What drives consumers to purchase or not purchase ethical products remains something of a puzzle for consumer behavior researchers. Existing theory—particularly the widely applied theory of planned ...behavior (TPB)—cannot fully explain ethical purchase decisions. This article contends that not only is the original TPB limited in its applicability to ethical purchasing contexts but also subsequent modifications to it have been generally unfitting. This study advances the literature by taking a different approach to recharacterize and re-extend the original components of the TPB in order to make it more relevant and effective for explaining and predicting ethical consumer decisions. This new theoretical framework of intention formation features four determinants (attitude, subjective norm, moral identity, and perceived behavior control) and a key moderator (level of confidence), and thereby possesses better explanatory and predictive abilities to understand ethical consumer decisions.
Fulfilling consumer expectations of corporate social responsibility (CSR) can bring strategic advantage to firms. However, research on the topic is fragmented across disparate disciplines, and a ...comprehensive framework to connect CSR supply and demand is missing. As a result, firms often supply CSR that does not attract demand, as signified by pessimism about ethical consumerism in recent years and the inconclusive link between corporate financial and social performance. In this study, we propose a framework of strategic CSR management to define how a company's supply of CSR could meet consumer demand for ethical products by aligning managerial and consumer perspectives. We then investigate empirically whether such a strategic approach, which integrates potential demand in CSR management, would influence consumer choice of products with CSR components. Our hybrid choice modeling allows the inclusion of psychological biases caused by social desirability and cynicism to increase result validity. The findings support the explanatory power of the framework and reveal that consumers prefer some CSR elements while others adversely aifect choices. This study advances the understanding of strategic CSR management and its impact on consumer choice and helps managers include the right mix of CSR characteristics in their products to satisfy ethical consumers.
Abstract With the discovery of the CRISPR/Cas9 technology, genome editing could be performed in a rapid, precise and effective manner. Its potential applications in functional interrogation of ...cancer-causing genes and cancer therapy have been extensively explored. In this study, we demonstrated the use of the CRISPR/Cas9 system to directly target the oncogene HER2 . Directing Cas9 to exons of the HER2 gene inhibited cell growth in breast cancer cell lines that harbor amplification of the HER2 locus. The inhibitory effect was potentiated with the addition of PARP inhibitors. Unexpectedly, CRISPR-induced mutations did not significantly affect the level of HER2 protein expression. Instead, CRISPR targeting appeared to exert its effect through a dominant negative mutation. This HER2 mutant interfered with the MAPK/ERK axis of HER2 downstream signaling. Our work provides a novel mechanism underlying the anti-cancer effects of HER2-targeting by CRISPR/Cas9, which is distinct from the clinical drug Herceptin. In addition, it opens up the possibility that incomplete CRISPR targeting of certain oncogenes could still have therapeutic value by generation of dominant negative mutants.
OBJECTIVE: 11-β-hydroxysteroid dehydrogenase type 1 (11βHSD1) converts inactive cortisone into active cortisol, thereby amplifying intracellular glucocorticoid action. The efficacy and safety of the ...11βHSD1 inhibitor INCB13739 were assessed when added to ongoing metformin monotherapy in patients with type 2 diabetes exhibiting inadequate glycemic control (A1C 7-11%). RESEARCH DESIGN AND METHODS: This double-blind placebo-controlled paralleled study randomized 302 patients with type 2 diabetes (mean A1C 8.3%) on metformin monotherapy (mean 1.5 g/day) to receive one of five INCB13739 doses or placebo once daily for 12 weeks. The primary end point was the change in A1C at study end. Other end points included changes in fasting glucose, lipids, weight, adverse events, and safety. RESULTS: After 12 weeks, 200 mg of INCB13739 resulted in significant reductions in A1C (-0.6%), fasting plasma glucose (-24 mg/dl), and homeostasis model assessment-insulin resistance (HOMA-IR) (-24%) compared with placebo. Total cholesterol, LDL cholesterol, and triglycerides were all significantly decreased in hyperlipidemic patients. Body weight decreased relative to placebo after INCB13739 therapy. A reversible dose-dependent elevation in adrenocorticotrophic hormone, generally within the normal reference range, was observed. Basal cortisol homeostasis, testosterone in men, and free androgen index in women were unchanged by INCB13739. Adverse events were similar across all treatment groups. CONCLUSIONS: INCB13739 added to ongoing metformin therapy was efficacious and well tolerated in patients with type 2 diabetes who had inadequate glycemic control with metformin alone. 11βHSD1 inhibition offers a new potential approach to control glucose and cardiovascular risk factors in type 2 diabetes.
