A three dimensional infinite wedge shaped solid block sliding into water along an inclined beach

The three dimensional (3D) problem of a solid block sliding into water along an inclined beach is investigated. The main part of the block is an infinite wedge cylinder and the front of the body is part of an elliptical cone. Incompressible velocity potential theory is used together with fully nonlinear boundary conditions. When gravity is ignored, it is found that self-similar solution is possible. The boundary element method is used to solve the problem. The free surface shape is updated together with the potential on the free surface until the flow has become self-similar. Convergence studies are taken with respect to marching step and element size. Simulations are made for different bodies and different beach angles. Extensive results are provided for the pressure as well as the free surface shape, and their implications in physics are discussed

Sustained delivery and molecular targeting of a therapeutic monoclonal antibody to metastases in the central nervous system of mice.

Approximately 15-40% of all cancers develop metastases in the central nervous system (CNS), yet few therapeutic options exist to treat them. Cancer therapies based on monoclonal antibodies are widely successful, yet have limited efficacy against CNS metastases, owing to the low levels of the drug reaching the tumour site. Here, we show that the encapsulation of rituximab within a crosslinked zwitterionic polymer layer leads to the sustained release of rituximab as the crosslinkers are gradually hydrolysed, enhancing the CNS levels of the antibody by approximately tenfold with respect to the administration of naked rituximab. When the nanocapsules were functionalized with CXCL13-the ligand for the chemokine receptor CXCR5, which is frequently found on B-cell lymphoma-a single dose led to improved control of CXCR5-expressing metastases in a murine xenograft model of non-Hodgkin lymphoma, and eliminated lymphoma in a xenografted humanized bone marrow-liver-thymus mouse model. Encapsulation and molecular targeting of therapeutic antibodies could become an option for the treatment of cancers with CNS metastases

Enhanced Delivery of Rituximab Into Brain and Lymph Nodes Using Timed-Release Nanocapsules in Non-Human Primates.

Tumor metastasis into the central nervous system (CNS) and lymph nodes (LNs) is a major obstacle for effective therapies. Therapeutic monoclonal antibodies (mAb) have revolutionized tumor treatment; however, their efficacy for treating metastatic tumors-particularly, CNS and LN metastases-is poor due to inefficient penetration into the CNS and LNs following intravenous injection. We recently reported an effective delivery of mAb to the CNS by encapsulating the anti-CD20 mAb rituximab (RTX) within a thin shell of polymer that contains the analogs of choline and acetylcholine receptors. This encapsulated RTX, denoted as n-RTX, eliminated lymphoma cells systemically in a xenografted humanized mouse model using an immunodeficient mouse as a recipient of human hematopoietic stem/progenitor cells and fetal thymus more effectively than native RTX; importantly, n-RTX showed notable anti-tumor effect on CNS metastases which is unable to show by native RTX. As an important step toward future clinical translation of this technology, we further analyzed the properties of n-RTX in immunocompetent animals, rats, and non-human primates (NHPs). Our results show that a single intravenous injection of n-RTX resulted in 10-fold greater levels in the CNS and 2-3-fold greater levels in the LNs of RTX, respectively, than the injection of native RTX in both rats and NHPs. In addition, we demonstrate the enhanced delivery and efficient B-cell depletion in lymphoid organs of NHPs with n-RTX. Moreover, detailed hematological analysis and liver enzyme activity tests indicate n-RTX treatment is safe in NHPs. As this nanocapsule platform can be universally applied to other therapeutic mAbs, it holds great promise for extending mAb therapy to poorly accessible body compartments

Novel lung imaging biomarkers and skin gene expression subsetting in dasatinib treatment of systemic sclerosis-associated interstitial lung disease.

BackgroundThere are no effective treatments or validated clinical response markers in systemic sclerosis (SSc). We assessed imaging biomarkers and performed gene expression profiling in a single-arm open-label clinical trial of tyrosine kinase inhibitor dasatinib in patients with SSc-associated interstitial lung disease (SSc-ILD).MethodsPrimary objectives were safety and pharmacokinetics. Secondary outcomes included clinical assessments, quantitative high-resolution computed tomography (HRCT) of the chest, serum biomarker assays and skin biopsy-based gene expression subset assignments. Clinical response was defined as decrease of >5 or >20% from baseline in the modified Rodnan Skin Score (MRSS). Pulmonary function was assessed at baseline and day 169.ResultsDasatinib was well-tolerated in 31 patients receiving drug for a median of nine months. No significant changes in clinical assessments or serum biomarkers were seen at six months. By quantitative HRCT, 65% of patients showed no progression of lung fibrosis, and 39% showed no progression of total ILD. Among 12 subjects with available baseline and post-treatment skin biopsies, three were improvers and nine were non-improvers. Improvers mapped to the fibroproliferative or normal-like subsets, while seven out of nine non-improvers were in the inflammatory subset (p = 0.0455). Improvers showed stability in forced vital capacity (FVC) and diffusing capacity for carbon monoxide (DLCO), while both measures showed a decline in non-improvers (p = 0.1289 and p = 0.0195, respectively). Inflammatory gene expression subset was associated with higher baseline HRCT score (p = 0.0556). Non-improvers showed significant increase in lung fibrosis (p = 0.0313).ConclusionsIn patients with SSc-ILD dasatinib treatment was associated with acceptable safety profile but no significant clinical efficacy. Patients in the inflammatory gene expression subset showed increase in skin fibrosis, decreasing pulmonary function and worsening lung fibrosis during the study. These findings suggest that target tissue-specific gene expression analyses can help match patients and therapeutic interventions in heterogeneous diseases such as SSc, and quantitative HRCT is useful for assessing clinical outcomes.Trial registrationClinicaltrials.gov NCT00764309

