Can resistance to trastuzumab be reversed by endocrine therapy? Combination of trastuzumab and letrozole after resistance to sequential trastuzumab and aromatase inhibitor monotherapies in patients with ER-positive, HER-2 positive, advanced breast cancer: a proof-of-concept trial (SAKK 23/03)

Introduction: Trastuzumab (T) is a cornerstone in the treatment of patients with HER2-overexpressing advanced breast cancer and development of resistance to T is a major therapeutic problem. HER-2 is part of a highly interactive signaling network that may impair efficacy of endocrine therapy. A sequential treatment design was chosen in this trial to ensure complete resistance to single agent therapy before receiving both a non-steroidal aromatase inhibitor (AI) and T. Any kind of clinical activity with combined treatment of AI and T after progression of single agent treatments could indicate restoration of sensitivity as a consequence of cross-talking and networking between both pathways. Methods: Key eligibility criteria included postmenopausal patients (pts.) with advanced, measurable, HER-2 positive (assessed by FISH, ratio (≥2)), HR positive disease and progression on prior treatment with a non-steroidal AI, e.g. letrozole or anastrozole, either in an adjuvant or advanced setting. Pts. received standard dose T monotherapy either weekly or three-weekly in step 1 and upon disease progression, continued T in combination with letrozole in step 2. The primary endpoint was clinical benefit response (CBR: CR, PR or SD for at least 24 weeks (+/- 1 week) according to RECIST) in step 2. Results: Thirteen pts. were enrolled in five centers in Switzerland. In step 1, six pts. (46%) achieved CBR. Median time to progression (TTP) was 161 days (Range: 50 - 627). Based on data collected until the end of May 2010, CBR was observed in seven out of the eleven evaluable pts. (64%) in step 2, including one pt. with partial response. Four of the seven pts. within step 2 that achieved CBR also had CBR in step 1. Seven out of eleven pts. have documented tumor progression during step 2 treatment. Median TTP for all eleven pts. was 184 days (range 61 - 471). Mean time on study treatment (TTP in step 1 plus TTP in step 2) for pts. reaching step 2 was 380 days (range 174 - 864). Adverse events were generally mild. Conclusion: Results of this proof-of-principle trial suggest that complete resistance to both AI and T can be overcome in a proportion of pts. by combined treatment of AI and T, as all pts. served as their own control. Our results appear promising for a new treatment strategy which offers a chemotherapy-free and well-tolerated option for at least a subset of the pts. with HR positive, HER-2 positive breast cancer. Further trials will need to corroborate this finding.

Effect of water contamination on the shear bond strength of five orthodontic adhesives

Objectives: To evaluate the shear bond strength and site of failure of brackets bonded to dry and wet enamel. Study design: 50 teeth were divided into ten groups of 5 teeth each (10 surfaces). In half the groups enamel was kept dry before bonding, and in the other half distilled water was applied to wet the surface after etching. The following groups were established: 1)Acid/Transbond-XT (dry/wet) XT; 2) Transbond Plus Self Etching Primer (TSEP)/Transbond-XT paste (dry/wet); 3) Concise (dry), Transbond MIP/Concise (wet), 4) FujiOrtho-LC (dry/wet); 5) SmartBond (dry/wet). Brackets were bonded to both buccal and lingual surfaces. Specimens were stored in distilled water (24 hours at 37ºC) and thermocycled. Brackets were debonded using a Universal testing machine (cross-head speed 1 mm/min). Failure sites were classified using a stereomicroscope. Results: No significant differences in bond strength were detected between the adhesives under wet and dry conditions except for Smart- Bond, whose bond strength was significantly lower under dry conditions. For all the adhesives most bond failures were of mixed site location except for Smartbond, which failed at the adhesive-bracket interface. Conclusions: Under wet conditions the bonding capacity of the adhesives tested was similar than under dry conditions, with the exception of SmartBond which improved under wet conditions

Development of fluid conduits in the auriferous shear zones of the Hutti Gold Mine, India: evidence for spatially and temporally heterogeneous fluid flow

