Vandetanib in locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 2 trial

BACKGROUND No effective standard treatment exists for patients with radioiodine-refractory, advanced differentiated thyroid carcinoma. We aimed to assess efficacy and safety of vandetanib, a tyrosine kinase inhibitor of RET, VEGFR and EGFR signalling, in this setting. METHODS In this randomised, double-blind, phase 2 trial, we enrolled adults (aged ≥18 years) with locally advanced or metastatic differentiated thyroid carcinoma (papillary, follicular, or poorly differentiated) at 16 European medical centres. Eligible patients were sequentially randomised in a 1:1 ratio with a standard computerised scheme to receive either vandetanib 300 mg per day (vandetanib group) or matched placebo (placebo group), balanced by centre. The primary endpoint was progression-free survival (PFS) in the intention-to-treat population based on investigator assessment. This study is registered with ClinicalTrials.gov, number NCT00537095. FINDINGS Between Sept 28, 2007, and Oct 16, 2008, we randomly allocated 72 patients to the vandetanib group and 73 patients to the placebo group. By data cutoff (Dec 2, 2009), 113 (78%) patients had progressed (52 [72%] patients in the vandetanib group and 61 [84%] in the placebo group) and 40 (28%) had died (19 [26%] patients in the vandetanib group and 21 [29%] in the placebo group). Patients who received vandetanib had longer PFS than did those who received placebo (hazard ratio [HR] 0·63, 60% CI 0·54-0·74; one-sided p=0·008): median PFS was 11·1 months (95% CI 7·7-14·0) for patients in the vandetanib group and 5·9 months (4·0-8·9) for patients in the placebo group. The most common grade 3 or worse adverse events were QTc prolongation (ten [14%] of 73 patients in the vandetanib group vs none in the placebo group), diarrhoea (seven [10%] vs none), asthenia (five [7%] vs three [4%]), and fatigue (four [5%] vs none). Two patients in the vandetanib group and one in the placebo group died from treatment-related serious adverse events (haemorrhage from skin metastases and pneumonia in the vandetanib group and pneumonia in the placebo group). INTERPRETATION Vandetanib is the first targeted drug to show evidence of efficacy in a randomised phase 2 trial in patients with locally advanced or metastatic differentiated thyroid carcinoma. Further investigation of tyrosine-kinase inhibitors in this setting is warranted. FUNDING AstraZeneca.

A novel blood-sparing agent in cardiac surgery? First in-patient experience with the synthetic serine protease inhibitor MDCO-2010: a phase II, randomized, double-blind, placebo-controlled study in patients undergoing coronary artery bypass grafting with cardiopulmonary bypass

BACKGROUND Antifibrinolytics have been used for 2 decades to reduce bleeding in cardiac surgery. MDCO-2010 is a novel, synthetic, serine protease inhibitor. We describe the first experience with this drug in patients. METHODS In this phase II, double-blind, placebo-controlled study, 32 patients undergoing isolated primary coronary artery bypass grafting with cardiopulmonary bypass were randomly assigned to 1 of 5 increasing dosage groups of MDCO-2010. The primary aim was to evaluate pharmacokinetics (PK) with assessment of plasmatic concentrations of the drug, short-term safety, and tolerance of MDCO-2010. Secondary end points were influence on coagulation, chest tube drainage, and transfusion requirements. RESULTS PK analysis showed linear dosage-proportional correlation between MDCO-2010 infusion rate and PK parameters. Blood loss was significantly reduced in the 3 highest dosage groups compared with control (P = 0.002, 0.004 and 0.011, respectively). The incidence of allogeneic blood product transfusions was lower with MDCO-2010 4/24 (17%) vs 4/8 (50%) in the control group. MDCO-2010 exhibited dosage-dependent antifibrinolytic effects through suppression of D-dimer generation and inhibition of tissue plasminogen activator-induced lysis in ROTEM analysis as well as anticoagulant effects demonstrated by prolongation of activated clotting time and activated partial thromboplastin time. No systematic differences in markers of end organ function were observed among treatment groups. Three patients in the MDCO-2010 groups experienced serious adverse events. One patient experienced intraoperative thrombosis of venous grafts considered possibly related to the study drug. No reexploration for mediastinal bleeding was required, and there were no deaths. CONCLUSIONS This first-in-patient study demonstrated dosage-proportional PK for MDCO-2010 and reduction of chest tube drainage and transfusions in patients undergoing primary coronary artery bypass grafting. Antifibrinolytic and anticoagulant effects were demonstrated using various markers of coagulation. MDCO-2010 was well tolerated and showed an acceptable initial safety profile. Larger multi-institutional studies are warranted to further investigate the safety and efficacy of this compound.

