Experiments on swirling turbulent flows. I - Similarity in swirling flows

The effects of swirl on internal turbulent flows are studied by conducting experiments on turbulent pipe flow with variable initial swirl. This first part of the study is primarily concerned with similarity laws. The mean velocity profiles, both away from and close to the wall, are found to admit similarity representations at sufficiently large Reynolds numbers, provided that flow reversal does not take place near the entrance. While the wall law is not sensibly dependent on swirl, the velocity defect law in its extended form is sensitive to swirl. Further, a logarithmic skin-friction law is obtained in which only the additive coefficient depends on swirl. This coefficient is found to vary linearly with the swirl angle in the range of the present experiments

On the representation of the drag polar of a fighter aircraft

The values of lift coefficient encountered during manoeuvres13; of a fighter aircraft are known to be wel1 beyond the range where the classical representation CD = CDo + k ci is a good approximation. Examination of available test data on several configurations showed that the drag polars can be approximately represented as CD = CDo + k ci + a C with a suitable choice of a and n.13; A simpler representation with the value of n equal to 413; was carefully tested against detailed test data on two configurations for Mach numbers ranging from 0.5 to 1.5 and angles of attack from -4xB0; to 20xB0;. Agreement was generally better than 5% in transonic and supersonic range. The agreement was satisfactory in the subsonic range, although the departures were occasionally larger in magnitude. It is suggested that the representation with n = 4 can be advantageously used in the turn calculations of fighter aircrafts

Abstract 4453: The dual CK2/TNIK inhibitor, ON108600 targets cancer stem cells and induces apoptosis of paclitaxel resistant triple-negative breast cancer cells

Abstract Triple negative breast cancer (TNBC) is associated with a poor prognosis and high frequency of recurrence. Because the molecular mechanisms that are deregulated in this tumor type are not well understood, there is a lack of targeted therapies that can effectively treat this disease. An unfortunate limitation of existing TNBC therapies is the frequency of relapse, which is highly resistant and metastatic and has been attributed to tumor-initiating stem cells (T-ICs). In patients with relapsed TNBC, T-ICs with a CD44high/CD24-/low antigenic phenotype are enriched in the tumor cell population. Our previous data illustrated that a small molecule kinase inhibitor, ON108600, potently inhibited the survival and growth of TNBC cell lines and mouse xenografts. To investigate whether ON108600 has a similar inhibitory effect on T-ICs, we performed clonogenic survival assays using sorted CD44high CD24-/low cells isolated from TNBC cell lines. ON108600 potently inhibited the stem cell activity and self-renewal ability of these T-ICs. Although paclitaxel (PTX) treatment improves survival of TNBC patients, acquired resistance to this drug is a common occurrence. Furthermore, strategies that target PTX resistant cells remain elusive. To investigate the molecular mechanisms underlying acquired PTX-resistance in TNBC and evaluate the efficacy of ON108600, we generated PTX-resistant cell lines using the MDA-MB-231 and BT-20 TNBC cell lines. Drug-resistant cells were established by exposure to increasing concentrations of Paclitaxel, and resistance was validated by cell viability and colony formation in the presence of high concentrations of PTX. PTX-resistant MDA-MB-231 and BT-20 cells exhibited an approximate 1000-fold increase in resistance to PTX as compared to the parental cells. Importantly, PTX-resistant TNBC cells displayed a stem-like phenotype characterized by loss of epithelial differentiation markers (e-Cadherin, CD24) and a gain of epithelial-mesenchymal transition markers (N-Cadherin, CD44, Oct4, Snail). Kinase profiling studies have indicated that ON108600 targets kinases CK2, and Traf2- and Nck-interacting kinase, TNIK. Although CK2 subunit levels in resistant cells were unchanged, PTX-resistant cells showed a marked upregulation of TNIK, an activating kinase for T-cell factor-4 (TCF-4) and consequently, a marked increase in β-catenin and Wnt target genes Axin-2 and Cyclin D1. We therefore examined whether dual inhibition of CK2 and TNIK was effective in killing PTX-resistant cells. Treatment of PTX-resistant TNBC cells with ON108600 resulted in marked increase in apoptosis and inhibition of clonogenic survival and mamosphere forming ability of these cells, suggesting that dual CK2/TNIK inhibition may be an effective way to overcome PTX-resistance in TNBC. We are currently testing the efficacy of ON108600 in paclitaxel resistant xenograft models. Citation Format: Amol Padgaonkar, Stephen Cosenza, Venkat Pallela, Venkata Subbaiah DRC, MV Ramana Reddy, E Premkumar Reddy. The dual CK2/TNIK inhibitor, ON108600 targets cancer stem cells and induces apoptosis of paclitaxel resistant triple-negative breast cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4453. doi:10.1158/1538-7445.AM2015-4453</jats:p