The gold mineralization of the Hutti Mine is hosted by nine parallel, N - S trending, steeply dipping, 2 - 10 m wide shear zones, that transect Archaean amphibolites. The shear zones were formed after peak metamorphism during retrograde ductile D, shearing in the lower amphibolite facies. They were reactivated in the lower to mid greenschist facies by brittle-ductile D-3 shearing and intense quartz veining. The development of a S-2-S-3 crenulation cleavage facilitates the discrimination between the two deformation events and contemporaneous alteration and gold mineralization. Ductile D, shearing is associated with a pervasively developed distal chlorite - sed cite alteration assemblage in the outer parts of the shear zones and the proximal biotite-plagioclase alteration in the center of the shear zones. D3 is characterized by development of the inner chlorite-K-feldspar alteration, which forms a centimeter-scale alteration halo surrounding the laminated quartz veins and replaces earlier biotite along S-3. The average size of the laminated vein systems is 30-50 m along strike as well as down-dip and 2-6 m in width. Mass balance calculations suggest strong metasomatic changes for the proximal biotite-plagioclase alteration yielding mass and volume increase of ca. 16% and 12%, respectively. The calculated mass and volume changes of the distal chlorite-sericite alteration (ca. 11%, ca. 8%) are lower. The decrease in 6180 values of the whole rock from around 7.5 parts per thousand for the host rocks to 6-7 parts per thousand for the distal chlorite-sericite and the proximal biotite-plagioclase alteration and around 5 parts per thousand for the inner chlorite-K-feldspar alteration suggests hydrothermal alteration during two-stage deformation and fluid flow. The ductile D-2 deformation in the lower amphibolite facies has provided grain scale porosities by microfracturing. The pervasive, steady-state fluid flow resulted in a disseminated style of gold-sulfide mineralization and a penetrative alteration of the host rocks. Alternating ductile and brittle D3 deformation during lower to mid greenschist facies conditions followed the fault-valve process. Ductile creep in the shear zones resulted in a low permeability environment leading to fluid pressure build-up. Strongly episodic fluid advection and mass transfer was controlled by repeated seismic fracturing during the formation of laminated quartz(-gold) veins. The limitation of quartz veins to the extent of earlier shear zones indicate the importance of preexisting anisotropies for fault-valve action and economic gold mineralization. (C) 2003 Elsevier B.V. All rights reserved.

A computationally efficient shear deformable beam element for large deformation multibody applications

In this paper, a new two-dimensional shear deformable beam element based on the absolute nodal coordinate formulation is proposed. The nonlinear elastic forces of the beam element are obtained using a continuum mechanics approach without employing a local element coordinate system. In this study, linear polynomials are used to interpolate both the transverse and longitudinal components of the displacement. This is different from other absolute nodal-coordinate-based beam elements where cubic polynomials are used in the longitudinal direction. The accompanying defects of the phenomenon known as shear locking are avoided through the adoption of selective integration within the numerical integration method. The proposed element is verified using several numerical examples, and the results are compared to analytical solutions and the results for an existing shear deformable beam element. It is shown that by using the proposed element, accurate linear and nonlinear static deformations, as well as realistic dynamic behavior, can be achieved with a smaller computational effort than by using existing shear deformable two-dimensional beam elements.

On the Reversed Brayton Cycle with High Speed Machinery

This work was carried out in the laboratory of Fluid Dynamics, at Lappeenranta University of Technology during the years 1991-1996. The research was a part of larger high speed technology development research. First, there was the idea of making high speed machinery applications with the Brayton cycle. There was a clear need to deepen theknowledge of the cycle itself and to make a new approach in the field of the research. Also, the removal of water from the humid air seemed very interesting. The goal of this work was to study methods of designing high speed machinery to the reversed Brayton cycle, from theoretical principles to practical applications. The reversed Brayton cycle can be employed as an air dryer, a heat pump or a refrigerating machine. In this research the use of humid air as a working fluid has an environmental advantage, as well. A new calculation method for the Braytoncycle is developed. In this method especially the expansion process in the turbine is important because of the condensation of the water vapour in the humid air. This physical phenomena can have significant effects on the level of performance of the application. Also, the influence of calculating the process with actual, achievable process equipment efficiencies is essential for the development of the future machinery. The above theoretical calculations are confirmed with two different laboratory prototypes. The high speed machinery concept allows one to build an application with only one rotating shaft including all the major parts: the high speed motor, the compressor and the turbine wheel. The use of oil free bearings and high rotational speed outlines give several advantages compared to conventional machineries: light weight, compact structure, safe operation andhigher efficiency at a large operational region. There are always problems whentheory is applied to practice. The calibrations of pressure, temperature and humidity probes were made with care but still measurable errors were not negligible. Several different separators were examined and in all cases the content of the separated water was not exact. Due to the compact sizes and structures of the prototypes, the process measurement was slightly difficult. The experimental results agree well with the theoretical calculations. These experiments prove the operation of the process and lay a ground for the further development. The results of this work give very promising possibilities for the design of new, commercially competitive applications that use high speed machinery and the reversed Brayton cycle.