Regulation of apoptosis during the pathogenesis of non -melanoma skin cancer

Previous studies from our lab have shown distinctive patterns of expression of bcl-2 gene family members in human nonmelanoma skin cancer (NMSC). To further evaluate the significance of these observations and to study the effects of cell death deregulation during skin carcinogenesis, we generated a transgenic mouse model (HK1.bcl-2) using the human keratin 1 promoter to target the expression of a human bcl-2 minigene to the epidermis. Transgenic protein expression was confirmed in all the layers of the epidermis except the stratum corneum using immunohistochemistry. Multifocal epidermal hyperplasia, without associated hyperkeratosis, was observed in newborn HK1.bcl-2 mice. Immunofluorescence staining using monoclonal antibodies specific for a variety of differentiation markers revealed aberrant expression of keratin 6 (K6) in the transgenic epidermis. Epidermal proliferative indexes, assessed by anti-BrdUrd immunofluorescence staining, were similar in control and transgenic newborn mice, but suprabasal proliferating cells were seen within the hyperplastic areas of the transgenic mouse skin. Spontaneous apoptotic indices of the epidermis were similar in both control and HK1.bcl-2 transgenic newborn mice, however, after UV-B irradiation, the number of "sunburn cells" was significantly higher in the control compared to the HK1.bcl-2 transgenic animals.^ Adult HK1.bcl-2 and control littermate mice were used in UV-B and chemical carcinogenesis protocols including DMBA + TPA. UV-B irradiated control and HK1.bcl-2 mice had comparable incidence of tumors than the controls, but the mean latency period was significantly shorter in the HK1.bcl-2 transgenic. Both control and transgenic animals included in chemical carcinogenesis protocols required application of both the initiating (DMBA) and promoting (TPA) agents to develop tumors. The frequency, number, and latency of tumor formation was similar in both groups of animals, however, HK1.bcl-2 mice exhibited a rate of conversion from benign papilloma to carcinoma 2.5 times greater than controls.^ Similar carcinogenesis experiments were performed using newborn mice. HK1.bcl-2 mice treated with UV-B plus TPA have a three fold greater incidence of tumor formation compared to controls littermates. HK1.bcl-2 transgenic animals also exhibited a shorter latency for papilloma formation when treated with DMBA plus TPA.^ HK1.bcl-2/v-Ha-ras double transgenic mice shared phenotypic features of both HK1.v-Ha-ras and HK1.bcl-2 transgenic mice, and exhibited focal areas of augmented hyperplasia. These double transgenic mice were susceptible to tumor formation by treatment with TPA alone.^ Cultures of primary keratinocytes were established from control, HK1.bcl-2, HK1.Ha-ras, and HK1.bcl-2/v-Ha-ras newborn mice. Cell viability was determined after exposure of the cells to UV-B irradiation, DMBA, TPA, or TGF-$\beta$1. Internucleosomal DNA fragmentation ("ladders") and morphological cellular changes compatible with apoptotic cell death were observed after the application of all these agents. HK1.bcl-2 keratinocytes were resistant to cell death induction by all of these agents except TGF-$\beta$1. HK1.Ha-ras cells had a higher spontaneous rate of cell death which could be compensated by co-expression of bcl-2.^ These findings suggest that bcl-2 dependent cell death suppression may be an important component of multistep skin carcinogenesis. ^

Functional studies of *Ras and Bcl-2 oncoproteins in keratinocyte homeostasis and multistep skin carcinogenesis

