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A class of invex nonlinear complementarity (NCP) functions is introduced. The existence of such a function is illustrated by citing nontrivial examples. Some interesting properties of invex NCP functions have been developed. Quasi-invex NCP functions and their properties are also presented. [ABSTRACT FROM AUTHOR]

A class of invex nonlinear complementarity (NCP) functions is introduced. The existence of such a function is illustrated by citing nontrivial examples. Some interesting properties of invex NCP functions have been developed. Quasi-invex NCP functions and their properties are also presented [ABSTRACT FROM AUTHOR]

A class of invex nonlinear complementarity (NCP) functions is introduced. The existence of such a function is illustrated by citing nontrivial examples. Some interesting properties of invex NCP functions have been developed. Quasi-invex NCP functions and their properties are also presented. [ABSTRACT FROM AUTHOR]

Background: Sensitizing effects of poly-ADP-ribose polymerase inhibitors have been studied in several preclinical models, but a clear understanding of predictive biomarkers is lacking. In this study, in vivo efficacy of veliparib combined with temozolomide (TMZ) was evaluated in a large panel of glioblastoma multiforme (GBM) patient-derived xenografts (PDX) and potential biomarkers were analyzed.Methods: The efficacy of TMZ alone vs TMZ/veliparib was compared in a panel of 28 GBM PDX lines grown as orthotopic xenografts (8-10 mice per group); all tests of statistical significance were two-sided. DNA damage was analyzed by γH2AX immunostaining and promoter methylation of DNA repair gene O6-methylguanine-DNA-methyltransferase (MGMT) by Clinical Laboratory Improvement Amendments-approved methylation-specific polymerase chain reaction.Results: The combination of TMZ/veliparib statistically significantly extended survival of GBM models (P < .05 by log-rank) compared with TMZ alone in five of 20 MGMT-hypermethylated lines (average extension in median survival = 87 days, range = 20-150 days), while the combination was ineffective in six MGMT-unmethylated lines. In the MGMT promoter-hypermethylated GBM12 line (median survival with TMZ+veliparib = 189 days, 95% confidence interval [CI] = 59 to 289 days, vs TMZ alone = 98 days, 95% CI = 49 to 210 days, P = .04), the profound TMZ-sensitizing effect of veliparib was lost when MGMT was overexpressed (median survival with TMZ+veliparib = 36 days, 95% CI = 28 to 38 days, vs TMZ alone = 35 days, 95% CI = 32 to 37 days, P = .87), and a similar association was observed in two nearly isogenic GBM28 sublines with an intact vs deleted MGMT locus. In comparing DNA damage signaling after dosing with veliparib/TMZ or TMZ alone, increased phosphorylation of damage-responsive proteins (KAP1, Chk1, Chk2, and H2AX) was observed only in MGMT promoter-hypermethylated lines.Conclusion: Veliparib statistically significantly enhances (P < .001) the efficacy of TMZ in tumors with MGMT promoter hypermethylation. Based on these data, MGMT promoter hypermethylation is being used as an eligibility criterion for A071102 (NCT02152982), the phase II/III clinical trial evaluating TMZ/veliparib combination in patients with GBM. [ABSTRACT FROM AUTHOR]

New series of 5-(o-hydroxy phenyl)-2-[4″aryl-3″chloro-2″azetidinon-1-yl]-1,3,4-thiadiazole have been synthesized and the structures of the new compounds were established on the basis of IR, 1H NMR spectral data. In vitro antifungal activity (MIC activity) was evaluated and compared with standard drugs of ketoconazole. Compounds 3c in the series has shown interesting antifungal activity against both C. albicans and A. niger fungus. In the gratifying result, most of the compounds were found to have moderate antifungal activity. [ABSTRACT FROM AUTHOR]

