An Exact Boundary Integral Equation Formulation for BEM Thermoelastic Analysis of Transversely Anisotropic Solids

Abstract: In BEM analysis of generally anisotropic solids, the additional volume integral associated with thermal effects that appears in the direct formulation of the boundary integral equation (BIE) has hitherto been successfully transformed in an analytically exact fashion into surface ones only for two-dimensions (2D), and not for the three-dimensional (3D) case. This is due to the mathematical complexity of the Green's function and its derivatives for the 3D solid. The presence of the domain integral destroys the distinctive feature of the boundary element method (BEM) as a truly boundary solution numerical analysis tool. As a precursor to treating this problem in 3D general anisotropy, the exact volume-to-surface integral transformation associated with thermal effects is successfully carried out in this study for the special case of 3D transverse isotropy and implemented in a BEM formulation. It follows a similar approach previously employed by the authors for the same task in 2D generally anisotropic thermoelastic BEM analysis. However, a numerical scheme needs to be introduced to evaluate some terms in the new surface integrals of the BIE. Two examples are presented to demonstrate the veracity of the analytical and numerical formulations implemented

Self-Assembled Polymeric Micellar Nanoparticles as Nanocarriers for Poorly Soluble Anticancer Drug Ethaselen

A series of monomethoxy poly(ethylene glycol)-poly(lactide) (mPEG-PLA) diblock copolymers were synthesized, and mPEG-PLA micelle was fabricated and used as a nanocarrier for solubilization and delivery of a promising anticancer drug ethaselen. Ethaselen was efficiently encapsulated into the micelles by the dialysis method, and the solubility of ethaselen in water was remarkably increased up to 82 μg/mL before freeze-drying. The mean diameter of ethaselen-loaded micelles ranged from 51 to 98 nm with a narrow size distribution and depended on the length of PLA block. In vitro hemolysis study indicated that mPEG-PLA copolymers and ethaselen-loaded polymeric micelles had no hemolytic effect on the erythrocyte. The enhanced antitumor efficacy and reduced toxic effect of ethaselen-loaded polymeric micelle when compared with ethaselen-HP-β-CD inclusion were observed at the same dose in H22human liver cancer cell bearing mouse models. These suggested that mPEG-PLA polymeric micelle nanoparticles had great potential as nanocarriers for effective solubilization of poorly soluble ethaselen and further reducing side effects and toxicities of the drug

Dynamic responses of DOC and DIC transport to different flow regimes in a subtropical small mountainous river

Transport of riverine dissolved carbon (including DOC and DIC) is a crucial process linking terrestrial and aquatic C reservoirs, but has rarely been examined in subtropical small mountainous rivers (SMRs). This study monitored DOC and DIC concentrations on a biweekly basis during non-event flow periods and at 3&thinsp;h intervals during two typhoon events in three SMRs in southwestern Taiwan between January 2014 and August 2016. Two models, HBV (the Hydrologiska Byråns Vattenbalansavdelning model) and a three-endmember mixing model, were applied to determine the quantities of DOC and DIC transport from different flow paths. The results show that the annual DOC and DIC fluxes were 2.7–4.8 and 48.4–54.3&thinsp;t&thinsp;C&thinsp;km−2&thinsp;yr−1, respectively, which were approx. 2 and 20 times higher than the global mean of 1.4 and 2.6&thinsp;t&thinsp;C&thinsp;km−2&thinsp;yr−1, respectively. The DIC&thinsp;∕&thinsp;DOC ratio was 14.08, which is much higher than the mean of large rivers worldwide (1.86), and indicates the high rates of chemical weathering in this region. The two typhoons contributed 12&thinsp;%–14&thinsp;% of the annual streamflow in only 3 days (about 1.0&thinsp;% of the annual time), whereas 15.0&thinsp;%–23.5&thinsp;% and 9.2&thinsp;%–12.6&thinsp;% of the annual DOC and DIC flux, respectively, suggested that typhoons play a more important role in DOC transport than DIC transport. The endmember mixing model suggested that DOC and DIC export was mainly from surface runoff and deep groundwater, respectively. The unique patterns seen in Taiwan SMRs characterized by high dissolved carbon flux, high DIC&thinsp;∕&thinsp;DOC ratio, and large transport by intense storms should be taken into consideration when estimating global carbon budgets.</p

Targeting Angiogenesis-Dependent Calcified Neoplasms Using Combined Polymer Therapeutics