Experimental insights into deformation dynamics and intermittency in rapid granular shear flows

This work concerns the experimental study of rapid granular shear flows in annular Couette geometry. The flow is induced by continuous driving of the horizontal plate at the top of the granular bed in an annulus. The compressive pressure, driving torque, instantaneous bed height and rotational speed of the shearing plate are measured. Moreover, local stress fluctuations are measured in a medium made of steel spheres 2 and 3 mm in diameter. Both monodisperse packing and bidisperse packing are investigated to reveal the influence of size diversity in intermittent features of granular materials. Experiments are conducted in an annulus that can contain up to 15 kg of spherical steel balls. The shearing granular medium takes place via the rotation of the upper plate which compresses the material loaded inside the annulus. Fluctuations of compressive force are locally measured at the bottom of the annulus using a piezoelectric sensor. Rapid shear flow experiments are pursued at different compressive forces and shear rates and the sensitivity of fluctuations are then investigated by different means through monodisperse and bidisperse packings. Another important feature of rapid granular shear flows is the formation of ordered structures upon shearing. It requires a certain range for the amount of granular material (uniform size distribution) loaded in the system in order to obtain stable flows. This is studied more deeply in this thesis. The results of the current work bring some new insights into deformation dynamics and intermittency in rapid granular shear flows. The experimental apparatus is modified in comparison to earlier investigations. The measurements produce data for various quantities continuously sampled from the start of shearing to the end. Static failure and dynamic shearing ofa granular medium is investigated. The results of this work revealed some important features of failure dynamics and structure formation in the system. Furthermore, some computer simulations are performed in a 2D annulus to examine the nature of kinetic energy dissipation. It is found that turbulent flow models can statistically represent rapid granular flows with high accuracy. In addition to academic outcomes and scientific publications our results have a number of technological applications associated with grinding, mining and massive grain storages.

Efeito do extrato de alho na quebra de dormência de gemas de videiras e no controle in vitro do agente causal da antracnose (Elsinoe ampelina Shear)

Considerando a redução ou eliminação do uso de substâncias sintéticas que preconizam os sistemas sustentáveis de produção de frutas, este trabalho teve como objetivo a busca de novas alternativas para a quebra de dormência e o controle de doenças em videiras. Estacas de videira contendo uma gema foram pulverizadas com os seguintes tratamentos: 1) testemunha; 2) OV (óleo vegetal) 1%; 3) extrato de alho (EA) 3%; 4) EA 3% + OV 1%. Posteriormente, as estacas foram mantidas em câmara de crescimento (25±2.5ºC) por 56 dias. O único tratamento que estimulou a brotação das estacas de videira cv. Isabel Precoce foi o EA 3% + OV 1%, que atingiu 35% de brotação, diferindo estatisticamente dos tratamentos- testemunha (12,5%), OV 1% (17,5%) e EA 3% (15,0%). Provavelmente, o estádio de endodormência profunda das gemas, após apenas 90 horas de frio ( < 7,0ºC), impediu melhores resultados dos tratamentos para quebra de dormência. Três experimentos, foram conduzidos in vitro, com diferentes doses de extrato de alho, com o objetivo de avaliar o controle do fungo Elsinoe ampelina. Em todos os experimentos, houve efeito quadrático no crescimento micelial, sem ter havido diferenças entre os tratamentos com extrato de alho, evidenciando o seu efeito fungicida, mesmo na dose mais baixa de EA (0,0615%).