To assess the effect of deregulated Ha-ras and bcl-2, individually and in combination on epidermal keratinocyte homeostasis and during multistep skin carcinogenesis, we generated skin-specific transgenic mice and keratinocyte transfectants constitutively expressing oncogenic Ha-ras and bcl-2 proteins. The deregulated Ha-ras and bcl-2 expression contributing to homeostatic imbalances in the skin had an additive effect on the probability of tumor development. They were also cooperative in incidence, growth, and latency of tumor formation, and they exhibited synergistic cooperation in malignant transformation of benign papillomas. To explain the homeostatic imbalances by Ha-ras and bcl-2 overexpression in the skin, we investigated the three major cellular processes of proliferation, cell death, and differentiation. Epidermal expression of Bcl-2 retarded keratinocyte proliferation in the epidermis of neonatal mice compared with results for control littermates. Constitutive expression of Ha-ras increased keratinocyte proliferation, and co-expression of bcl-2 modestly suppressed the ras-mediated abnormal proliferation of neonatal keratinocytes. Bcl-2 proteins in keratinocytes protected UV-treated cells from apoptotic cell death regardless of oncogenic ras expression in both non-neoplastic neonatal epidermis and human keratinocyte cell lines. The spontaneous apoptotic index (AI) was also lower in papillomas constitutively expressing bcl-2 compared with the ones that developed in control mice. Ras-overexpressing epidermis, including that in ras/bcl-2 double transgenic mice, had abnormal differentiation patterns compared with controls. The oncogenic ras protein had alterations in both epidermal distribution and the extent of cytokeratin 14 and involucrin expression. Abnormal expression of the hyperproliferation marker cytokeratin 6 and modest down regulation of cytokeratin 1 were also detected. Late appearance of filaggrin was another abnormal phenotype of the ras-expressing epidermis. Overexpression of bcl-2 had no effect on epidermal differentiation. Together, these findings suggest that constitutive expression of oncogenic Ha-ras and bcl-2 are important determinants of epidermal proliferation, viability and differentiation. In summary, our results demonstrated that the disruption of epidermal homeostasis by overexpressed ras and bcl-2 predisposes to hyperplastic growth of the epidermis and to papilloma development and that these proteins with distinct mechanisms for oncogenesis are functionally synergistic for malignant transformation of chemically induced skin carcinogenesis. ^

Concrete Swelling in Two Spanish Dams

Several chemical reactions are able to produce swelling of concrete for decades after its initial curing, a problem that affects a considerable number of concrete dams around the world. Principia has had several contracts to study this problem in recent years, which have required reviewing the state-ofthe-art, adopting appropriate mathematical descriptions, programming them into user routines in Abaqus, determining model parameters on the basis of some parts of the dams’ monitored histories, ensuring reliability using some other parts, and finally predicting the future evolution of the dams and their safety margins. The paper describes some of the above experience, including the programming of sophisticated nonisotropic swelling models, that must be compatible with cracking and other nonlinearities involved in concrete behaviour. The applications concentrate on two specific cases, an arch-gravity dam and a double-curvature arch dam, both with a long history of concrete swelling and which, interestingly, entailed different degrees of success in the modelling efforts

Concrete Swelling in Existing Dams

Several chemical reactions are able to produce swelling of concrete for decades after its initial curing, a problem that affects a considerable number of concrete dams around the world. Principia has had several contracts to study this problem in recent years, which have required reviewing the state-of-the-art, adopting appropriate mathematical descriptions, programming them into user routines in Abaqus, determining model parameters on the basis of some parts of the dams’ monitored histories, ensuring reliability using some other parts, and finally predicting the future evolution of the dams and their safety margins. The paper describes some of the above experience, including the programming of sophisticated non-isotropic swelling models, that must be compatible with cracking and other nonlinearities involved in concrete behaviour. The applications concentrate on two specific cases, an archgravity dam and a double-curvature arch dam, both with a long history of concrete swelling and which, interestingly, entailed different degrees of success in the modelling efforts

Concrete Swelling in Two Spanish Dams

Several chemical reactions are able to produce swelling of concrete for decades after its initial curing, a problem that affects a considerable number of concrete dams around the world. Principia has had several contracts to study this problem in recent years, which have required reviewing the state-ofthe-art, adopting appropriate mathematical descriptions, programming them into user routines in Abaqus, determining model parameters on the basis of some parts of the dams’ monitored histories, ensuring reliability using some other parts, and finally predicting the future evolution of the dams and their safety margins. The paper describes some of the above experience, including the programming of sophisticated nonisotropic swelling models, that must be compatible with cracking and other nonlinearities involved in concrete behaviour. The applications concentrate on two specific cases, an arch-gravity dam and a double-curvature arch dam, both with a long history of concrete swelling and which, interestingly, entailed different degrees of success in the modelling efforts.

