37 research outputs found

    The Changeless Core in a Changing Business Environment

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    Rapid change in business environment poses threat to business survival. It is crucial to examine the core of business sustainability. This paper proposes changeless factors in response to today’s business environment. Specifically, it addresses (1) the people factor (2) the purpose factor and (3) the principle factor as the pillars through which an organization finds its stability in the sea of business change. This paper demonstrates the unchanged factors to ensure business sustainability and to achieve long term objectives. After mapping the conceptual model, the paper devotes particular attention to conceptualizing the changeless cores of business. This research contributes practical insights for managers to further understand the cores of business sustainability. Specifically, it will assist managers to have clear goals in making decisions and managing change to enhance competitiveness in the business environment

    Application and optimisation of the Comparison on Extreme Laboratory Tests (CERT) algorithm for detection of adverse drug reactions: Transferability across national boundaries.

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    PURPOSE: The Singapore regulatory agency for health products (Health Sciences Authority), in performing active surveillance of medicines and their potential harms, is open to new methods to achieve this goal. Laboratory tests are a potential source of data for this purpose. We have examined the performance of the Comparison on Extreme Laboratory Tests (CERT) algorithm, developed by Ajou University, Korea, as a potential tool for adverse drug reaction detection based on the electronic medical records of the Singapore health care system. METHODS: We implemented the original CERT algorithm, comparing extreme laboratory results pre- and post-drug exposure, and 5 variations thereof using 4.5 years of National University Hospital (NUH) electronic medical record data (31 869 588 laboratory tests, 6 699 591 drug dispensings from 272 328 hospitalizations). We investigated 6 drugs from the original CERT paper and an additional 47 drugs. We benchmarked results against a reference standard that we created from UpToDate 2015. RESULTS: The original CERT algorithm applied to all 53 drugs and 44 laboratory abnormalities yielded a positive predictive value (PPV) and sensitivity of 50.3% and 54.1%, respectively. By raising the minimum number of cases for each drug-laboratory abnormality pair from 2 to 400, the PPV and sensitivity increased to 53.9% and 67.2%, respectively. This post hoc variation, named CERT400, performed particularly well for drug-induced hepatic and renal toxicities. DISCUSSION: We have demonstrated that the CERT algorithm can be applied across national boundaries. One modification (CERT400) was able to identify adverse drug reaction signals from laboratory data with reasonable PPV and sensitivity, which indicates potential utility as a supplementary pharmacovigilance tool

    Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)

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    In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure fl ux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defi ned as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (inmost higher eukaryotes and some protists such as Dictyostelium ) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the fi eld understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation it is imperative to delete or knock down more than one autophagy-related gene. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways so not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field

    Effects of palbociclib in oral squamous cell carcinoma and the role of PIK3CA in conferring resistance

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    Objective: Lack of effective therapies remains a problem in the treatment of oral squamous cell carcinoma (OSCC), especially in patients with advanced tumors. OSCC development is driven by multiple aberrancies within the cell cycle pathway, including amplification of cyclin D1 and loss of p16. Hence, cell cycle inhibitors of the CDK4/6-cyclin D axis are appealing targets for OSCC treatment. Here, we determined the potency of palbociclib and identified genetic features that are associated with the response of palbociclib in OSCC. Methods: The effect of palbociclib was evaluated in a panel of well-characterized OSCC cell lines by cell proliferation assays and further confirmed by in vivo evaluation in xenograft models. PIK3CA-mutant isogenic cell lines were used to investigate the effect of PIK3CA mutation towards palbociclib response. Results: We demonstrated that 80% of OSCC cell lines are sensitive to palbociclib at sub-micromolar concentrations. Consistently, palbociclib was effective in controlling tumor growth in mice. We identified that palbociclib-resistant cells harbored mutations in PIK3CA. Using isogenic cell lines, we showed that PIK3CA mutant cells are less responsive to palbociclib as compared to wild-type cells with concurrent upregulation of CDK2 and cyclin El protein levels. We further demonstrated that the combination of a PI3K/mTOR inhibitor (PF-04691502) and palbociclib completely controlled tumor growth in mice. Conclusions: This study demonstrated the potency of palbociclib in OSCC models and provides a rationale for the inclusion of PIK3CA testing in the clinical evaluation of CDK4/6 inhibitors and suggests combination approaches for further clinical studies

    Zerumbone targets the CXCR4-RhoA and PI3K-mTOR signaling axis to reduce motility and proliferation of oral cancer cells

