ISOLATION AND CHARACTERISATION OF RAPAMYCIN, TEMSIROLIMUS REGIO ISOMER (MONOESTER) AND TEMSIROLIMUS DIESTER IN TEMSIROLIMUS DRUG

Objective: Separation and identification of the process impurities in the manufacture of temsirolimus drug viz., rapamycin, temsirolimus regioisomer (monoester) (TS monoester), and temsirolimus diester (TS diester). Methods: During the process development of temsirolimus (TS), three process impurities-rapamycin, temsirolimus regioisomer (monoester) and temsirolimus diester-were detected by high-performance liquid chromatography (HPLC). Impurities were isolated by medium pressure liquid Chromatography (MPLC) and characterized by ESI-MS/MS, 1H NMR, FT-IR spectral data. Results: These impurities are characterised with the help of ESI MS/MS, 1H NMR, and FT-IR data. The impurities are identified and characterised as the process impurities. One of them is the starting material i.e. rapamycin and the other two are formed during the manufacture of the drug. This method offers advantages over using photodiode-array UV detection (LC-PDA) for the determination of peak purity, viz. components with similar UV spectra can be distinguished. Conclusion: The structures of these impurities were characterized as rapamycin, TS Monoester, and TS Diester. Out of these process impurities, rapamycin has been previously identified while the other two are previously unreported

The determinants of Western Australia’s foreign investment in China

The growing economic importance of China with its major economic power in the East Asia region has become a popular host destination for receiving foreign investment from Hong Kong, Korea, and Taiwan. With China’s growth and development, this nation has over time become one of Australia’s main trading partners. As new investment opportunities have emerged, Australian companies, especially from Western Australia have shown interest in the Chinese marketplace. Despite the popular consensus that Australian companies are increasingly investing in China, to date relevant literature examining this notion is limited. Specifically, studies of elements that motivate or deter owners / managers of Australian companies, especially from Western Australia to invest in China are restricted. Consequently, the purpose of this study was to investigate the likely relationships between four independent constructs (1. market size, 2. labour cost, 3. infrastructure, and 4. business ethics) in China and the intensity of foreign investment from Western Australia, and to evaluate if and how these relationships are mediated by personality attributes (i.e., gender), organisational properties (i.e., size), and networking.To empirically investigate the determining factor for undertaking investment in China, this study employed both quantitative and qualitative approaches. The use of the quantitative method positivist approach is deemed as a suitable, partial approach, which assists in determining the statistical relationships between the investigated variables. Moreover, a qualitative approach was used in a complementing context to understand the quantitative results. Given the dynamic business environment in China, the use of a qualitative approach has potential for gaining a more comprehensive understanding of quantitative findings as well as providing rich information for further interpretations.This study was conducted with 43 respondents of Western Australian companies. A salient feature of the study companies is that they either have capabilities to invest or are already investing in mainland China (People’s Republic of China, in this study identified as China). The targeted companies are involved in manufacturing and services industries, such as mining, education, banking, and telecommunication. Although collecting primary data appeared to be a challenge, the data were robust for statistical analysis. In addition, the data were from decision makers of the study companies, which further indicate the richness of the sample.The findings of this study revealed that China’s large market size plays a positive role in attracting investments from WA to China. Similarly, the adequate level of infrastructure and the level of familiarity of business ethics in China tend to somewhat encourage WA investors to conduct business in China. In contrast, China’s cheap labour cost was not the primary driver that motivates WA companies to invest in China. In relation to the mediating effects of personality attributes (e.g., gender), organisational properties (i.e., size), and networking the study findings revealed that networking plays a significant mediating role in the investment decision. However, due to the relatively small sample size, personality attributes and organisational properties were established to provide insufficient analytical rigor in the decision to invest in China by WA companies.The implications for this study may offer insightful information to enrich the understanding of the determinants of Australian foreign investment in general, and in the Chinese marketplace in particular. In addition, by empirically investigating the perceptions of the decision makers of WA companies in relation to their investment decisions in China, the findings of this research may assist foreign companies to undertake better planning of their investment decisions. More specifically, this study may offer additional insight to those companies that are operating or planning to invest in the Chinese marketplace. For example, this study may be particularly useful for international managers or owners, as it may provide some fruitful information to assist a better understanding of the issues that relate to business ethics with Chinese operations. In addition, the phenomenon of guanxi in China has been considered as a major determinant for facilitating business engagement in the Chinese marketplace. It may, therefore, be argued that the phenomenon of guanxi in assisting business operations in China has become increasingly important, and international managers or owners may need to gain a deeper understanding of this phenomenon

