Mechanotransduction in tumor dynamics modeling.

Mechanotherapy is a groundbreaking approach to impact carcinogenesis. Cells sense and respond to mechanical stimuli, translating them into biochemical signals in a process known as mechanotransduction. The impact of stress on tumor growth has been studied in the last three decades, and many papers highlight the role of mechanics as a critical self-inducer of tumor fate at the in vitro and in vivo biological levels. Meanwhile, mathematical models attempt to determine laws to reproduce tumor dynamics. This review discusses biological mechanotransduction mechanisms and mathematical-biomechanical models together. The aim is to provide a common framework for the different approaches that have emerged in the literature from the perspective of tumor avascularity and to provide insight into emerging mechanotherapies that have attracted interest in recent years.

Viscoelastic model characterization of human cervical tissue by torsional waves.

The understanding of changes in the viscoelastic properties of cervical tissue during the gestation process is a challenging problem. In this work, we explore the importance of considering the multilayer nature (epithelial and connective layers) of human cervical tissue for characterizing the viscoelastic parameters from torsional waves. For this purpose, torsional wave propagations are simulated in three multilayer cervical tissue models (pure elastic, Kelvin-Voigt (KV) and Maxwell) using the finite difference time domain method. High-speed camera measurements have been carried out in tissue-mimicking phantoms in order to obtain the boundary conditions of the numerical simulations. Finally, a parametric modeling study through a probabilistic inverse procedure was performed to rank the most plausible rheological model and to reconstruct the viscoelastic parameters. The procedure consist in comparing the experimental signals obtained in human cervical tissues using the Torsional Wave Elastography (TWE) technique with the synthetic signals from the numerical models. It is shown that the rheological model that best describes the nature of cervical tissue is the Kelvin-Voigt model. Once the most plausible model has been selected, the stiffness and viscosity parameters have been reconstructed of the epithelial and connective layers for the measurements of the 18 pregnant women, along with the thickness of the epithelial layer.

Pore geometry influences growth and cell adhesion of infrapatellar mesenchymal stem cells in biofabricated 3D thermoplastic scaffolds useful for cartilage tissue engineering.

The most pressing need in cartilage tissue engineering (CTE) is the creation of a biomaterial capable to tailor the complex extracellular matrix of the tissue. Despite the standardized used of polycaprolactone (PCL) for osteochondral scaffolds, the pronounced stiffness mismatch between PCL scaffold and the tissue it replaces remarks the biomechanical incompatibility as main limitation. To overcome it, the present work was focused in the design and analysis of several geometries and pore sizes and how they affect cell adhesion and proliferation of infrapatellar fat pad-derived mesenchymal stem cells (IPFP-MSCs) loaded in biofabricated 3D thermoplastic scaffolds. A novel biomaterial for CTE, the 1,4-butanediol thermoplastic polyurethane (b-TPUe) together PCL were studied to compare their mechanical properties. Three different geometrical patterns were included: hexagonal (H), square (S), and, triangular (T); each one was printed with three different pore sizes (PS): 1, 1.5 and 2 mm. Results showed differences in cell adhesion, cell proliferation and mechanical properties depending on the geometry, porosity and type of biomaterial used. Finally, the microstructure of the two optimal geometries (T1.5 and T2) was deeply analyzed using multiaxial mechanical tests, with and without perimeters, µCT for microstructure analysis, DNA quantification and degradation assays. In conclusion, our results evidenced that IPFP-MSCs-loaded b-TPUe scaffolds had higher similarity with cartilage mechanics and T1.5 was the best adapted morphology for CTE.

Characterization of non-linear mechanical behavior of the cornea.