Myelofibrosis (MF) is associated with a variety of burdensome symptoms and reduced survival compared with age-/sex-matched controls. This analysis evaluated the long-term survival benefit with ...ruxolitinib, a Janus kinase (JAK)1/JAK2 inhibitor, in patients with intermediate-2 (int-2) or high-risk MF.
This was an exploratory analysis of 5-year data pooled from the phase 3 COMFORT-I and -II trials. In both trials, patients could cross over to ruxolitinib from the control group (COMFORT-I, placebo; COMFORT-II, best available therapy). All continuing patients in the control groups crossed over to ruxolitinib by the 3-year follow-up. Overall survival (OS; a secondary endpoint in both trials) was evaluated using pooled intent-to-treat data from patients randomized to ruxolitinib or the control groups. OS was also evaluated in subgroups stratified by baseline anemia and transfusion status at week 24.
A total of 528 patients were included in this analysis; 301 were originally randomized to ruxolitinib (COMFORT-I, n = 155; COMFORT-II, n = 146) and 227 to control (n = 154 and n = 73, respectively). The risk of death was reduced by 30% among patients randomized to ruxolitinib compared with patients in the control group (median OS, 5.3 vs 3.8 years, respectively; hazard ratio HR, 0.70 95% CI, 0.54-0.91; P = 0.0065). After correcting for crossover using a rank-preserving structural failure time (RPSFT) method, the OS advantage was more pronounced for patients who were originally randomized to ruxolitinib compared with patients who crossed over from control to ruxolitinib (median OS, 5.3 vs 2.3 years; HR ruxolitinib vs RPSFT, 0.35 95% CI, 0.23-0.59). An analysis of OS censoring patients at the time of crossover also demonstrated that ruxolitinib prolonged OS compared with control (median OS, 5.3 vs 2.4 years; HR ruxolitinib vs censored at crossover, 0.53 95% CI, 0.36-0.78; P = 0.0013). The survival benefit with ruxolitinib was observed irrespective of baseline anemia status or transfusion requirements at week 24.
These findings support ruxolitinib treatment for patients with int-2 or high-risk MF, regardless of anemia or transfusion status. Further analyses will be important for exploring ruxolitinib earlier in the disease course to assess the effect on the natural history of MF.
ClinicalTrials.gov identifiers, NCT00952289 and NCT00934544 .
This trial showed clinically significant responses in spleen size and quality of life among patients with myelofibrosis receiving ruxolitinib, a JAK1 and JAK2 inhibitor. The agent has some ...myelotoxicity, but this study showed a survival advantage with ruxolitinib.
Myelofibrosis, a myeloproliferative neoplasm, is manifested by abnormal blood counts (anemia, thrombocytosis or thrombocytopenia, and leukocytosis or leukopenia), splenomegaly, and debilitating symptoms (e.g., fatigue, weakness, abdominal pain, cachexia, weight loss, pruritus, night sweats, and bone pain), which are thought to be caused by the combined effects of massive splenomegaly and elevated levels of proinflammatory cytokines.
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Survival ranges from approximately 2 to 11 years, depending on defined prognostic factors.
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Traditional therapeutic options, including splenectomy, have limited benefit.
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Although allogeneic stem-cell transplantation may cure myelofibrosis, few patients are eligible for this treatment.
Although the gain-of-function mutation in the gene encoding Janus kinase . . .