Abstract 3239: Discovery and biological characterization of ON108600, a small molecule inhibitor of protein kinase CK2.

Abstract Protein kinase CK2 (Casein kinase 2) is a highly conserved, constitutively active Ser/Thr protein kinase implicated in cellular transformation and tumorigenesis. CK2 regulates multiple oncogenic pathways involved in cell cycle progression, suppression of apoptosis, hypoxia, angiogenesis, inflammation and DNA repair. Unlike other signaling molecules such as PI3K, RAF, RAS, where genetic alterations lead to deregulated signaling pathways, in the case of CK2, only its high expression levels have been associated with a disease state and no mutations have been found to date. Here we describe the mechanism of action of ON108600 a potent small molecule inhibitor of both catalytic subunits of protein kinase CK2. ON108600 showed broad-spectrum anti-proliferative and cytotoxic activity in multiple cancer cell lines while having little or no effect on normal cells. CK2 regulates Akt signaling through phosphorylation and inactivation of PTEN and via direct and specific phosphorylation of Akt at S129. Treatment with ON108600 resulted in dramatic reductions of phosphorylation of PTEN and Akt S129 and downstream targets of Akt in multiple cancer cell lines. Further, phosphorylation of p21Cip1/Waf1 at Thr145 and its cytoplasmic localization has been shown to be a poor prognostic marker in breast cancer. ON108600 showed a dose and time dependant dephosphorylation of p21 at Thr145 and induced a potent mitotic cell cycle arrest in most cancer cell lines. CK2 has also been implicated in regulating Caspase signaling via phosphorylation of caspase cleavage sites and thus exerting its pro-survival effects. ON108600 treatment induced potent apoptosis by activating the Caspase 3/7 signaling cascade. To understand the structural basis of CK2 inhibition by ON108600 we performed x-ray crystallographic studies of ON108600-CK2. The co-crystal structure of ON108600-CK2 revealed that ON108600 binds in the active site pocket of CK2α wherein it mimics the binding of GTP in the CK2 active site. Structural studies also revealed that ON108600 induces a conformational change in the β4-β5 loop of the catalytic subunit which is known to interact with the β-regulatory subunit of CK2 and critical for substrate recognition and activation. CK2α has been reported to be a structural microtubule associated protein and the CK2 holoenzyme has been shown to regulate microtubule dynamics. Interestingly, ON108600 was found to inhibit CK2 holoenzyme mediated polymerization of β-tubulins in in-vitro assays. CK2 has emerged as novel druggable target and selective inhibitors of CK2 such as ON108600 may prove as a potential anti-cancer therapy. Our ongoing studies are focused towards identifying novel combinations of ON108600 with existing chemotherapeutic agents in multiple myeloma, prostate and breast cancer. Citation Format: Amol Padgaonkar, Olga Rechkoblit, Stephen Cosenza, Venkat R. Pallela, Venkata Subbaiah DRC, MV Ramana Reddy, Aneel Aggarwal, E Premkumar Reddy. Discovery and biological characterization of ON108600, a small molecule inhibitor of protein kinase CK2. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3239. doi:10.1158/1538-7445.AM2013-3239 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.</jats:p