The objective of this study was to evaluate which hyperelastic model could best describe the non-linear mechanical behavior of the cornea, in order to characterize the capability of the non-linear model parameters to discriminate structural changes in a damaged cornea. Porcine corneas were used, establishing two different groups: control (non-treated) and NaOH-treated (damaged) corneas (n = 8). NaOH causes a chemical burn to the corneal tissue, simulating a disease associated to structural damage of the stromal layer. Quasi-static uniaxial tensile tests were performed in nasal-temporal direction immediately after preparing corneal strips from the two groups. Three non-linear hyperelastic models (i.e. Hamilton-Zabolotskaya model, Ogden model and Mooney-Rivlin model) were fitted to the stress-strain curves obtained in the tensile tests and statistically compared. The corneas from the two groups showed a non-linear mechanical behavior that was best described by the Hamilton-Zabolotskaya model, obtaining the highest coefficient of determination (R2 > 0.95). Moreover, Hamilton-Zabolotskaya model showed the highest discriminative capability of the non-linear model parameter (Parameter A) for the tissue structural changes between the two sample groups (p = 0.0005). The present work determines the best hyperelastic model with the highest discriminative capability in description of the non-linear mechanical behavior of the cornea.

Monitoring anti-Xa levels in patients with cancer-associated venous thromboembolism treated with bemiparin.

OBJECTIVE: To analyze the relationship between therapeutic (weight-adjusted) dose of bemiparin and anti-Xa activity in patients with venous thromboembolism (VTE) and cancer in comparison with a cohort of patients with VTE without cancer, and its relationship with outcomes. MATERIALS AND METHODS: This is a prospective cohort study that comprised a cohort of patients with cancer-associated VTE and a cohort of non-cancer patients with VTE, all of them treated with bemiparin. The ethics committee approved the study and informed consent was obtained from the patients. RESULTS: One hundred patients were included (52 with cancer and 48 without cancer), with a median follow-up of 9.8 months. Mean anti-Xa activity was 0.89 (± 0.33) UI/mL in oncological patients and 0.83 (± 0.30) UI/mL in non-cancer patients (mean difference - 0.05 95% CI - 0.18; 0.06). A multiple linear regression model showed that anti-Xa peak was associated with the dose/kg independently of possible confounding variables (presence of cancer, age, sex and eGFR-estimated Glomerular Filtration Rate), in a way that for every 1 UI of dose/kg increase, the anti-Xa peak activity increased 0.006 UI/mL (95% CI 0.003; 0.009) (p < 0.001). The predictive capacity of anti-Xa peak in the oncology cohort showed an area under the ROC curve of 0.46 (95% CI 0.24-0.68), 0.70 (95% CI 0.49-0.91) and 0.74 (95% CI 0.44-0.94) for death, first bleeding and recurrence of VTE, respectively, and none was statistically significant. CONCLUSION: In patients with venous thromboembolism treated with bemiparin, anti-Xa levels were not influenced by the presence of cancer.

Cartilage biomechanics: A key factor for osteoarthritis regenerative medicine.

Osteoarthritis (OA) is a joint disorder that is highly extended in the global population. Several researches and therapeutic strategies have been probed on OA but without satisfactory long-term results in joint replacement. Recent evidences show how the cartilage biomechanics plays a crucial role in tissue development. This review describes how physics alters cartilage and its extracellular matrix (ECM); and its role in OA development. The ECM of the articular cartilage (AC) is widely involved in cartilage turnover processes being crucial in regeneration and joint diseases. We also review the importance of physicochemical pathways following the external forces in AC. Moreover, new techniques probed in cartilage tissue engineering for biomechanical stimulation are reviewed. The final objective of these novel approaches is to create a cellular implant that maintains all the biochemical and biomechanical properties of the original tissue for long-term replacements in patients with OA.

Damage prediction via nonlinear ultrasound: A micro-mechanical approach.

Nonlinear constitutive mechanical parameters, predominantly governed by micro-damage, interact with ultrasound to generate harmonics that are not present in the excitation. In principle, this phenomenon therefore permits early stage damage identification if these higher harmonics can be measured. To understand the underlying mechanism of harmonic generation, a nonlinear micro-mechanical approach is proposed here, that relates a distribution of clapping micro-cracks to the measurable macroscopic acoustic nonlinearity by representing the crack as an effective inclusion with Landau type nonlinearity at small strain. The clapping mechanism inside each micro-crack is represented by a Taylor expansion of the stress-strain constitutive law, whereby nonlinear terms arise. The micro-cracks are considered distributed in a macroscopic medium and the effective nonlinearity parameter associated with compression is determined via a nonlinear Mori-Tanaka homogenization theory. Relationships are thus obtained between the measurable acoustic nonlinearity and the Landau-type nonlinearity. The framework developed therefore yields links with nonlinear ultrasound, where the dependency of measurable acoustic nonlinearity is, under certain hypotheses, formally related to the density of micro-cracks and the bulk material properties.