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    Background: The CXCR4-RhoA and PI3K-mTOR signaling pathways play crucial roles in the dissemination and tumorigenesis of oral squamous cell carcinoma (OSCC). Activation of these pathways have made them promising molecular targets in the treatment of OSCC. Zerumbone, a bioactive monocyclic sesquiterpene isolated from the rhizomes of tropical ginger, Zingiber zerumbet (L.) Roscoe ex Sm. has displayed promising anticancer properties with the ability to modulate multiple molecular targets involved in carcinogenesis. While the anticancer activities of zerumbone have been well explored across different types of cancer, the molecular mechanism of action of zerumbone in OSCC remains largely unknown. Purpose: Here, we investigated whether OSCC cells were sensitive towards zerumbone treatment and further determined the molecular pathways involved in the mechanism of action. Methods: Cytotoxicity, anti-proliferative, anti-migratory and anti-invasive effects of zerumbone were tested on a panel of OSCC cell lines. The mechanism of action of zerumbone was investigated by analysing the effects on the CXCR4-RhoA and PI3K-mTOR pathways by western blotting. Results: Our panel of OSCC cells was broadly sensitive towards zerumbone with IC50 values of less than 5 µM whereas normal keratinocyte cells were less responsive with IC50 values of more than 25 µM. Representative OSCC cells revealed that zerumbone inhibited OSCC proliferation and induced cell cycle arrest and apoptosis. In addition, zerumbone treatment inhibited migration and invasion of OSCC cells, with concurrent suppression of endogenous CXCR4 protein expression in a time and dose-dependent manner. RhoA-pull down assay showed reduction in the expression of RhoA-GTP, suggesting the inactivation of RhoA by zerumbone. In association with this, zerumbone also inhibited the PI3K-mTOR pathway through the inactivation of Akt and S6 proteins. Conclusion: We provide evidence that zerumbone could inhibit the activation of CXCR4-RhoA and PI3K-mTOR signaling pathways leading to the reduced cell viability of OSCC cells. Our results suggest that zerumbone is a promising phytoagent for development of new therapeutics for OSCC treatment

    Determinants of Survival and Post-Progression Outcomes by Sorafenib–Regorafenib Sequencing for Unresectable Hepatocellular Carcinoma

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    The predictors of response and survival in patients with hepatocellular carcinoma (HCC) receiving regorafenib remain unclear. This study aimed to delineate the determinants of response and survival after regorafenib and evaluate post-progression treatment and outcomes. We retrospectively enrolled 108 patients with unresectable HCC receiving regorafenib after sorafenib failure. Progression-free survival (PFS), overall survival (OS), post-progression survival (PPS) and post-progression treatments were evaluated. The median PFS, OS and PPS were 3.1, 13.1 and 10.3 months, respectively. Achieving disease control by prior sorafenib, early AFP reduction and hand-foot skin reaction (HFSR) were associated with significantly better radiologic responses. By multivariate analysis, the time to progression on prior sorafenib, HFSR and early AFP reduction were associated with PFS; ALBI grade, portal vein invasion, HFSR and early AFP reduction were associated with OS. ALBI grade at disease progression, main portal vein invasion, high tumor burden and next-line therapy were associated with PPS. The median PPS was 12 months in patients who received next-line therapy, and the PPS was comparable between patients who received next-line targeted agents and immunotherapy. In conclusion, survival outcomes of regorafenib for HCC have improved in the era of multi-line sequential therapy. Preserved liver function and next-line therapy are important prognostic factors after regorafenib failure

    Determinants of Survival and Post-Progression Outcomes by Sorafenib–Regorafenib Sequencing for Unresectable Hepatocellular Carcinoma

    No full text
    The predictors of response and survival in patients with hepatocellular carcinoma (HCC) receiving regorafenib remain unclear. This study aimed to delineate the determinants of response and survival after regorafenib and evaluate post-progression treatment and outcomes. We retrospectively enrolled 108 patients with unresectable HCC receiving regorafenib after sorafenib failure. Progression-free survival (PFS), overall survival (OS), post-progression survival (PPS) and post-progression treatments were evaluated. The median PFS, OS and PPS were 3.1, 13.1 and 10.3 months, respectively. Achieving disease control by prior sorafenib, early AFP reduction and hand-foot skin reaction (HFSR) were associated with significantly better radiologic responses. By multivariate analysis, the time to progression on prior sorafenib, HFSR and early AFP reduction were associated with PFS; ALBI grade, portal vein invasion, HFSR and early AFP reduction were associated with OS. ALBI grade at disease progression, main portal vein invasion, high tumor burden and next-line therapy were associated with PPS. The median PPS was 12 months in patients who received next-line therapy, and the PPS was comparable between patients who received next-line targeted agents and immunotherapy. In conclusion, survival outcomes of regorafenib for HCC have improved in the era of multi-line sequential therapy. Preserved liver function and next-line therapy are important prognostic factors after regorafenib failure

    The 4717C > G polymorphism in periplakin modulates sensitivity to EGFR inhibitors

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    Abstract The use of EGFR inhibitors on oral squamous cell carcinoma (OSCC) as monotherapy yielded modest clinical outcomes and therefore would benefit from biomarkers that could predict which patient subsets are likely to respond. Here, we determined the efficacy of erlotinib in OSCC cell lines, and by comparing sensitive and resistant lines to identify potential biomarkers. We focused on the 4717C > G polymorphism in periplakin (PPL) where the CC genotype was associated with erlotinib resistance. To validate this, erlotinib-resistant cell lines harbouring CC genotype were engineered to overexpress the GG genotype and vice versa. Isogenic cell lines were then studied for their response to erlotinib treatment. We demonstrated that overexpression of the GG genotype in erlotinib-resistant lines sensitized them to erlotinib and inhibition of AKT phosphorylation. Similarly, the expression of the CC genotype conferred resistance to erlotinib with a concomitant increase in AKT phosphorylation. We also demonstrated that cell lines with the CC genotype generally are more resistant to other EGFR inhibitors than those with the GG genotype. Overall, we showed that a specific polymorphism in the PPL gene could confer resistance to erlotinib and other EGFR inhibitors and further work to evaluate these as biomarkers of response is warranted
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