The Dynamics of Force Fluctuations in Shear Granular Flows

Tämän työn tavoitteena oli tutkia rakeisen materiaalin kinematiikkaa ja rakentaa koelaitteisto rakeisen materiaalin leikkausjännitysvirtauksien tutkimiseen. Kokeellisessa osassa on keskitytty sisäisiin voimaheilahteluihin ja niiden ymmärtämiseen. Teoriaosassa on käyty läpi rakeisen materiaalin yleisiä ominaisuuksia ja lisäksi on esitetty kaksi eri tapaa mallintaa fysikaalisien ominaisuuksien heilahteluja rakeisessa materiaalissa. Nämä kaksi esitettyä mallinnusmenetelmää ovat skalaarinen q-malli ja simulointi. Skalaarinen q-malli määrittelee jokaiseen yksittäiseen rakeeseen kohdistuvan jännityksen, rakeen ollessa osa 2- tai 3-dimensionaalista asetelmaa. Tämän mallin perusidea on kuvata jännityksien epähomogeenisuutta, joka johtuu rakeiden satunnaisasettelusta. Simulointimallinnus perustuu event-driven algoritmiin, missä systeemin dynamiikkaa kuvataan yksittäisillä partikkelien törmäyksillä. Törmäyksien vaiheet ratkaistiin käyttämällä liikemääräyhtälöitä ja restituution määritelmää. Teoriaosuudessa käytiin vielä pieniltä osin läpi syitä jännitysheilahteluihin ja rakeisen materiaalin lukkiintumiseen. Tutkimuslaitteistolla tutkittiin rakeisen materiaalin käyttäytymistä rengasmaisessa leikkausjännitysvirtauksessa. Tutkimusosuuden päätavoitteena oli mitata partikkelien kosketuksista ja törmäyksistä johtuvia hetkellisiä voimaheilahteluja rengastilavuuden pohjalta. Rakeisena materiaalina tutkimuksessa käytettiin teräskuulia. Jännityssignaali ajan funktiona osoittaa suurta heilahtelua, joka voi olla jopa kertalukua keskiarvosta suurempaa. Tällainen suuren amplitudin omaava heilahtelu on merkittävä haittapuoli yleisesti rakeisissa materiaaleissa käytettyjen jatkuvuusmallien kanssa. Tällainen heilahtelu tekee käytetyt jatkuvuusmallit epäpäteviksi. Yleisellä tasolla jännityksien todennäköisyysjakauma on yhtäpitävä skalaarisen q-mallin tuloksien kanssa. Molemmissa tapauksissa todennäköisyysjakaumalla on eksponentiaalinen muoto.

Relation between plaque type, plaque thickness, blood shear stress, and plaque stress in coronary arteries assessed by X-ray Angiography and Intravascular Ultrasound

Purpose: Atheromatic plaque progression is affected, among others phenomena, by biomechanical, biochemical, and physiological factors. In this paper, the authors introduce a novel framework able to provide both morphological (vessel radius, plaque thickness, and type) and biomechanical (wall shear stress and Von Mises stress) indices of coronary arteries. Methods: First, the approach reconstructs the three-dimensional morphology of the vessel from intravascular ultrasound(IVUS) and Angiographic sequences, requiring minimal user interaction. Then, a computational pipeline allows to automatically assess fluid-dynamic and mechanical indices. Ten coronary arteries are analyzed illustrating the capabilities of the tool and confirming previous technical and clinical observations. Results: The relations between the arterial indices obtained by IVUS measurement and simulations have been quantitatively analyzed along the whole surface of the artery, extending the analysis of the coronary arteries shown in previous state of the art studies. Additionally, for the first time in the literature, the framework allows the computation of the membrane stresses using a simplified mechanical model of the arterial wall. Conclusions: Circumferentially (within a given frame), statistical analysis shows an inverse relation between the wall shear stress and the plaque thickness. At the global level (comparing a frame within the entire vessel), it is observed that heavy plaque accumulations are in general calcified and are located in the areas of the vessel having high wall shear stress. Finally, in their experiments the inverse proportionality between fluid and structural stresses is observed.