Ultrasonic tissue characterization for monitoring nanostructured TiO2-induced bone growth.

The use of bioactive nanostructured TiO2 has recently been proposed for improving orthopaedic implant adhesion due to its improved biocompatibility with bone, since it induces: (i) osteoblast function, (ii) apatite nucleation and (iii) protein adsorption. The present work focuses on a non-ionizing radiation emitting technique for quantifying in real time the improvement in terms of mechanical properties of the surrounding bone due to the presence of the nanostructured TiO2 prepared by controlled precipitation and acid ageing. The mechanical strength is the ultimate goal of a bone implant and is directly related to the elastic moduli. Ultrasonics are high frequency mechanical waves and are therefore suited for characterizing elastic moduli. As opposed to echographic techniques, which are not correlated to elastic properties and are not able to penetrate bone, a low frequency ultrasonic transmission test is proposed, in which a P-wave is transmitted through the specimen and recorded. The problem is posed as an inverse problem, in which the unknown is a set of parameters that describe the mechanical constants of the sequence of layers. A finite element numerical model that depends on these parameters is used to predict the transformation of the waveform and compare to the measurement. The parameters that best describe the real tissue are obtained by minimizing the discrepancy between the real and numerically predicted waveforms. A sensitivity study to the uncertainties of the model is performed for establishing the feasibility of using this technique to investigate the macroscopic effect on bone growth of nanostructured TiO2 and its beneficial effect on implant adhesion.

A sparse digital signal model for ultrasonic nondestructive evaluation of layered materials.

Signal modeling has been proven to be an useful tool to characterize damaged materials under ultrasonic nondestructive evaluation (NDE). In this paper, we introduce a novel digital signal model for ultrasonic NDE of multilayered materials. This model borrows concepts from lattice filter theory, and bridges them to the physics involved in the wave-material interactions. In particular, the proposed theoretical framework shows that any multilayered material can be characterized by a transfer function with sparse coefficients. The filter coefficients are linked to the physical properties of the material and are analytically obtained from them, whereas a sparse distribution naturally arises and does not rely on heuristic approaches. The developed model is first validated with experimental measurements obtained from multilayered media consisting of homogeneous solids. Then, the sparse structure of the obtained digital filter is exploited through a model-based inverse problem for damage identification in a carbon fiber-reinforced polymer (CFRP) plate.

Mechanical assessment of cervical remodelling in pregnancy: insight from a synthetic model.

During the gestation and the cervical remodelling, several changes occur progressively in the structure of the tissue. An increase in the hydration, disorganisation of collagen network and decrease in elasticity can be observed. The collagen structure disorganisation is particularly complex: collagen fibres turn thicker and more wavy as the gestation progresses in a transition from relatively straight fibres to wavy fibres, while pores between collagen fibres become larger and separated. Shear wave elastography is a promising but not yet fully understood tool to assess these structural changes and the cervix׳s ability to dilate. To this end, a numerical histo-mechanical model is proposed in the present study, which aims at linking variations in the microscopic histo-biomechanical processes with shear wave propagation characteristics. Parametric simulations are carried out for a broad range of mechanical and geometrical parameters. Results show a direct relationship between the histological and morphological changes during pregnancy and the viscoelastic behaviour of the tissue.

Assessing viscoelasticity of shear wave propagation in cervical tissue by multiscale computational simulation.