COMPARATIVE STUDY ON ANALYSIS AND DESIGN OF FLEXIBLE AND RIGID PAVEMENTS

A highway pavement is really a structure composed of superimposed layers of processed materials over the natural soil sub grade, whose primary function would be to distribute the applied vehicle loads towards the sub-grade. To create the street stretch like a flexible pavement by utilizing style of flexible pavement by CBR method like a rigid pavement for that collected design upon given black cotton soil sub-grade and also to estimations the development price of designed pavement. The primary purpose of this research would be to develop an approach to choose the most inexpensive pavement design method to handle for that parts of a highway network also to find out the cost analysis of pavement designs. Various grades of concrete under similar condition of traffic and style concrete road are located to more appropriate than bituminous road. Because the whole existence cycle cost arrives to become reduced the plethora of 30% to 50% however for streets getting traffic under 400 cv/day and road is within good shape, the main difference between whole existence prices of concrete overlay is 15% to 60% greater than the flexible overlay. The best goal is to make sure that the sent stresses because of wheel load are sufficiently reduced, so they won't exceed bearing capacity from the sub-grade

Glycosylation of Erythrocyte Spectrin and Its Modification in Visceral Leishmaniasis

Using a lectin, Achatinin-H, having preferential specificity for glycoproteins with terminal 9-O-acetyl sialic acid derivatives linked in α2-6 linkages to subterminal N-acetylgalactosamine, eight distinct disease-associated 9-O-acetylated sialoglycoproteins was purified from erythrocytes of visceral leishmaniaisis (VL) patients (RBCVL). Analyses of tryptic fragments by mass spectrometry led to the identification of two high-molecular weight 9-O-acetylated sialoglycoproteins as human erythrocytic α- and β-spectrin. Total spectrin purified from erythrocytes of VL patients (spectrinVL) was reactive with Achatinin-H. Interestingly, along with two high molecular weight bands corresponding to α- and β-spectrin another low molecular weight 60 kDa band was observed. Total spectrin was also purified from normal human erythrocytes (spectrinN) and insignificant binding with Achatinin-H was demonstrated. Additionally, this 60 kDa fragment was totally absent in spectrinN. Although the presence of both N- and O-glycosylations was found both in spectrinN and spectrinVL, enhanced sialylation was predominantly induced in spectrinVL. Sialic acids accounted for approximately 1.25 kDa mass of the 60 kDa polypeptide. The demonstration of a few identified sialylated tryptic fragments of α- and β-spectrinVL confirmed the presence of terminal sialic acids. Molecular modelling studies of spectrin suggest that a sugar moiety can fit into the potential glycosylation sites. Interestingly, highly sialylated spectrinVL showed decreased binding with spectrin-depleted inside-out membrane vesicles of normal erythrocytes compared to spectrinN suggesting functional abnormality. Taken together this is the first report of glycosylated eythrocytic spectrin in normal erythrocytes and its enhanced sialylation in RBCVL. The enhanced sialylation of this cytoskeleton protein is possibly related to the fragmentation of spectrinVL as evidenced by the presence of an additional 60 kDa fragment, absent in spectrinN which possibly affects the biology of RBCVL linked to both severe distortion of erythrocyte development and impairment of erythrocyte membrane integrity and may provide an explanation for their sensitivity to hemolysis and anemia in VL patients

Mechanisms of Sorafenib Resistance in HCC Culture Relate to the Impaired Membrane Expression of Organic Cation Transporter 1 (OCT1)