Effect of adhesive thickness and concrete strength on FRP-Concrete Bonds

The use of fiber-reinforced polymer (FRP) composites for strengthening, repairing, or rehabilitating concrete structures has become more and more popular in the last 10 years. Irrespective of the type of strengthening used, design is conditioned, among others, by concrete-composite bond failure, normally attributed to stress at the interface between these two materials. Single shear, double shear, and notched beam tests are the bond tests most commonly used by the scientific community to estimate bond strength, effective length, and the bond stress-slip relationship. The present paper discusses the effect of concrete strength and adhesive thickness on the results of beam tests, which reproduce debonding conditions around bending cracks much more accurately. The bond stress-slip relationship was analyzed in a cross section near the inner edge, where stress was observed to concentrate. The ultimate load and the bond stress-slip relationship were visibly affected by concrete strength. Adhesive thickness, in turn, was found to have no significant impact on low-strength concrete but a somewhat greater effect on higher strength materials.

Study of concrete cracking during accelerated corrosion tests in reinforced concrete

Cracking of reinforced concrete can occur in certain environments due to rebar corrosion. The oxide layer growing around the bars introduces a pressure which may be enough to lead to the fracture of concrete. To study such an effect, the results of accelerated corrosion tests and finite ele- ment simulations are combined in this work. In previous works, a numerical model for the expansive layer, called expansive joint element , was programmed by the authors to reproduce the effect of the oxide over the concrete. In that model, the expansion of the oxide layer in stress free conditions is simulated as an uniform expansion perpendicular to the steel surface. The cracking of concrete is simulated by means of finite elements with an embedded adaptable cohesive crack that follow the standard cohesive model. In the present work, further accelerated tests with imposed constant cur- rent have been carried out on the same type of specimens tested in previous works (with an embedded steel tube), while measuring, among other things, the main-crack mouth opening. Then, the tests have been numerically simulated using the expansive joint element and the tube as the corroding electrode (rather than a bar). As a result of the comparison of numerical and experimental results, both for the crack mouth opening and the crack pattern, new insight is gained into the behavior of the oxide layer. In particular, quantitative assessment of the oxide expansion relation is deduced from the ex- periments, and a narrower interval for the shear stiffness of the oxide layer is obtained, which could not be achieved using bars as the corroding element, because in that case the numerical results were insensitive to the shear stiffness of the oxide layer within many orders of magnitude

The influence of the section shape of box-girder decks on the steady aerodynamic yawing moment of double cantilever bridges under construction

The yawing moment acting on the box-girder deck of reinforced concrete bridges constructed using the balanced cantilever method during the erection stage has been experimentally analyzed by testing different types of bridge cross-sections. Experimental results show that the yawing moment coefficient decreases as the bridge decks become streamlined, and that the yawing moment coefficient reaches a maximum when the bridge deck length is nearly twice the deck width.

Experimental and numerical study of cracking of concrete due to reinforcement corrosion

