. The protein complex composed of vesicle-associated membrane protein 2, synaptosomal-associated protein of 25 kDa, and syntaxin 1 [soluble N-ethyl-maleimide-sensitive factor attachment protein receptor (SNARE) complex] is essential for docking and fusion of neurotransmitter-filled synaptic vesicles with the presynaptic membrane. To better understand the fusion mechanisms, we reconstituted the synaptic SNARE complex in the imaging chamber of an atomic force microscope and measured the interaction forces between its components. Each protein was tested against the two others, taken either individually or as binary complexes. This approach allowed us to determine specific interaction forces and dissociation kinetics of the SNAREs and led us to propose a sequence of interactions. A theoretical model based on our measurements suggests that a minimum of four complexes is probably necessary for fusion to occur. We also showed that the regulatory protein neuronal Sec1 injected into the atomic force microscope chamber prevented the complex formation. Finally, we measured the effect of tetanus toxin protease on the SNARE complex and its activity by on-line registration during tetanus toxin injection. These experiments provide a basis for the functional study of protein microdomains and also suggest opportunities for sensitive screening of drugs that can modulate protein-protein interactions. [ABSTRACT FROM AUTHOR]

We introduce a simplified protein model where the water degrees of freedom appear explicitly (although in an extremely simplified fashion). Using thismodel we are able to recover both the warm and the cold protein denaturation within a single framework, while addressing important issues about the structure of model proteins. [ABSTRACT FROM AUTHOR]

Objectives: Obesity, hypertension and diabetes are closely associated with endometrial cancer (EC). This study evaluates the relationship between diabetes and risk of EC on the basis of obesity.Methods: A case control study was carried out in Mexico City from 1995 to 1997. Eighty-five histologically confirmed cases were compared with 668 population-based controls obtained through frequency matching. Diabetes status, weight, height and other factors were determined through personal interviews among both cases and controls.Results: Compared to women without diabetes, those with diabetes had an adjusted odds ratio of 3.6 (95% CI = 1.7, 7.4) for EC. This association was modified by body mass index (p interaction < 0.001). Compared to non-overweight and non-diabetic women, non-overweight (OR = 3.9. 95% CI = 0.88, 18.0) and overweight (OR = 5.9, 95% CI = 1.6, 21.1) diabetic women had a non-significant elevated risk of EC. However, elevated risk estimates were observed for obese diabetic women (OR = 8.0, 95% CI = 2.8, 22.7).Conclusions: Our results strongly suggest an interaction effect between obesity and diabetes that significantly increases the risk of EC. This, in turn, may explain the growing number of new EC cases recently observed in developing countries with reduced birth rates and an increased incidence of both obesity and diabetes mellitus. [ABSTRACT FROM AUTHOR]