Nanocharacterization of Soft Biological Samples in Shear Mode with Quartz Tuning Fork Probes

Quartz tuning forks are extremely good resonators and their use is growing in scanning probe microscopy. Nevertheless, only a few studies on soft biological samples have been reported using these probes. In this work, we present the methodology to develop and use these nanosensors to properly work with biological samples. The working principles, fabrication and experimental setup are presented. The results in the nanocharacterization of different samples in different ambients are presented by using different working modes: amplitude modulation with and without the use of a Phase-Locked Loop (PLL) and frequency modulation. Pseudomonas aeruginosa bacteria are imaged in nitrogen using amplitude modulation. Microcontact printed antibodies are imaged in buffer using amplitude modulation with a PLL. Finally, metastatic cells are imaged in air using frequency modulation.

The Sottunga-Jurmo shear zone : structure and deformation history of a crustal-scale ductile shear zone in SW Finland

The aim of this study is to gain a better understanding of the structure and the deformation history of a NW-SE trending regional, crustal-scale shear structure in the Åland archipelago, SW Finland, called the Sottunga-Jurmo shear zone (SJSZ). Approaches involving e.g. structural geology, geochronology, geochemistry and metamorphic petrology were utilised in order to reconstruct the overall deformation history of the study area. The study therefore describes several features of the shear zone including structures, kinematics and lithologies within the study area, the ages of the different deformation phases (ductile to brittle) within the shear zone, as well as some geothermobarometric results. The results indicate that the SJSZ outlines a major crustal discontinuity between the extensively migmatized rocks NE of the shear zone and the unmigmatised, amphibolite facies rocks SW of the zone. The main SJSZ shows overall dextral lateral kinematics with a SW-side up vertical component and deformation partitioning into pure shear and simple shear dominated deformation styles that was intensified toward later stages of the deformation history. The deformation partitioning resulted in complex folding and refolding against the SW margin of the SJSZ, including conical and sheath folds, and in a formation of several minor strike-slip shear zones both parallel and conjugate to the main SJSZ in order to accommodate the regional transpressive stresses. Different deformation phases within the study area were dated by SIMS (zircon U-Pb), ID-TIMS (titanite U-Pb) and 40Ar/39Ar (pseudotachylyte wholerock) methods. The first deformation phase within the ca. 1.88 Ga rocks of the study area is dated at ca. 1.85 Ga, and the shear zone was reactivated twice within the ductile regime (at ca. 1.83 Ga and 1.79 Ga), during which the strain was successively increasingly partitioned into the main SJSZ and the minor shear zones. The age determinations suggest that the orogenic processes within the study area did not occur in a temporal continuum; instead, the metamorphic zircon rims and titanites show distinct, 10-20 Ma long breaks in deformation between phases of active deformation. The results of this study further imply slow cooling of the rocks through 600-700ºC so that at 1.79 Ga, 2 the temperature was still at least 600ºC. The highest recorded metamorphic pressures are 6.4-7.1 kbar. At the late stages or soon after the last ductile phase (ca. 1.79 Ga), relatively high-T mylonites and ultramylonites were formed, witnessing extreme deformation partitioning and high strain rates. After the rocks reached lower amphibolite facies to amphibolite-greenschist facies transitional conditions (ca. 500-550ºC), they cooled rapidly, probably due to crustal uplift and exhumation. The shear zone was reactivated at least once within the semi-brittle to brittle regime between ca. 1.79 Ga and 1.58 Ga, as evidenced by cataclasites and pseudotachylytes. In summary, the results of this study suggest that the Sottunga-Jurmo shear zone (and the South Finland shear zone) defines a major crustal discontinuity, and played a central role in accommodating the regional stresses during and after the Svecofennian orogeny.

FOXC2 and fluid shear stress stabilize postnatal lymphatic vasculature.

