Glycogen synthase kinase 3 beta (GSK3β) is highly inactivated in epithelial cancers and is known to inhibit tumor migration and invasion. The zinc-finger-containing transcriptional repressor, Slug, ...represses E-cadherin transcription and enhances epithelial-mesenchymal transition (EMT). In this study, we find that the GSK3β-pSer9 level is associated with the expression of Slug in non-small cell lung cancer. GSK3β-mediated phosphorylation of Slug facilitates Slug protein turnover. Proteomic analysis reveals that the carboxyl terminus of Hsc70-interacting protein (CHIP) interacts with wild-type Slug (wtSlug). Knockdown of CHIP stabilizes the wtSlug protein and reduces Slug ubiquitylation and degradation. In contrast, nonphosphorylatable Slug-4SA is not degraded by CHIP. The accumulation of nondegradable Slug may further lead to the repression of E-cadherin expression and promote cancer cell migration, invasion and metastasis. Our findings provide evidence of a de novo GSK3β-CHIP-Slug pathway that may be involved in the progression of metastasis in lung cancer.
Essentials
High‐quality data are lacking on use of prophylaxis in adults with hemophilia and arthropathy.
SPINART was a 3‐year randomized clinical trial of late/tertiary prophylaxis vs on‐demand ...therapy.
Prophylaxis improved function, quality of life, activity and pain but not joint structure by MRI.
Prophylaxis improves function but must start before joint bleeding onset to prevent arthropathy.
Summary
Background
Limited data exist on the impact of prophylaxis on adults with severe hemophilia A and pre‐existing joint disease.
Objectives
To describe 3‐year bleeding, joint health and structure, health‐related quality‐of‐life (HRQoL) and other outcomes from the open‐label, randomized, multinational SPINART study.
Patients/Methods
Males aged 12–50 years with severe hemophilia A, ≥ 150 factor VIII exposure days, no inhibitors and no prophylaxis for > 12 consecutive months in the past 5 years were randomized to sucrose‐formulated recombinant FVIII prophylaxis or on‐demand therapy (OD). Data collected included total and joint bleeding events (BEs), joint structure (magnetic resonance imaging MRI), joint health (Colorado Adult Joint Assessment Scale CAJAS), HRQoL, pain, healthcare resource utilization (HRU), activity, and treatment satisfaction.
Results
Following 3 years of prophylaxis, adults maintained excellent adherence, with a 94% reduction in BEs despite severe pre‐existing arthropathy; 35.7% and 76.2% of prophylaxis participants were bleed‐free or had fewer than two BEs per year, respectively. As compared with OD, prophylaxis was associated with improved CAJAS scores (least squares LS mean, − 0.31 n = 42 versus + 0.63 n = 42) and HAEMO‐QoL‐A scores (LS mean, + 3.98 n = 41 versus − 6.00 n = 42), less chronic pain (50% decrease), and approximately two‐fold less HRU; activity, Euro QoL‐5D‐3L (EQ‐5D‐3L) scores and satisfaction scores also favored prophylaxis. However, MRI score changes were not different for prophylaxis versus OD (LS mean, + 0.79 n = 41 versus + 0.96 n = 38).
Conclusions
Over a period of 3 years, prophylaxis versus OD in adults with severe hemophilia A and arthropathy led to decreased bleeding, pain, and HRU, better joint health, activity, satisfaction, and HRQoL, but no reduction in structural arthropathy progression, suggesting that pre‐existing joint arthropathy may be irreversible.
NTRK1, NTRK2 and NTRK3 gene fusions (NTRK gene fusions) occur in a range of adult cancers. Larotrectinib is a potent and highly selective ATP-competitive inhibitor of TRK kinases and has demonstrated ...activity in patients with tumours harbouring NTRK gene fusions.
This multi-centre, phase I dose escalation study enrolled adults with metastatic solid tumours, regardless of NTRK gene fusion status. Key inclusion criteria included evaluable and/or measurable disease, Eastern Cooperative Oncology Group performance status 0–2, and adequate organ function. Larotrectinib was administered orally once or twice daily, on a continuous 28-day schedule, in increasing dose levels according to a standard 3 + 3 dose escalation scheme. The primary end point was the safety of larotrectinib, including dose-limiting toxicity.