The viscoelastic properties are recently being reported to be particularly sensitive to the gestation process, and to be intimately related to the microstructure of the cervical tissue. However, this link is not fully understood yet. In this work, we explore the importance of the heterogeneous multi-scale nature of cervical tissue for quantifying both elasticity and viscosity from shear waves velocity. To this end, shear wave propagations are simulated in a microscopic cervical tissue model using the finite difference time domain technique, over a wide frequency range from 15 to 200 kHz. Three standard rheological models (Voigt, Maxwell and Zener) are evaluated regarding their ability to reproduce the simulated dispersion curves, and their plausibility to describe cervical tissue is ranked by a stochastic model-class selection formulation. It is shown that the simplest model, i.e. that with less parameters, which best describes the simulated dispersion curves in cervical tissue is the Maxwell model. Furthermore, results show that the excitation frequency determines which rheological model can be representative for the tissue. Typically, viscoelastic parameters tend to converge for excitation frequencies over 100 kHz.

Copper deficiency with pancytopenia due to enteral nutrition through jejunostomy.

Copper deficiency is a rare complication of enteral nutrition. Haematologic abnormalities such as neutropenia and anaemia, but not pancytopenia, have been described associated to copper deficiency. We report the case of a patient requiring long term enteral nutrition through jejunostomy who developed copper deficiency and pancytopenia. In 1991, a 47-year-old woman was admitted with severe gastroesophageal mucositis after an attempted suicide with caustic intake. Enteral nutrition with a commercial, polymeric, fiber-containing formula was started. Twenty-eight months later, the patient developed anemia and neutropenia that did not respond to combined iron and parenteral vitamin B(12) supplementation. In 1996 the patient showed pancytopenia and low serum levels of copper and ceruloplasmin. Pancytopenia improved after copper supplementation. Possible mechanism causing copper deficiency and pancytopenia are discussed. We conclude that assessment of copper status is advisable in patients receiving long-term enteral nutrition by jejunostomy.

Torsional ultrasonic transducer computational design optimization.

A torsional piezoelectric ultrasonic sensor design is proposed in this paper and computationally tested and optimized to measure shear stiffness properties of soft tissue. These are correlated with a number of pathologies like tumors, hepatic lesions and others. The reason is that, whereas compressibility is predominantly governed by the fluid phase of the tissue, the shear stiffness is dependent on the stroma micro-architecture, which is directly affected by those pathologies. However, diagnostic tools to quantify them are currently not well developed. The first contribution is a new typology of design adapted to quasifluids. A second contribution is the procedure for design optimization, for which an analytical estimate of the Robust Probability Of Detection, called RPOD, is presented for use as optimality criteria. The RPOD is formulated probabilistically to maximize the probability of detecting the least possible pathology while minimizing the effect of noise. The resulting optimal transducer has a resonance frequency of 28 kHz.

Differential cross sections for collisions of hexapole state-selected NO with He.

The first measurements of differential inelastic collision cross sections of fully state-selected NO (j=12, Omega=12, epsilon= -1) with He are presented. Full state selection is achieved by a 2 m long hexapole, which allows for a systematic study of the effect of parity conservation and breaking on the differential cross section. The collisionally excited NO molecules are detected using a resonant (1+1') REMPI ionization scheme in combination with the velocity-mapped, ion-imaging technique. The current experimental configuration minimizes the contribution of noncolliding NO molecules in other rotational states j, Omega, epsilon--that contaminates images--and allows for study of the collision process at an unprecedented level of detail. A simple method to correct ion images for collision-induced alignment is presented as well and its performance is demonstrated. The present results show a significant difference between differential cross sections for scattering into the upper and lower component of the Lambda-doublet of NO. This result cannot be due to the energy splitting between these components.

[Myelodysplastic syndromes. Hematologic phenotypes, cytogenetic expression and clinical course in 133 cases (1979-1989)]. / Síndromes mielodisplásticos. Fenotipos hematológicos, expresión citogenética y patrones evolutivos de 133 casos (1979-1989).