Srinivas Chava,1 Nergiz Ekmen,2 Pauline Ferraris,1 Yucel Aydin,2 Krzysztof Moroz,1 Tong Wu,1 Swan N Thung,3 Srikanta Dash1,2,4 1Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, LA, USA; 2Department of Gastroenterology and Hepatology, Tulane University Health Sciences Center, New Orleans, LA, USA; 3Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; 4Southeast Louisiana Veterans Health Care System, New Orleans, LA, USACorrespondence: Srikanta Dash, Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, 1430 Tulane Avenue, New Orleans, LA, 70112, USA, Tel +1 504-988-2519, Fax +1 504-988-7389, Email [email protected]: Sorafenib, an FDA-approved drug for advanced hepatocellular carcinoma (HCC) treatment, encounters resistance in many patients. Deciphering the mechanisms underlying sorafenib resistance is crucial for devising alternative strategies to overcome it.Aim: This study aimed to investigate sorafenib resistance mechanisms using a diverse panel of HCC cell lines.Methods: HCC cell lines were subjected to continuous sorafenib treatment, and stable cell lines (Huh 7.5 and Huh 7PX) exhibiting sustained growth in its presence were isolated. The investigation of drug resistance mechanisms involved a comparative analysis of drug-targeted signal transduction pathways (EGFR/RAF/MEK/ERK/Cyclin D), sorafenib uptake, and membrane expression of the drug uptake transporter.Results: HCC cell lines (Huh 7.5 and Huh 7PX) with a higher IC50 (10μM) displayed a more frequent development of sorafenib resistance compared to those with a lower IC50 (2– 4.8μM), indicating a potential impact of IC50 variation on initial treatment response. Our findings reveal that activated overexpression of Raf1 kinases and impaired sorafenib uptake, mediated by reduced membrane expression of organic cation transporter-1 (OCT1), contribute to sorafenib resistance in HCC cultures. Stable expression of the drug transporter OCT1 through cDNA transfection or adenoviral delivery of OCT1 mRNA increased sorafenib uptake and successfully overcame sorafenib resistance. Additionally, consistent with sorafenib resistance in HCC cultures, cirrhotic liver-associated human HCC tumors often exhibited impaired membrane expression of OCT1 and OCT3.Conclusion: Intrinsic differences among HCC cell clones, affecting sorafenib sensitivity at the expression level of Raf kinases, drug uptake, and OCT1 transporters, were identified. This study underscores the potential of HCC tumor targeted OCT1 expression to enhance sorafenib treatment response.Keywords: hepatocellular carcinoma, HCC, cholangiocarcinoma, CCA, tyrosine kinase inhibitors, TKI, organic cation transporter-1, OCT1, organic cation transporter-3, OCT3, sorafenib resistance cell lines, SR huh

The Influence of Rigid Foam Density on the Flexural Properties of Glass Fabric/Epoxy-Polyurethane Foam Sandwich Composites

Abstract: Sandwich composites with glass fabric and epoxy matrix as the skin and rigid polyurethane foam (PUF) as the core were prepared in the shape of panels. Three panels were fabricated with the rigid foam densities of 125, 250 and 500 kg/m 3 , separately. The Flexural properties were compared and detailed analyses done, on the influence of different foam densities on otherwise identical sandwich composite beams, prepared from the panels. All the panels were fabricated with the skin weight maintained to about 40% of the foam weight

Modulation of Sn concentration in ZnO nanorod array: intensification on the conductivity and humidity sensing properties

Tin (Sn)-doped zinc oxide (ZnO) nanorod arrays (TZO) were synthesized onto aluminum-doped ZnO-coated glass substrate via a facile sonicated sol–gel immersion method for humidity sensor applications. These nanorod arrays were grown at different Sn concentrations ranging from 0.6 to 3 at.%. X-ray diffraction patterns showed that the deposited TZO arrays exhibited a wurtzite structure. The stress/strain condition of the ZnO film metamorphosed from tensile strain/compressive stress to compressive strain/tensile stress when the Sn concentrations increased. Results indicated that 1 at.% Sn doping of TZO, which has the lowest tensile stress of 0.14 GPa, generated the highest conductivity of 1.31 S cm− 1. In addition, 1 at.% Sn doping of TZO possessed superior sensitivity to a humidity of 3.36. These results revealed that the optimum performance of a humidity-sensing device can be obtained mainly by controlling the amount of extrinsic element in a ZnO film

Prediction meets causal inference: the role of treatment in clinical prediction models

In this paper we study approaches for dealing with treatment when developing a clinical prediction model. Analogous to the estimand framework recently proposed by the European Medicines Agency for clinical trials, we propose a ‘predictimand’ framework of different questions that may be of interest when predicting risk in relation to treatment started after baseline. We provide a formal definition of the estimands matching these questions, give examples of settings in which each is useful and discuss appropriate estimators including their assumptions. We illustrate the impact of the predictimand choice in a dataset of patients with end-stage kidney disease. We argue that clearly defining the estimand is equally important in prediction research as in causal inference