Integrin α9β1 mediates accelerated cell adhesion and migration through interactions with a number of diverse extracellular ligands. We have shown previously that it directly binds the vascular endothelial growth factors (VEGF) A, C, and D and contributes to VEGF-induced angiogenesis and lymphangiogenesis. Until now, the α9β1 binding site in VEGF has not been identified. Here, we report that the three-amino acid sequence, EYP, encoded by exon 3 of VEGF-A is essential for binding of VEGF to integrin α9β1 and induces adhesion and migration of endothelial and cancer cells. EYP is specific for α9β1 binding and neither requires nor activates VEGFR-2, the cognate receptor for VEGF-A. Following binding to EYP, integrin α9β1 transduces cell migration through direct activation of the integrin signaling intermediates Src and focal adhesion kinase. This interaction is biologically important because it mediates in vitro endothelial cell tube formation, wound healing, and cancer cell invasion. These novel findings identify EYP as a potential site for directed pharmacotherapy. [ABSTRACT FROM AUTHOR]

The article presents a study of cubic polynomial, a natural function coupled with rational roots and critical points. It explores primitive solutions which use some basic facts from elementary number theory and taught in any introductory course. It also mentions that the aim of the study was to describe all such cubics and explain how to generate them.

Gadd45a, gadd45b and gadd45g (Gadd45/MyD118/CR6) are genes that are rapidly induced by genotoxic stress. However, the exact function of Gadd45 proteins in the response of mammalian cells to genotoxic stress is unclear. Here, advantage was taken of gadd45a- and gadd45b-deficient mice to determine the role gadd45a and gadd45b play in the response of bone marrow (BM) cells to genotoxic stress. BM cells from gadd45a- and gadd45b-deficient mice were observed to be more sensitive to ultraviolet radiation chemotherapy (UVC), VP-16 and daunorubicin (DNR)-induced apoptosis compared to wild-type (wt) cells. The increased apoptosis in gadd45a- and gadd45b-deficient cells was evident also by enhanced activation of caspase-3 and poly-ADP-ribose polymerase cleavage and decreased expression of c-inhibitor of apoptotic protein-1, Bcl-2, Bcl-xL compared to wt cells. Reintroduction of gadd45 into gadd45-deficient BM cells restored the wt apoptotic phenotype. Both gadd45a- and gadd45b-deficient BM cells also displayed defective G2/M arrest following exposure to UVC and VP-16, but not to DNR, indicating the existence of different G2/M checkpoints that are either dependent or independent of gadd45. Taken together, these findings identify gadd45a and gadd45b as antiapoptotic genes that increase the survival of hematopoietic cells following exposure to UV radiation and certain anticancer drugs.Oncogene (2005) 24, 7170–7179. doi:10.1038/sj.onc.1208847; published online 19 September 2005 [ABSTRACT FROM AUTHOR]

Seeds of Artemisia annua cv. Jeevanraksha were sown in the nursery in the middle of December in 1997, 1998 and 1999. About 1-month old seedlings were transplanted in the field having sandy loam soil in the subtropical agroclimate of Lucknow, India. The plant tops were sampled fortnightly for leaves during vegetative phase and for leaves and capitula during post-flowering stages for the estimation of artemisinin content. The A. annua plants continued to grow logarithmically in height from the end of rosette phase at about 9 weeks to the pre-flowering stage at about 44 weeks age and attained a height of 3.4 m. The artemisinin content of the leaves was observed to be high from 0.8 to 1.0% in May and 0.8 to 1.3% through late July to late September. Subsequently, plants entered the reproductive phase. While in the vegetative phase, 90% of artemisinin was in the leaves, in the mature plants, about 30% of the artemisinin was in the leaves and 40% was in capitula. In the vegetative stage plants the younger leaves born on the tops of secondary and higher order branches were richer in the artemisinin than the older leaves. The tops of A. annua plants in their vegetative growth phase possessed low levels of essential oil at about 0.2% as compared to 1.2% of essential oil in the full blooming stage plants. The extraction of artemisinin from leaves is more economic than from the mixture of leaves and capitula on account of higher levels of lipids in the extract of the latter. Since A. annua plants grew logarithmically all through vegetative phase from March to late September and artemisinin content in the leaves was high in May and from late July to late September, it is suggested that under the subtropical agroclimates, A. annua crops may be harvested more than once. The ratooning is expected to reduce losses in artemisinin yield resulting from senescence caused dropping of old leaves and favour preponderance of young leaves found richer in artemisinin content. [Copyright &y& Elsevier]