La corrosión del acero es una de las patologías más importantes que afectan a las estructuras de hormigón armado que están expuestas a ambientes marinos o al ataque de sales fundentes. Cuando se produce corrosión, se genera una capa de óxido alrededor de la superficie de las armaduras, que ocupa un volumen mayor que el acero inicial; como consecuencia, el óxido ejerce presiones internas en el hormigón circundante, que lleva a la fisuración y, ocasionalmente, al desprendimiento del recubrimiento de hormigón. Durante los últimos años, numerosos estudios han contribuido a ampliar el conocimiento sobre el proceso de fisuración; sin embargo, aún existen muchas incertidumbres respecto al comportamiento mecánico de la capa de óxido, que es fundamental para predecir la fisuración. Por ello, en esta tesis se ha desarrollado y aplicado una metodología, para mejorar el conocimiento respecto al comportamiento del sistema acero-óxido-hormigón, combinando experimentos y simulaciones numéricas. Se han realizado ensayos de corrosión acelerada en condiciones de laboratorio, utilizando la técnica de corriente impresa. Con el objetivo de obtener información cercana a la capa de acero, como muestras se seleccionaron prismas de hormigón con un tubo de acero liso como armadura, que se diseñaron para conseguir la formación de una única fisura principal en el recubrimiento. Durante los ensayos, las muestras se equiparon con instrumentos especialmente diseñados para medir la variación de diámetro y volumen interior de los tubos, y se midió la apertura de la fisura principal utilizando un extensómetro comercial, adaptado a la geometría de las muestras. Las condiciones de contorno se diseñaron cuidadosamente para que los campos de corriente y deformación fuesen planos durante los ensayos, resultando en corrosión uniforme a lo largo del tubo, para poder reproducir los ensayos en simulaciones numéricas. Se ensayaron series con varias densidades de corriente y varias profundidades de corrosión. De manera complementaria, el comportamiento en fractura del hormigón se caracterizó en ensayos independientes, y se midió la pérdida gravimétrica de los tubos siguiendo procedimientos estándar. En todos los ensayos, la fisura principal creció muy despacio durante las primeras micras de profundidad de corrosión, pero después de una cierta profundidad crítica, la fisura se desarrolló completamente, con un aumento rápido de su apertura; la densidad de corriente influye en la profundidad de corrosión crítica. Las variaciones de diámetro interior y de volumen interior de los tubos mostraron tendencias diferentes entre sí, lo que indica que la deformación del tubo no fue uniforme. Después de la corrosión acelerada, las muestras se cortaron en rebanadas, que se utilizaron en ensayos post-corrosión. El patrón de fisuración se estudió a lo largo del tubo, en rebanadas que se impregnaron en vacío con resina y fluoresceína para mejorar la visibilidad de las fisuras bajo luz ultravioleta, y se estudió la presencia de óxido dentro de las grietas. En todas las muestras, se formó una fisura principal en el recubrimiento, infiltrada con óxido, y varias fisuras secundarias finas alrededor del tubo; el número de fisuras varió con la profundidad de corrosión de las muestras. Para muestras con la misma corrosión, el número de fisuras y su posición fue diferente entre muestras y entre secciones de una misma muestra, debido a la heterogeneidad del hormigón. Finalmente, se investigó la adherencia entre el acero y el hormigón, utilizando un dispositivo diseñado para empujar el tubo en el hormigón. Las curvas de tensión frente a desplazamiento del tubo presentaron un pico marcado, seguido de un descenso constante; la profundidad de corrosión y la apertura de fisura de las muestras influyeron notablemente en la tensión residual del ensayo. Para simular la fisuración del hormigón causada por la corrosión de las armaduras, se programó un modelo numérico. Éste combina elementos finitos con fisura embebida adaptable que reproducen la fractura del hormigón conforme al modelo de fisura cohesiva estándar, y elementos de interfaz llamados elementos junta expansiva, que se programaron específicamente para reproducir la expansión volumétrica del óxido y que incorporan su comportamiento mecánico. En el elemento junta expansiva se implementó un fenómeno de despegue, concretamente de deslizamiento y separación, que resultó fundamental para obtener localización de fisuras adecuada, y que se consiguió con una fuerte reducción de la rigidez tangencial y la rigidez en tracción del óxido. Con este modelo, se realizaron simulaciones de los ensayos, utilizando modelos bidimensionales de las muestras con elementos finitos. Como datos para el comportamiento en fractura del hormigón, se utilizaron las propiedades determinadas en experimentos. Para el óxido, inicialmente se supuso un comportamiento fluido, con deslizamiento y separación casi perfectos. Después, se realizó un ajuste de los parámetros del elemento junta expansiva para reproducir los resultados experimentales. Se observó que variaciones en la rigidez normal del óxido apenas afectaban a los resultados, y que los demás parámetros apenas afectaban a la apertura de fisura; sin embargo, la deformación del tubo resultó ser muy sensible a variaciones en los parámetros del óxido, debido a la flexibilidad de la pared de los tubos, lo que resultó fundamental para determinar indirectamente los valores de los parámetros constitutivos del óxido. Finalmente, se realizaron simulaciones definitivas de los ensayos. El modelo reprodujo la profundidad de corrosión crítica y el comportamiento final de las curvas experimentales; se comprobó que la variación de diámetro interior de los tubos está fuertemente influenciada por su posición relativa respecto a