Seventy patients (8 with tumours with NTRK gene fusions; 62 with tumours without a documented NTRK gene fusion) were enrolled to 6 dose cohorts. There were four dose-limiting toxicities; none led to study drug discontinuation. The maximum tolerated dose was not reached. Larotrectinib-related adverse events were predominantly grade 1; none were grade 4 or 5. The most common grade 3 larotrectinib-related adverse event was anaemia 4 (6%) of 70 patients. A dose of 100 mg twice daily was recommended for phase II studies based on tolerability and antitumour activity. In patients with evaluable TRK fusion cancer, the objective response rate by independent review was 100% (eight of the eight patients). Eight (12%) of the 67 assessable patients overall had an objective response by investigator assessment. Median duration of response was not reached. Larotrectinib had limited activity in tumours with NTRK mutations or amplifications. Pharmacokinetic analysis showed exposure was generally proportional to administered dose.
Larotrectinib was well tolerated, demonstrated activity in all patients with tumours harbouring NTRK gene fusions, and represents a new treatment option for such patients.
NCT02122913.
Purpose
This paper aims to go through all Peter Senge’s books since his influential book The Fifth Discipline: The Art and Practice of the Learning Organization in 1990 and see what kind of ideas he ...has developed and the impact his books have created.
Design/methodology/approach
The author uses book review method to identify prominent ideas in those books that not only have significantly challenged but also contributed to transforming the world of business and management in both academia and practice.
Findings
Among many great ideas that Senge has developed, spirituality, mental models, systems thinking, and a sustainability mentality are prominent ones, which have set up trends for both researchers and practitioners in business and management.
Originality/value
Those ideas are interwoven, intertwined and have powerfully shaped new ways to see the world and act upon.
Primaquine (PQ), an 8-aminoquinoline, is the only drug approved by the United States Food and Drug Administration for radical cure and prevention of relapse in Plasmodium vivax infections. Knowledge ...of the metabolism of PQ is critical for understanding the therapeutic efficacy and hemolytic toxicity of this drug. Recent in vitro studies with primary human hepatocytes have been useful for developing the ultra high-performance liquid chromatography coupled with high-resolution mass spectrometric (UHPLC-QToF-MS) methods for simultaneous determination of PQ and its metabolites generated through phase I and phase II pathways for drug metabolism.
These methods were further optimized and applied for phenotyping PQ metabolites from plasma and urine from healthy human volunteers treated with single 45 mg dose of PQ. Identity of the metabolites was predicted by MetaboLynx using LC-MS/MS fragmentation patterns. Selected metabolites were confirmed with appropriate standards.
Besides PQ and carboxy PQ (cPQ), the major plasma metabolite, thirty-four additional metabolites were identified in human plasma and urine. Based on these metabolites, PQ is viewed as metabolized in humans via three pathways. Pathway 1 involves direct glucuronide/glucose/carbamate/acetate conjugation of PQ. Pathway 2 involves hydroxylation (likely cytochrome P450-mediated) at different positions on the quinoline ring, with mono-, di-, or even tri-hydroxylations possible, and subsequent glucuronide conjugation of the hydroxylated metabolites. Pathway 3 involves the monoamine oxidase catalyzed oxidative deamination of PQ resulting in formation of PQ-aldehyde, PQ alcohol and cPQ, which are further metabolized through additional phase I hydroxylations and/or phase II glucuronide conjugations.
This approach and these findings augment our understanding and provide comprehensive view of pathways for PQ metabolism in humans. These will advance the clinical studies of PQ metabolism in different populations for different therapeutic regimens and an understanding of the role these play in PQ efficacy and safety outcomes, and their possible relation to metabolizing enzyme polymorphisms.