Double/triple-hit lymphomas (DHL/THL) account for 5–10% of diffuse large B cell lymphoma (DLBCL) with rearrangement of MYC and BCL2 and/or BCL6 resulting in MYC overexpression. Despite the poor prognosis of DHL, R-CHOP chemotherapy remains the treatment backbone and new targeted therapy is needed. We performed comprehensive cytogenetic studies/fluorescence in situ hybridization on DLBCL and Burkitt lymphoma cell lines (n = 11) to identify the DHL/THL DLBCL in vitro model. We identified MYC/IG in Raji and Ramos (single hit); MYC/IG-BCL2 (DHL) in DOHH2, OCI-LY1, SUDHL2, and OCI-LY10; MYC/IG-BCL2/BCL6 (THL) in VAL; and no MYC rearrangement in U2932 and HBL1 (WT-MYC). Targeting MYC in the DHL/THL DLBCLs through bromodomain extra-terminal inhibitors (BETi) (JQ1, I-BET, and OTX015) significantly (p < 0.05) reduced proliferation, similar to WT-MYC cells, accompanied by decreased MYC but not BCL2 protein. Moreover, BETi suppressed MYC transcription and decreased BRD4 binding to MYC promoter in DHL cells. CD47 and PD-L1 are immunoregulatory molecules often expressed on tumors and regulated by MYC. High levels of surface CD47 but not surface PD-L1 was observed in DHL/THL, which was reduced by JQ1 treatment. BETi in combination with Pan-HDAC inhibitor had a limited effect on survival of DHL/THL, while combination of BETi and BCL2 inhibitor (ABT-199) had a significant (p < 0.005) inhibitory effect on survival followed by BCL-XL inhibition. Overall, the data suggests that MYC-expressing DLBCLs are probably addicted to the MYC-oncogenic effect regardless of MYC rearrangements. In summary, we identified an in vitro model for DHL/THL DLBCLs and provide evidence for the therapeutic potential of BET inhibitor alone or in combination with BCL2 inhibitor. [ABSTRACT FROM AUTHOR]

Integrins are important mediators of cell adhesion and migration, which in turn are essential for diverse biological functions, including wound healing and cancer metastasis. The integrin α9β1 is expressed on numerous mammalian tissues and can mediate accelerated cell migration. As the molecular signaling mechanisms that transduce this effect are poorly defined, we investigated the pathways by which activated integrin α9β1 signals migration. We found for the first time that specific ligation of integrin α9β1 rapidly activates Src tyrosine kinase, with concomitant tyrosine phosphorylation of p130Cas and activation of Rac-1. Furthermore, activation of integrin α9β1 also enhanced NO production through activation of inducible nitric oxide synthase (iNOS). Inhibition of Src tyrosine kinase or NOS decreased integrin-α9β1-dependent cell migration. Src appeared to function most proximal in the signaling cascade, in a FAK-independent manner to facilitate iNOS activation and NO-dependent cell migration. The cytoplasmic domain of integrin α9 was crucial for integrin-α9β1-induced Src activation, subsequent signaling events and cell migration. When taken together, our results describe a novel and unique mechanism of coordinated interactions of the integrin α9 cytoplasmic domain, Src tyrosine kinase and iNOS to transduce integrin-α9β1-mediated cell migration. [ABSTRACT FROM AUTHOR]

Transforming growth factor β (TGFβ) has significant profibrotic activity both in vitro and in vivo. This reflects its capacity to stimulate fibrogenic mediators and induce the expression of other profibrotic cytokines such as platelet-derived growth factor (PDGF) and epidermal growth factor (EGF/ErbB) ligands. Here we address both the mechanisms by which TGFβ induced ErbB ligands and the physiological significance of inhibiting multiple TGFβ-regulated processes. The data document that Erbβ ligand induction requires PDGF receptor (PDGFR) mediation and engages a positive autocrine/ paracrine feedback loop via Erbβ receptors. Whereas PDGFRs are essential for TGFβ-stimulated ErbB ligand up-regulation, TGFβ-specific signals are also required for ErbB receptor activation. Subsequent profibrotic responses are shown to involve the cooperative action of PDGF and ErbB signaling. Moreover, using a murine treatment model of bleomycin-induced pulmonary fibro-sis we found that inhibition of TGFβ/PDGF and ErbB pathways with imatinib plus lapatinib, respectively, not only prevented myofibroblast gene expression to a greater extent than either drug alone, but also essentially stabilized gas exchange (oxygen saturation) as an overall measure of lung function. These observations provide important mechanistic insights into profibrotic TGFp signaling and indicate that targeting multiple cytokines represents a possible strategy to ameliorate organ fibrosis dependent on TGFβ. [ABSTRACT FROM AUTHOR]