Measured and calculated seismic velocities and densities for granulites from xenolith occurrences and adjacent exposed lower crustal sections: A comparative study from the North China craton

Granulites from the Neogene xenolith-bearing Hannuoba alkaline basalt and from the Manjinggou-Wayaokou exposed lower crustal section in the Archean Huai'an terrain, which occurs within and surrounds the Hannuoba basalt, provide a unique opportunity for a comparative study on petrophysical properties and composition of the lower crust represented by these two types of samples. P and S wave velocities and densities of 12 Hannuoba lower crustal xenoliths and one associated spinel lherzolite xenolith as well as nine granulites and granulite-facies metasedimentary rocks from the Archean Huai'an terrain were measured in laboratory at pressures up to 600 MPa and temperatures up to 600°C. Calculations of P and S wave velocities were also made for the same suite of samples based on modal mineralogy and single-crystal velocities whose variations with composition are considered by using microprobe analyses and velocities of end members. The measured and calculated Vp at room temperature and 600 MPa, where the microcrack effect is considered to be almost eliminated, agree within 4% for rocks from the Manjinggou-Wayaokou section and the adjacent Wutai-Jining upper crustal to upper lower crustal section. In contrast, the xenoliths show systematically lower measured Vp by up to 15% relative to calculated velocities, even if decompression-induced products of kelyphite and glass are taken into account. The lower measured velocities for xenoliths are attributed to grain boundary alteration and residual porosity. This implies that although granulite xenoliths provide direct information about lower crustal constitution and chemical composition, they are not faithful samples for studying in situ seismic properties of the lower crust in terms of measured velocities due to alterations during their entrainment to the surface, which changes their physical properties significantly. In this respect, granulites from high-grade terrains are better samples because they are not subjected to significant changes during their slow transport to the surface and because physical properties depend primarily on mineralogy in addition to pressure and temperature. On the other hand, calculated velocities for granulite xenoliths are consistent with velocities for granulites from terrains, suggesting that they can be also used to infer lower crust composition by correlating with results from seismic refraction studies. Copyright 2000 by the American Geophysical Union.published_or_final_versio

High Fidelity Tape Transfer Printing Based On Chemically Induced Adhesive Strength Modulation

Transfer printing, a two-step process (i.e. picking up and printing) for heterogeneous integration, has been widely exploited for the fabrication of functional electronics system. To ensure a reliable process, strong adhesion for picking up and weak or no adhesion for printing are required. However, it is challenging to meet the requirements of switchable stamp adhesion. Here we introduce a simple, high fidelity process, namely tape transfer printing(TTP), enabled by chemically induced dramatic modulation in tape adhesive strength. We describe the working mechanism of the adhesion modulation that governs this process and demonstrate the method by high fidelity tape transfer printing several types of materials and devices, including Si pellets arrays, photodetector arrays, and electromyography (EMG) sensors, from their preparation substrates to various alien substrates. High fidelity tape transfer printing of components onto curvilinear surfaces is also illustrated

The novel mTOR inhibitor RAD001 (Everolimus) induces antiproliferative effects in human pancreatic neuroendocrine tumor cells

Background/Aim: Tumors exhibiting constitutively activated PI(3) K/Akt/mTOR signaling are hypersensitive to mTOR inhibitors such as RAD001 (everolimus) which is presently being investigated in clinical phase II trials in various tumor entities, including neuroendocrine tumors (NETs). However, no preclinical data about the effects of RAD001 on NET cells have been published. In this study, we aimed to evaluate the effects of RAD001 on BON cells, a human pancreatic NET cell line that exhibits constitutively activated PI(3) K/Akt/mTOR signaling. Methods: BON cells were treated with different concentrations of RAD001 to analyze its effect on cell growth using proliferation assays. Apoptosis was examined by Western blot analysis of caspase-3/PARP cleavage and by FACS analysis of DNA fragmentation. Results: RAD001 potently inhibited BON cell growth in a dose-dependent manner which was dependent on the serum concentration in the medium. RAD001-induced growth inhibition involved G0/G1-phase arrest as well as induction of apoptosis. Conclusion: In summary, our data demonstrate antiproliferative and apoptotic effects of RAD001 in NET cells in vitro supporting its clinical use in current phase II trials in NET patients. Copyright (c) 2007 S. Karger AG, Basel

Tectonic affinity of the west Qinling terrane (central China): North China or Yangtze?

[33] Neogene (̃14 Ma) basaltic magmatism has occurred in west Qinling, at the northeastern corner of the Tibetan Plateau. Furthermore, U-Pb ages and Hf isotopic data of xenocrystic zircons indicate that the unexposed Neoarchean (2.7-2.5 Ga) basement beneath the Phanerozoic outcrops in west Qinling has affinities with the southern margin of the north China block. The basement has a complex evolution, including the addition of juvenile mantle material at ̃2.7- 2.4 Ga and 1.1-0.8 Ga and reworking at ̃1.8 Ga and possibly at 1.4 Ga. Phanerozoic thermal events at 320-300 Ma, 230 Ma, and 160 Ma also have affected the basement. We interpret the west Qinling orogenic terrane as originally separated from the north China block, joined to the northern Yangtze block during the Meso-Neoproterozoic, and finally involved in the northward subduction and collision of the Yangtze block in the Paleozoic and early Mesozoic and subsequent lithospheric extension in the Jurassic. © 2010 by the American Geophysical Union.published_or_final_versio

Intracellular interferons in fish : a unique means to combat viral infection

Peer reviewedPublisher PD