la fisura principal, en concordancia con los resultados experimentales. De la comparación de los resultados experimentales y numéricos, se pudo extraer información sobre las propiedades del óxido que de otra manera no habría podido obtenerse. Corrosion of steel is one of the main pathologies affecting reinforced concrete structures exposed to marine environments or to molten salt. When corrosion occurs, an oxide layer develops around the reinforcement surface, which occupies a greater volume than the initial steel; thus, it induces internal pressure on the surrounding concrete that leads to cracking and, eventually, to full-spalling of the concrete cover. During the last years much effort has been devoted to understand the process of cracking; however, there is still a lack of knowledge regarding the mechanical behavior of the oxide layer, which is essential in the prediction of cracking. Thus, a methodology has been developed and applied in this thesis to gain further understanding of the behavior of the steel-oxide-concrete system, combining experiments and numerical simulations. Accelerated corrosion tests were carried out in laboratory conditions, using the impressed current technique. To get experimental information close to the oxide layer, concrete prisms with a smooth steel tube as reinforcement were selected as specimens, which were designed to get a single main crack across the cover. During the tests, the specimens were equipped with instruments that were specially designed to measure the variation of inner diameter and volume of the tubes, and the width of the main crack was recorded using a commercial extensometer that was adapted to the geometry of the specimens. The boundary conditions were carefully designed so that plane current and strain fields were expected during the tests, resulting in nearly uniform corrosion along the length of the tube, so that the tests could be reproduced in numerical simulations. Series of tests were carried out with various current densities and corrosion depths. Complementarily, the fracture behavior of concrete was characterized in independent tests, and the gravimetric loss of the steel tubes was determined by standard means. In all the tests, the main crack grew very slowly during the first microns of corrosion depth, but after a critical corrosion depth it fully developed and opened faster; the current density influenced the critical corrosion depth. The variation of inner diameter and inner volume of the tubes had different trends, which indicates that the deformation of the tube was not uniform. After accelerated corrosion, the specimens were cut into slices, which were used in post-corrosion tests. The pattern of cracking along the reinforcement was investigated in slices that were impregnated under vacuum with resin containing fluorescein to enhance the visibility of cracks under ultraviolet lightening and a study was carried out to assess the presence of oxide into the cracks. In all the specimens, a main crack developed through the concrete cover, which was infiltrated with oxide, and several thin secondary cracks around the reinforcement; the number of cracks diminished with the corrosion depth of the specimen. For specimens with the same corrosion, the number of cracks and their position varied from one specimen to another and between cross-sections of a given specimen, due to the heterogeneity of concrete. Finally, the bond between the steel and the concrete was investigated, using a device designed to push the tubes of steel in the concrete. The curves of stress versus displacement of the tube presented a marked peak, followed by a steady descent, with notably influence of the corrosion depth and the crack width on the residual stress. To simulate cracking of concrete due to corrosion of the reinforcement, a numerical model was implemented. It combines finite elements with an embedded adaptable crack that reproduces cracking of concrete according to the basic cohesive model, and interface elements so-called expansive joint elements, which were specially designed to reproduce the volumetric expansion of oxide and incorporate its mechanical behavior. In the expansive joint element, a debonding effect was implemented consisting of sliding and separation, which was proved to be essential to achieve proper localization of cracks, and was achieved by strongly reducing the shear and the tensile stiffnesses of the oxide. With that model, simulations of the accelerated corrosion tests were carried out on 2- dimensional finite element models of the specimens. For the fracture behavior of concrete, the properties experimentally determined were used as input. For the oxide, initially a fluidlike behavior was assumed with nearly perfect sliding and separation; then the parameters of the expansive joint element were modified to fit the experimental results. Changes in the bulk modulus of the oxide barely affected the results and changes in the remaining parameters had a moderate effect on the predicted crack width; however, the deformation of the tube was very sensitive to variations in the parameters of oxide, due to the flexibility of the tube wall, which was crucial for indirect determination of the constitutive parameters of oxide. Finally, definitive simulations of the tests were carried out. The model reproduced the critical corrosion depth and the final behavior of the experimental curves; it was assessed that the variation of inner diameter of the tubes is highly influenced by its relative position with respect to the main crack, in accordance with the experimental observations. From the comparison of the experimental and numerical results, some properties of the mechanical behavior of the oxide were disclosed that otherwise could not have been measured.

