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The BRAF V600E mutation is commonly observed in papillary thyroid cancer (PTC) and predominantly activates the MAPK pathway. Presence of BRAF V600E predicts increasing risk of recurrence and higher mortality rate, and treatment options for such patients are limited. Vemurafenib, a BRAF V600E inhibitor, is initially effective, but cells inevitably develop alternative mechanisms of pathway activation. Mechanisms of primary resistance have been described in short-term cultures of PTC cells; however, mechanisms of acquired resistance have not. In the present study, we investigated possible adaptive mechanisms of BRAF V600E inhibitor resistance in KTC1 thyroid cancer cells following long-term vemurafenib exposure. We found that a subpopulation of KTC1 cells acquired resistance to vemurafenib following 5 months of treatment with the inhibitor. Resistance coincided with the spontaneous acquisition of a KRAS G12D activating mutation. Increases in activated AKT, ERK1/2, and EGFR were observed in these cells. In addition, the resistant cells were less sensitive to combinations of vemurafenib and MEK1 inhibitor or AKT inhibitor. These results support the KRAS G12D mutation as a genetic mechanism of spontaneously acquired secondary BRAF inhibitor resistance in BRAF V600E thyroid cancer cells.

The ETS family of transcription factors is involved in several normal remodeling events and pathological processes including tumor progression. ETS transcription factors are divided into subfamilies based on the sequence and location of the ETS domain. ETV5 (Ets variant gene 5; also known as ERM) is a member of the PEA3 subfamily. Our meta-analysis of normal, benign, and malignant thyroid samples demonstrated that ETV5 expression is upregulated in papillary thyroid cancer and was predominantly associated with BRAF V600E or RAS mutations. However, the precise role of ETV5 in these lesions is unknown. In this study, we used the KTC1 cell line as a model for human advanced papillary thyroid cancer (PTC) because the cells harbor the heterozygous BRAF (V600E) mutation together with the C250T TERT promoter mutation. The role of ETV5 in PTC proliferation was tested using RNAi followed by high-throughput screening. Signaling pathways driving ETV5 expression were identified using specific pharmacological inhibitors. To determine if ETV5 influences the expression of epithelial-to-mesenchymal (EMT) markers in these cells, an EMT PCR array was used, and data were confirmed by qPCR and ChIP-qPCR. We found that ETV5 is critical for PTC cell growth, is expressed downstream of the MAPK pathway, and directly upregulates the transcription factor TWIST1, a known marker of intravasation and metastasis. Increased ETV5 expression could therefore be considered as a marker for advanced PTCs and a possible future therapeutic target.

Purpose – The purpose of this paper is to examine the constructs and establish causal relationship between factors for strategically governing a technical university in Indian context. Further, the paper carries out a systemic study to emphasize on the need for these universities to design strategies that are endurable and sustainable. Design/methodology/approach – A structured questionnaire survey was carried out (207 responses). Factor analysis was carried out to bring out the latent variables representing the attributes, and later, the causality between these variables was established using structural equation modelling (SEM). These relationships between the factors helped in developing a robust system dynamic model for strategic management of technical universities. Findings – The peak points on the contours for varying strategic orientation revealed the adaptability and the time required for attaining that level of adaptability. The contour plots also revealed the limiting values in each case. Finally, it is concluded that university adaptability increases with increasing strategic orientation. The analysis also revealed that the process by which the technical universities formulate their strategies is an important determinant of various factors. Originality/value – Universities looking to implement strategic management-related methodologies for the improved management focusing on developing effective methods for developing strategy can be expected to yield better performance, rather than concentrating on the technologies and supporting infrastructures.

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PurposeThe paper aims to identify causality amongst small and medium enterprises' (SMEs') performance indicators, propose an integrated index of business performance and quality practices and investigate the effect of quality management system (QMS) on business performance.Design/methodology/approachThis study proposes a two-stage approach. In the first stage, the authors gathered responses with a questionnaire on variables affecting business performance and identified dimensions using exploratory and confirmatory factor analyses. Path analysis was carried out to identify causality between the dimensions. In the next stage, the validation of stage 1 findings was carried out to substantiate the proposition that QMS affects performance. Questionnaire survey and in-depth interviews were conducted during the second stage. The analysis was done following the case study protocol – within- and cross-case analysis and validated with supportive and conflicting literature.FindingsThe results show that the employee – dimension is crucial to process effectiveness, customer satisfaction and finances. Customer satisfaction results from employee satisfaction and processes. QMS impacts processes and employee performance, thus establishes the causality between business performance factors and QMS. QMS impacts finances in the short run but yields long-term benefits and is dependent on two factors – degree of knowledge of quality practices and its application in business.Originality/valueThis study reveals the performance dimensions of SMEs, their causality and the impact of QMS on performance. It suggests a shift from traditional approaches, correcting defects using statistical quality control approaches, to a sustainable growth path – a long-term approach. This study puts forward two associated indices – the business performance and the knowledge of quality practices and its application index.

Purpose Cross border trade, involving different business environments between the sellers’ and buyers’ countries, may result in conflicts because of asymmetry in the information structure across the borders. The International Chambers of Commerce (ICC) has laid down ground rules on terms of shipment and payment, enabling harmonization and standardization of business process, and fixing of responsibilities for international trade. The international commercial (INCO) terms by ICC define the duties, obligations and cost borne by the exporter and the importer. An exporter’s uncertainty looms once the goods cross his/her border. Therefore, there is a need for a smart contract that is secured, transparent, legitimate and trustworthy. The authors propose a blockchain technology-based smart global contract (BTGC) framework for international trade. Design/methodology/approach In this paper, the authors develop the framework based on value chain analysis (VCA) of international trade and an ontology-driven-blockchain-design approach. The paper analyzes the sequence of activities in the value chain of global trade, the terms of the contract, the data structure templates, the validation rules and the points-of-failure, and proposes the smart contract blockchain structure. Findings This paper proposes the BTGC framework considering the INCO terms 2020; it provides the validation rules and the probability of failures; and identifies the elements that cause the halting of contracts and conditions of creation of side blockchains. The framework also includes the governance of the BTGC system. Research limitations/implications The proposed framework not only has implications at the firm level as it automates and secures a global sale contract but also is expected to harmonize the global-trade process as well. The developers may use the attributes, data structure templates and the rules identified in this paper for developing the GC software. Future research may consider using case analysis, class diagrams and the related steps for developing the blockchain software. Originality/value This paper proposes a complete value chain of global contract (GC) concerning exports, an ontology of GC and a blockchain-based smart-contract framework based on global standards. Besides, it specifies the elements of fraud (such as the non-integration of side chains) and uncertainty, i.e. the probability of failures. Such a framework will harmonize the global-trade process and build an international standards for smart GC based on blockchain technology (ISSGCBT), which is not yet done.

In this article, an attempt has been made to identify the effect of liberalization on the efficiencies of container terminals of major ports of India. In India, the liberalization process started since 1991. As a result, many of the major ports, administered by the union government of India privatized their container terminals. In this study, the efficiency of privately managed terminals, under major ports, has been compared with public container terminals using data envelopment analysis (DEA). In this article, output-oriented DEA using DEAP (Data Envelopment Analysis (Computer) Programme) software has been carried out where the inverse of turnaround time per thousand twenty equivalent units (TEUs) has been taken as the output. The results of the study show that though the efficiency of containers terminals are affected by privatization to a great extent, they depend on other factors too.