One hundred and thirty-three cases of myelodysplastic syndromes studied during the last ten years were revised. Of them, 79 were males and 54 females, and their ages ranged between 15 and 91 years (median, 69 years). Five patients (3.7%) had secondary myelodysplasias. The haematological phenotype (FAB) of the cases was: RA, 41.3%; SRA, 24%; RAEB, 18%; RAEBT, 3.7%; CMML, 8.3%. Leucopenia/thrombocytopenia without initial anaemia was present in 4.5% of the cases. Abnormal karyotype was found in 54 patients (40.6%), MIKA in 41 cases and MAKA in 13 cases. The cytogenetic anomalies most commonly found were +8, 5q-, -7, 11q- and 13q-. Cytogenetic abnormalities were commonest amongst the RAEB (50%), and least frequent in CMML (18.2%). Thirty-one patients evolved into acute leukaemia (29 ANLL and 2 ALL). Such blastic changes were more frequent in RAEB (62.5%) and rarest in SRA (9.4%), and they appeared mostly in patients with complex karyotype (MAKA) (53.8%) as compared with those who had normal karyotype (17.7%). Short-lasting complete remission was achieved by 40% of the patients treated with conventional chemotherapy. The survival of the group as a whole (median 30 months) varied in accordance with the haematological phenotype: SRA, 81 months; RA, 65 months; CMML, 13 months; RAEB +/- T, 8 months. The finding of a MAKA karyotype significantly shortened the survival (4 months) with regard to MIKA (44 months) or normal karyotype (39 months). The following median survivals were attained after patients' staging (Bournemouth's criteria): stage A, 84 months; stage B, 22 months, and stage C, 5 months.(ABSTRACT TRUNCATED AT 250 WORDS)

Peripheral thrombocytopenia, accessory spleen and Hodgkin's disease: an unusual combination.

A 32-year-old male developed severe autoimmune thrombocytopenia refractory to conventional immunosuppression. He had been treated with radiotherapy for stage I-A Hodgkin's disease (HD) 2 years earlier after a staging laparotomy and splenectomy. A 3-cm accessory spleen was detected using computed tomography scan and 99mTc scintigraphy. Resection resulted in normalization of the platelet counts. Two years later the patient remains in remission of both diseases. Immune thrombocytopenia is rarely associated with HD and its remission following resection of an accessory spleen is an unusual finding.

Biological significance of nonlymphocytic oligoblastic leukemia. Cytokinetic behavior of dividing granulocytic precursors in 11 patients.

Kinetic studies of marrow dividing granulocytic precursors (mitotic index and flash labeling index with 3H-TDR) were carried out in 11 patients with oligoblastic leukemia (OBL). The results were compared with similar data from cases of conventional acute non-lymphocytic leukemia (ANLL). The cytokinetic results were as follows: MI (%) in OBL, mean = 0.75; MI (%) in ANLL, mean = 0.66; p greater than 0.7; LI (%) in OBL, mean = 15.0; LI (%) in ANLL, mean = 15.4, p greater than 0.7. The lack of cytokinetic differences between these two groups of patients stands in favor of the hypothesis that OBL might represent a special type of smoldering leukemia with a 'plateau' of blast cell accumulation established at a subleukemic level.

Acute lymphoblastic leukaemia in adults: results of a 'total-therapy' programme in 47 patients over 15 years old.

For the last 13 years, 47 patients with ALL over 15 years old (range 15-72; median 21) entered a 'total-therapy' programme. All cases received a 6-8 week induction course of PRD, VCR, DRB and/or L-ASN. Prophylaxis of CNS was done by cranial radiotherapy plus i.t. MTX in 32/45 patients who attained complete remission (CR). After CR, subsequent therapy involved a programme of maintenance with 6MP and MTX at full doses. Pulses of intermittent reinforcement (PRD, VCR and DRB) were done for 2 weeks, every 3 months, for at least 3 years. CR was achieved in 42/47 patients (89.3%). The median relapse-free survival of the patients who attained CR was 57 months, with an 8-year estimated disease-free survival rate of 43% for those cases. If actuarial assumptions were to be sustained, it would indicate an encouraging cure rate of 38% of all our adult ALL patients (mainly in those cases between 15 and 30 years old).