Osteosarcoma survival rate has not improved over the past three decades, and the debilitating side effects of the surgical treatment suggest the need for alternative local control approaches. Radiotherapy is largely ineffective in osteosarcoma, indicating a potential role for radiosensitizers. Blocking DNA repair, particularly by inhibiting the catalytic subunit of DNA-dependent protein kinase (DNA-PK CS ), is an attractive option for the radiosensitization of osteosarcoma. In this study, the expression of DNA-PK CS in osteosarcoma tissue specimens and cell lines was examined. Moreover, the small molecule DNA-PK CS inhibitor, KU60648, was investigated as a radiosensitizing strategy for osteosarcoma cells in vitro . DNA-PK CS was consistently expressed in the osteosarcoma tissue specimens and cell lines studied. Additionally, KU60648 effectively sensitized two of those osteosarcoma cell lines (143B cells by 1.5-fold and U2OS cells by 2.5-fold). KU60648 co-treatment also altered cell cycle distribution and enhanced DNA damage. Cell accumulation at the G2/M transition point increased by 55% and 45%, while the percentage of cells with >20 γH2AX foci were enhanced by 59% and 107% for 143B and U2OS cells, respectively. These results indicate that the DNA-PK CS inhibitor, KU60648, is a promising radiosensitizing agent for osteosarcoma. [ABSTRACT FROM AUTHOR]

We report non-zero-crossing bipolar current–voltage characteristics, and ferroelectric photovoltaic-like effects in flexible organosilicate polymer films. These film are composed of 5,10,15,20-terakis(4-hydroxyphenyl)-21H,23H-porphine and 5,10,15,20-tetra(4-pyridyl)-21H,23H-porphine embedded in (3-aminopropyl)trimethoxysilane network. The films were prepared on gold coated bi-axially oriented polyethylene terephthalate (BoPET) substrate by sol–gel method. For electrical characterizations, gold (40 nm) was deposited on the film for using as top contact. The current–voltage characteristics of devices, BoPET/gold/film/gold, have shown hysteresis with two current peaks in opposite direction. The open circuit voltage (∼±0.8 V) and short circuit current (∼±6 μA) that arise from non zero-crossing current–voltage characteristics have been utilized to read the ON and OFF states for non-volatile memory application of the devices. Furthermore, the studies on redox induced polarization in the polymer matrix by charge–voltage, capacitance–voltage, and positive-up and negative-down measurements reveal the characteristics of ferroelectric materials. The photovoltaic behaviors such as short circuit photocurrent were studied under blue LED source after polarizing BoPET/gold/polymer film/gold device by electric field as done for classical ferroelectric materials. The observed memory, ferroelectric-like and photovoltaic effects of organosilicate film were explained from quasi-reversible oxidation and reduction of moisture that diffuse into the film and dissociate to ions under applied electric field. These findings are important for designing new solution processible polymer materials which could find applications in flexible memory, ferroelectric based memory and switchable photovoltaic effects. [ABSTRACT FROM AUTHOR]

We report an improved H 2 S response of flexible gold (Au)–cobalt phthalocyanine (CoPc) heterojunction thin films at room temperature. The Au–CoPc films exhibit very high charge carrier density at the surface due to (i) the difference in work function of Au and CoPc and (ii) enhanced adsorbed oxygen on the CoPc surface owing to spillover effect. Both of these effects make the Au–CoPc films more oxidative to the H 2 S in comparison to pure CoPc films. The response of the films on exposure to H 2 S is attributed to the shrinkage of the hole accumulation layer of CoPc due to electron transfer from adsorbed electron donor H 2 S. The gas sensing characteristics of the films were found to be stable for the bending radius >20 mm. [ABSTRACT FROM AUTHOR]