Flow-cytometric monitoring of disease-associated expression of 9-O-acetylated sialoglycoproteins in combination with known CD antigens, as an index for MRD in children with acute lymphoblastic leukaemia: a two-year longitudinal follow-up study

<p>Abstract</p> <p>Background</p> <p>Over expression of 9-<it>O-</it>acetylated sialoglycoproteins (Neu5,9Ac₂-GPs, abbreviated as <it>O</it>AcSGP) has been demonstrated as a disease-associated antigen on the lymphoblasts of childhood acute lymphoblastic leukaemia (ALL). Achatinin-H, a lectin, has selective affinity towards terminal 9-<it>O-</it>acetylated sialic acids-α2-6-<it>N</it>acetylated galactosamine. Exploring this affinity, enhanced expression of <it>O</it>AcSGP was observed, at the onset of disease, followed by its decrease with chemotherapy and reappearance with relapse. In spite of treatment, patients retain the diseased cells referred to as minimal residual disease (MRD) responsible for relapse. Our aim was to select a suitable template by using the differential expression of <it>O</it>AcSGP along with other known CD antigens to monitor MRD in peripheral blood (PB) and bone marrow (BM) of Indian patients with B- or T-ALL during treatment and correlate it with the disease status.</p> <p>Methods</p> <p>A two-year longitudinal follow-up study was done with 109 patients from the onset of the disease till the end of chemotherapy, treated under MCP841protocol. Paired samples of PB (n = 1667) and BM (n = 999) were monitored by flow cytometry. Three templates selected for this investigation were <it>O</it>AcSGP⁺CD10⁺CD19⁺or <it>O</it>AcSGP⁺CD34⁺CD19⁺for B-ALL and <it>O</it>AcSGP⁺CD7⁺CD3⁺for T-ALL.</p> <p>Results</p> <p>Using each template the level of MRD detection reached 0.01% for a patient in clinical remission (CR). 81.65% of the patients were in CR during these two years while the remaining relapsed. Failure in early clearance of lymphoblasts, as indicated by higher MRD, implied an elevated risk of relapse. Soaring MRD during the chemotherapeutic regimen predicted clinical relapse, at least a month before medical manifestation. Irrespective of B- or T-lineage ALL, the MRD in PB and BM correlated well.</p> <p>Conclusion</p> <p>A range of MRD values can be predicted for the patients in CR, irrespective of their lineage, being 0.03 ± 0.01% (PB) and 0.05 ± 0.015% (BM). These patients may not be stated as normal with respect to the presence of MRD. Hence, MRD study beyond two-years follow-up is necessary to investigate further reduction in MRD, thereby ensuring their disease-free survival. Therefore, we suggest use of these templates for MRD detection, during and post-chemotherapy for proper patient management strategies, thereby helping in personalizing the treatment.</p

Having a lot of a good thing: multiple important group memberships as a source of self-esteem.

Copyright: © 2015 Jetten et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are creditedMembership in important social groups can promote a positive identity. We propose and test an identity resource model in which personal self-esteem is boosted by membership in additional important social groups. Belonging to multiple important group memberships predicts personal self-esteem in children (Study 1a), older adults (Study 1b), and former residents of a homeless shelter (Study 1c). Study 2 shows that the effects of multiple important group memberships on personal self-esteem are not reducible to number of interpersonal ties. Studies 3a and 3b provide longitudinal evidence that multiple important group memberships predict personal self-esteem over time. Studies 4 and 5 show that collective self-esteem mediates this effect, suggesting that membership in multiple important groups boosts personal self-esteem because people take pride in, and derive meaning from, important group memberships. Discussion focuses on when and why important group memberships act as a social resource that fuels personal self-esteem.This study was supported by 1. Australian Research Council Future Fellowship (FT110100238) awarded to Jolanda Jetten (see http://www.arc.gov.au) 2. Australian Research Council Linkage Grant (LP110200437) to Jolanda Jetten and Genevieve Dingle (see http://www.arc.gov.au) 3. support from the Canadian Institute for Advanced Research Social Interactions, Identity and Well-Being Program to Nyla Branscombe, S. Alexander Haslam, and Catherine Haslam (see http://www.cifar.ca)