There is an immense clinical need for novel therapeutics for the treatment of angiogenesis-dependent calcified neoplasms such as osteosarcomas and bone metastases. We developed a new therapeutic strategy to target bone metastases and calcified neoplasms using combined polymer-bound angiogenesis inhibitors. Using an advanced "living polymerization" technique, the reversible addition-fragmentation chain transfer (RAFT), we conjugated the aminobisphosphonate alendronate (ALN), and the potent anti-angiogenic agent TNP-470 with N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer through a Glycine-Glycine-Proline-Norleucine linker, cleaved by cathepsin K, a cysteine protease overexpressed at resorption sites in bone tissues. In this approach, dual targeting is achieved. Passive accumulation is possible due to the increase in molecular weight following polymer conjugation of the drugs, thus extravasating from the tumor leaky vessels and not from normal healthy vessels. Active targeting to the calcified tissues is achieved by ALN's affinity to bone mineral.The anti-angiogenic and antitumor potency of HPMA copolymer-ALN-TNP-470 conjugate was evaluated both in vitro and in vivo. We show that free and conjugated ALN-TNP-470 have synergistic anti-angiogenic and antitumor activity by inhibiting proliferation, migration and capillary-like tube formation of endothelial and human osteosarcoma cells in vitro. Evaluation of anti-angiogenic, antitumor activity and body distribution of HPMA copolymer-ALN-TNP-470 conjugate was performed on severe combined immunodeficiency (SCID) male mice inoculated with mCherry-labeled MG-63-Ras human osteosarcoma and by modified Miles permeability assay. Our targeted bi-specific conjugate reduced VEGF-induced vascular hyperpermeability by 92% and remarkably inhibited osteosarcoma growth in mice by 96%.This is the first report to describe a new concept of a narrowly-dispersed combined polymer therapeutic designed to target both tumor and endothelial compartments of bone metastases and calcified neoplasms at a single administration. This new approach of co-delivery of two synergistic drugs may have clinical utility as a potential therapy for angiogenesis-dependent cancers such as osteosarcoma and bone metastases

Endoplasmic Reticulum Stress-Induced JNK Activation Is a Critical Event Leading to Mitochondria-Mediated Cell Death Caused by β-Lapachone Treatment

β-lapachone (β-lap) is a bioreductive agent that is activated by the two-electron reductase NAD(P)H quinone oxidoreductase 1 (NQO1). Although β-lap has been reported to induce apoptosis in various cancer types in an NQO1-dependent manner, the signaling pathways by which β-lap causes apoptosis are poorly understood.β-lap-induced apoptosis and related molecular signaling pathways in NQO1-negative and NQO1-overexpressing MDA-MB-231 cells were investigated. Pharmacological inhibitors or siRNAs against factors involved in β-lap-induced apoptosis were used to clarify the roles played by such factors in β-lap-activated apoptotic signaling pathways. β-lap leads to clonogenic cell death and apoptosis in an NQO1- dependent manner. Treatment of NQO1-overexpressing MDA-MB-231 cells with β-lap causes rapid disruption of mitochondrial membrane potential, nuclear translocation of AIF and Endo G from mitochondria, and subsequent caspase-independent apoptotic cell death. siRNAs targeting AIF and Endo G effectively attenuate β-lap-induced clonogenic and apoptotic cell death. Moreover, β-lap induces cleavage of Bax, which accumulates in mitochondria, coinciding with the observed changes in mitochondria membrane potential. Pretreatment with Salubrinal (Sal), an endoplasmic reticulum (ER) stress inhibitor, efficiently attenuates JNK activation caused by β-lap, and subsequent mitochondria-mediated cell death. In addition, β-lap-induced generation and mitochondrial translocation of cleaved Bax are efficiently blocked by JNK inhibition.Our results indicate that β-lap triggers induction of endoplasmic reticulum (ER) stress, thereby leading to JNK activation and mitochondria-mediated apoptosis. The signaling pathways that we revealed in this study may significantly contribute to an improvement of NQO1-directed tumor therapies

Role of DNA methylation in head and neck cancer

Head and neck cancer (HNC) is a heterogenous and complex entity including diverse anatomical sites and a variety of tumor types displaying unique characteristics and different etilogies. Both environmental and genetic factors play a role in the development of the disease, but the underlying mechanism is still far from clear. Previous studies suggest that alterations in the genes acting in cellular signal pathways may contribute to head and neck carcinogenesis. In cancer, DNA methylation patterns display specific aberrations even in the early and precancerous stages and may confer susceptibility to further genetic or epigenetic changes. Silencing of the genes by hypermethylation or induction of oncogenes by promoter hypomethylation are frequent mechanisms in different types of cancer and achieve increasing diagnostic and therapeutic importance since the changes are reversible. Therefore, methylation analysis may provide promising clinical applications, including the development of new biomarkers and prediction of the therapeutic response or prognosis. In this review, we aimed to analyze the available information indicating a role for the epigenetic changes in HNC