Biomechanical forces, such as fluid shear stress, govern multiple aspects of endothelial cell biology. In blood vessels, disturbed flow is associated with vascular diseases, such as atherosclerosis, and promotes endothelial cell proliferation and apoptosis. Here, we identified an important role for disturbed flow in lymphatic vessels, in which it cooperates with the transcription factor FOXC2 to ensure lifelong stability of the lymphatic vasculature. In cultured lymphatic endothelial cells, FOXC2 inactivation conferred abnormal shear stress sensing, promoting junction disassembly and entry into the cell cycle. Loss of FOXC2-dependent quiescence was mediated by the Hippo pathway transcriptional coactivator TAZ and, ultimately, led to cell death. In murine models, inducible deletion of Foxc2 within the lymphatic vasculature led to cell-cell junction defects, regression of valves, and focal vascular lumen collapse, which triggered generalized lymphatic vascular dysfunction and lethality. Together, our work describes a fundamental mechanism by which FOXC2 and oscillatory shear stress maintain lymphatic endothelial cell quiescence through intercellular junction and cytoskeleton stabilization and provides an essential link between biomechanical forces and endothelial cell identity that is necessary for postnatal vessel homeostasis. As FOXC2 is mutated in lymphedema-distichiasis syndrome, our data also underscore the role of impaired mechanotransduction in the pathology of this hereditary human disease.

A system to assess the stability of airborne nanoparticle agglomerates under aerodynamic shear

Stability of airborne nanoparticle agglomerates is important for occupational exposure and risk assessment in determining particle size distribution of nanomaterials. In this study, we developed an integrated method to test the stability of aerosols created using different types of nanomaterials. An aerosolization method, that resembles an industrial fluidized bed process, was used to aerosolize dry nanopowders. We produced aerosols with stable particle number concentrations and size distributions, which was important for the characterization of the aerosols' properties. Next, in order to test their potential for deagglomeration, a critical orifice was used to apply a range of shear forces to them. The mean particle size of tested aerosols became smaller, whereas the total number of particles generated grew. The fraction of particles in the lower size range increased, and the fraction in the upper size range decreased. The reproducibility and repeatability of the results were good. Transmission electron microscopy imaging showed that most of the nanoparticles were still agglomerated after passing through the orifice. However, primary particle geometry was very different. These results are encouraging for the use of our system for routine tests of the deagglomeration potential of nanomaterials. Furthermore, the particle concentrations and small quantities of raw materials used suggested that our system might also be able to serve as an alternative method to test dustiness in existing processes.

Systematic evaluation of matrix effects in hydrophilic interaction chromatography versus reversed phase liquid chromatography coupled to mass spectrometry.

Reversed phase liquid chromatography (RPLC) coupled to mass spectrometry (MS) is the gold standard technique in bioanalysis. However, hydrophilic interaction chromatography (HILIC) could represent a viable alternative to RPLC for the analysis of polar and/or ionizable compounds, as it often provides higher MS sensitivity and alternative selectivity. Nevertheless, this technique can be also prone to matrix effects (ME). ME are one of the major issues in quantitative LC-MS bioanalysis. To ensure acceptable method performance (i.e., trueness and precision), a careful evaluation and minimization of ME is required. In the present study, the incidence of ME in HILIC-MS/MS and RPLC-MS/MS was compared for plasma and urine samples using two representative sets of 38 pharmaceutical compounds and 40 doping agents, respectively. The optimal generic chromatographic conditions in terms of selectivity with respect to interfering compounds were established in both chromatographic modes by testing three different stationary phases in each mode with different mobile phase pH. A second step involved the assessment of ME in RPLC and HILIC under the best generic conditions, using the post-extraction addition method. Biological samples were prepared using two different sample pre-treatments, i.e., a non-selective sample clean-up procedure (protein precipitation and simple dilution for plasma and urine samples, respectively) and a selective sample preparation, i.e., solid phase extraction for both matrices. The non-selective pretreatments led to significantly less ME in RPLC vs. HILIC conditions regardless of the matrix. On the contrary, HILIC appeared as a valuable alternative to RPLC for plasma and urine samples treated by a selective sample preparation. Indeed, in the case of selective sample preparation, the compounds influenced by ME were different in HILIC and RPLC, and lower and similar ME occurrence was generally observed in RPLC vs. HILIC for urine and plasma samples, respectively. The complementary of both chromatographic modes was also demonstrated, as ME was observed only scarcely for urine and plasma samples when selecting the most appropriate chromatographic mode.