Purpose: To describe the design and dosimetric characterization of a simple and economical small animal irradiator. Materials and methods: A high dose rate (HDR) 192Ir brachytherapy source from a commercially available afterloader was used with a 1.3 cm thick tungsten collimator to provide sharp beam penumbra suitable for hemi-brain irradiation of mice. The unit was equipped with continuous gas anesthesia to allow robust animal immobilization. Dosimetric characterization of the device was performed with Gafchromic film measurements. Results: The tungsten collimator provided a sharp penumbra suitable for hemi-brain irradiation, and dose rates on the order of 200 cGy/minute were achieved. The sharpness of the penumbra attainable with this device compares favorably to those measured experimentally for 6 MV photons, and 6 and 20 MeV electron beams from a linear accelerator, and was comparable to those measured for a 300 kVp orthovoltage beam and a Monte Carlo simulated 90 MeV proton beam. Conclusions: Due to its simplicity and low cost, the apparatus described is an attractive alternative for small animal irradiation experiments requiring steep dose gradients. [ABSTRACT FROM AUTHOR]

Highlights: [•] Flexible PANI–Ag nanocomposites films were synthesized on APTMS modified BOPET. [•] PANI–Ag films exhibit highly selective/sensitive detection of H2S at ppm level. [•] The films prepared on modified BOPET shows enhanced response in comparison to that on pristine one. [ABSTRACT FROM AUTHOR]

Highlights: [•] Non-conjugated polymer chains were incorporated during polymerization of pyrrole. [•] Polymerization was carried out at air/water interface. [•] Free-standing polypyrrole films show re-writable and read-once memory effects. [•] The observed memory effects are due to the presence of non-conjugated polymer chains. [ABSTRACT FROM AUTHOR]

Abstract: A jaw-like bis-porphyrin (bis-TPP) molecule was synthesized anchoring of two porphyrin molecules to a benzene ring at the meta positions through the ester linkage. The bis-TPP molecule and its zinc-derivative (Zn-bis-TPP) were spin-coated on glass surfaces to construct two chemiresistive room temperature NH3 gas sensors. Both the films showed high selectivity, reproducibility and reversibility in sensing NH3 gas (5–40ppm) in air. The sensing characteristics of the Zn-bis-TPP films (response (2s) and recovery (2.5min) times; linear response (952%)) were better than that of the bis-TPP films (response (8s) and recovery (7.5min) times; linear response (131%)). This is attributed to the amorphous nature of the former. [Copyright &y& Elsevier]

TGF-β modulates numerous diverse cellular phenotypes including growth arrest in epithelial cells and proliferation in fibroblasts, Although the Smad pathway is fundamental for the majority of these responses, recent evidence indicates that non-Smad pathways may also have a critical role. Here we report a novel mechanism whereby the nonreceptor tyrosine focal adhesion kinase (FAK) functions as an adaptor necessary for cell type-specific responses to TGF-β. We show that in contrast to Smad actions, non-Smad pathways, including c-Abl, PAK2, and Akt, display an obligate requirement for FAK. Interestingly, this occurs in Src null SYF cells and is independent of FAK tyrosine phosphorylation, kinase activity, and/or proline-rich sequences in the C-terminal FAT domain. FAK binds the phosphatidylinositol 3-kinase (PI3K) p85 regulatory subunit following TGF-β treatment in a subset of fibroblasts but not epithelial cells and has an obligate role in TGF-β-stimulated anchorage-independent growth and migration. Together, these results uncover a new scaffolding role for FAK as the most upstream component regulating the profibrogenic action of TGF-β and suggest that inhibiting this interaction may be useful in treating a number of fibrotic diseases. [ABSTRACT FROM AUTHOR]

The structural and charge transport characteristics of cobalt phthalocyanine (CoPc) films deposited on flexible bi-axially oriented polyethylene terephthalate (BOPET) substrates are investigated. CoPc films exhibited a preferential (200) orientation with charge carrier mobility of ∼118 cm2 V-1 s-1 (at 300 K). These films exhibited a reversible resistance changes upon bending them to different radius of curvature. The charge transport in CoPc films is governed by a bias dependent crossover from ohmic (J-V) to trap-free space-charge limited conduction (J-V2). These results demonstrate that CoPc films on flexible BOPET having high mobility and high mechanical flexibility are a potential candidate for flexible electronic devices. [ABSTRACT FROM AUTHOR]