Wind-induced loads over double cantilever bridges under construction

Within the last century the interest in wind-induced loads over civil engineering structures has become more and more important, the reason being that the development of new construction techniques and materials has allowed engineers and architects to design new structures far from the traditional concepts, and in many cases wind actions over these singular structures are not included in the existing codes of practice. In this paper the windinduced static loads over bridges constructed by the double cantilever method during erection stages are considered. The aerodynamic load over a double cantilever bridge under a yawing-angled wind produces a yawing (torsional) moment on the bridge deck, which can lead to undesirable rotation of the deck about the supporting pier. The effects of the wind yaw angle and the length of the deck are analysed. The wind action caused by the presence of sliding concrete forms at the ends of the deck is also studied.

Analysis of Combined Bending and Punching Tests of Reinforced Concrete Slabs within IMPACT III Project

The paper reports on a collaborative effort between the Swiss Federal Nuclear Safety Inspectorate (ENSI) and their consultants Principia and Stangenberg. As part of the IMPACT III project, reduced scale impact tests of reinforced concrete structures were carried out. The simulation of test X3 is presented here and the numerical results are compared with those obtained in the test, carried out in August 2013. The general object is to improve the safety of nuclear facilities and, more specifically, to demonstrate the capabilities of current simulation techniques to reproduce the behaviour of a reinforced concrete structure impacted by a soft missile. The missile is a steel tube with a mass of 50 kg and travelling at 140 m/s. The target is a 250 mm thick, 2,1 m by 2,1 m reinforced concrete wall, held in a stiff supporting frame. The reinforcement includes both longitudinal and transverse rebars. Calculations were carried out before and after the test with Abaqus (Principia) and SOFiSTiK (Stangenberg). In the Abaqus simulation the concrete is modelled using solid elements and a damaged plasticity formulation, the rebars with embedded beam elements, and the missile with shell elements. In SOFiSTiK the target is modelled with non-linear, layered shell elements for the reinforcement on both sides; non-linear shear deformations of shell/plate elements are approximately included. The results generally indicate a good agreement between calculations and measurements.

Enzyme plus light therapy to repair DNA damage in ultraviolet-B-irradiated human skin

Ultraviolet-B (UVB) (290–320 nm) radiation-induced cyclobutane pyrimidine dimers within the DNA of epidermal cells are detrimental to human health by causing mutations and immunosuppressive effects that presumably contribute to photocarcinogenesis. Conventional photoprotection by sunscreens is exclusively prophylactic in nature and of no value once DNA damage has occurred. In this paper, we have therefore assessed whether it is possible to repair UVB radiation-induced DNA damage through topical application of the DNA-repair enzyme photolyase, derived from Anacystis nidulans, that specifically converts cyclobutane dimers into their original DNA structure after exposure to photoreactivating light. When a dose of UVB radiation sufficient to induce erythema was administered to the skin of healthy subjects, significant numbers of dimers were formed within epidermal cells. Topical application of photolyase-containing liposomes to UVB-irradiated skin and subsequent exposure to photoreactivating light decreased the number of UVB radiation-induced dimers by 40–45%. No reduction was observed if the liposomes were not filled with photolyase or if photoreactivating exposure preceded the application of filled liposomes. The UVB dose administered resulted in suppression of intercellular adhesion molecule-1 (ICAM-1), a molecule required for immunity and inflammatory events in the epidermis. In addition, in subjects hypersensitive to nickel sulfate, elicitation of the hypersensitivity reaction in irradiated skin areas was prevented. Photolyase-induced dimer repair completely prevented these UVB radiation-induced immunosuppressive effects as well as erythema and sunburn-cell formation. These studies demonstrate that topical application of photolyase is effective in dimer reversal and thereby leads to immunoprotection.