In the phase III COMFORT-I study, the Janus kinase 1 (JAK1)/JAK2 inhibitor ruxolitinib provided significant improvements in splenomegaly, key symptoms, and quality-of-life measures and was associated ...with an overall survival benefit relative to placebo in patients with intermediate-2 or high-risk myelofibrosis. This planned analysis assessed the long-term efficacy and safety of ruxolitinib at a median follow-up of 149 weeks. At data cutoff, approximately 50% of patients originally randomized to ruxolitinib remained on treatment whereas all patients originally assigned to placebo had discontinued or crossed over to ruxolitinib. At week 144, mean spleen volume reduction was 34% with ruxolitinib. Previously observed improvements in quality-of-life measures were sustained with longer-term ruxolitinib therapy. Overall survival continued to favor ruxolitinib despite the majority of placebo patients crossing over to ruxolitinib hazard ratio 0.69 (95% confidence interval: 0.46-1.03); P = 0.067. Exploratory analyses suggest that crossover may have contributed to an underestimation of the true survival difference between the treatment groups. Ruxolitinib continued to be generally well tolerated; there was no pattern of worsening grade ≥ 3 anemia or thrombocytopenia with longer-term ruxolitinib exposure. These longer-term data continue to support the efficacy and safety of ruxolitinib in patients with myelofibrosis. The study is registered at clinicaltrials.gov: NCT00952289.
Human embryonic stem cells (hESC), with their ability to differentiate into cardiomyocytes in culture, hold great potential for cell replacement therapies and provide an in vitro model of human heart ...development. A genomewide characterization of the molecular phenotype of hESC‐derived cardiomyocytes is important for their envisioned applications. We have employed a lineage selection strategy to generate a pure population of cardiomyocytes (>99%) from transgenic hESC lines. Global gene expression profiling showed that these cardiomyocytes are distinct from pluripotent and differentiated hESC cultures. Pure cardiomyocytes displayed similarities with heart tissue, but in many aspects presented an individual transcriptome pattern. A subset of 1,311 cardiac‐enriched transcripts was identified, which were significantly overpresented (p < .01) in the Gene Ontology (GO) categories of heart function and heart development. Focused analysis of the GO categories ion transport, sarcomere, and heart development uncovered a unique molecular signature of hESC cardiomyocytes. Pathway analysis revealed an extensive cardiac transcription factor network and novel peroxisome proliferator‐activated receptor signaling components within the cardiac‐enriched genes. Notably, approximately 80% of these genes were previously uncharacterized. We have evaluated the biological relevance of four candidates—Rbm24, Tcea3, Fhod3, and C15orf52—by in situ hybridization during early mouse development and report that all were prominently expressed in cardiac structures. Our results provide the fundamental basis for a comprehensive understanding of gene expression patterns of hESC cardiomyocytes and will greatly help define biological processes and signaling pathways involved in hESC cardiomyogenic differentiation and in human heart development. STEM CELLS 2009;27:2163–2174
ADP ribosylation factor 1 (Arf1) plays a critical role in regulating secretory traffic and membrane transport within the Golgi of eukaryotic cells. Arf1 is activated by guanine nucleotide exchange ...factors (ArfGEFs), which confer spatial and temporal specificity to vesicular transport. We describe here the discovery and characterization of golgicide A, a potent, highly specific, reversible inhibitor of the cis-Golgi ArfGEF GBF1. Inhibition of GBF1 function resulted in rapid dissociation of COPI vesicle coat from Golgi membranes and subsequent disassembly of the Golgi and trans-Golgi network. Secretion of soluble and membrane-associated proteins was arrested at the endoplasmic reticulum-Golgi intermediate compartment, whereas endocytosis and recycling of transferrin were unaffected by GBF1 inhibition. Internalized shiga toxin was arrested within the endocytic compartment and was unable to reach the dispersed trans-Golgi network. Collectively, these results highlight the central role for GBF1 in coordinating bidirectional transport and maintaining structural integrity of the Golgi.
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