This study uses a quasi-experimental design to investigate what happens to individual socially responsible attitudes when they are exposed to group dynamics. Findings show that group engagement ...increases individual attitudes toward social responsibility. We also found that individuals with low attitudes toward social responsibility are more likely to change their opinions when group members show more positive attitudes toward social responsibility. Conversely, individuals with high attitudes do not change much, independent of group characteristics. To better analyze the effect of group dynamics, the study proposes to split social responsibility into relative and absolute components. Findings show that relative social responsibility is correlated with but different from absolute social responsibility although the latter is more susceptible than the former to group dynamics.
PurposeDrawing on the social exchange perspective, the authors explore the roles of satisfaction over material rewards, perceived organizational politics and career ambition in the relationship ...between harmonious workplace climate and employee altruistic behavior in the context of British public sector.Design/methodology/approachThe authors employed SPSS software to estimate ordinary least squares models to test their hypotheses by analyzing data from 161 supervisor–employee dyads from a UK local government.FindingsSatisfaction over material rewards mediates the relationship between harmonious workplace climate and employee altruistic behavior. Both perceived organizational politics and career ambition moderate the mediated effect of harmonious workplace climate on employee altruistic behavior via satisfaction over material rewards.Originality/valueThis study advances the social exchange theory by showing that the norm of reciprocity (e.g. harmonious workplace climate in this study) may not be the only key driver of exchange for altruistic behavior among public sector workers. Still, it can be mediated by satisfaction with pay and promotion opportunities and may be conditional upon individuals' career ambition or their perceptions of organizational politics.
PurposeUnderpinned by institutional legitimacy, this study explores how South African public university senior managers struggled to maintain legitimacy during an unplanned radical change ...process.Design/methodology/approachGioia's grounded theory analysis approach is employed to analyse interviews with 37 senior managers of public-funded universities in South Africa.FindingsThis study's findings show that a change without proper planning severely damages institutions in all aspects of leadership's normative, empirical, moral and pragmatic legitimacy.Research limitations/implicationsThis study contributes to the literature on legitimacy by illustrating the importance of institutional legitimacy during unplanned social change and the factors that negate legitimacy.Originality/valueThough other legitimacy models have been well developed, they do not apply to such unplanned social change in organisations. This study shows a different angle of the legitimacy crisis under unplanned social change conditions.
While numerous models examine the linkages between improvisation and innovation, the factors that moderate this relationship at the team level are unknown. Consequently, this study builds on ...principles and insights from the jazz jam session framework used by jazz musicians and regression analysis to examine the nature of the improvisation process and consider how it affects innovation. By using unbalanced panel data on 2,749 teams containing between two and eight employees in the United Kingdom during 2002–2016, this study demonstrates that the success of the improvisation process relies on both internal and external factors conducive to innovation. Subsequently, the conclusions drawn may help entrepreneurs and team managers think differently about the role improvisation plays in the innovation activity. As a result, important practical implications are drawn for team managers and entrepreneurs intending to cultivate a willingness to improvise in teams and nurture collaborative relationships with external partners for innovation.
The Bemisia tabaci Mediterranean (MED) cryptic species is an invasive pest, distributed worldwide, with high ecological adaptability and thermotolerance. DNA methylation (a reversible chromatin ...modification) is one possible change that may occur within an organism subjected to environmental stress. To assess the effects of temperature stress on DNA methyltransferase 3 (Dnmt3) in MED, we cloned and sequenced BtDnmt3 and identified its functions in response to high and low temperatures. The full‐length cDNA of BtDnmt3 was 3913 bp, with an open reading frame of 1962 bp, encoding a 73.89 kDa protein. In situ hybridization showed that BtDnmt3 was expressed mainly in the posterior region. BtDnmt3 messenger RNA expression levels were significantly down‐regulated after exposure to heat shock and significantly up‐regulated after exposure to cold shock. Furthermore, after feeding on double‐stranded RNA specific for BtDnmt3, both heat resistance and cold resistance were significantly decreased, suggesting that BtDnmt3 is associated with thermal stress response and indicating a differential response to high‐ and low‐temperature stress in MED. Together, these results highlight a potential role for DNA methylation in thermal resistance, which is a process important to successful invasion and colonization of an alien species in various environments.
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