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Recent progress in targeting KRAS G12C has provided both insight and inspiration for targeting alternative KRAS mutants. In this study, we evaluated the mechanism of action and anti-tumor efficacy of MRTX1133, a potent, selective and non-covalent KRAS G12D inhibitor. MRTX1133 demonstrated a high-affinity interaction with GDP-loaded KRAS G12D with K D and IC 50 values of ~0.2 pM and <2 nM, respectively, and ~700-fold selectivity for binding to KRAS G12D as compared to KRAS WT . MRTX1133 also demonstrated potent inhibition of activated KRAS G12D based on biochemical and co-crystal structural analyses. MRTX1133 inhibited ERK1/2 phosphorylation and cell viability in KRAS G12D -mutant cell lines, with median IC 50 values of ~5 nM, and demonstrated >1,000-fold selectivity compared to KRAS WT cell lines. MRTX1133 exhibited dose-dependent inhibition of KRAS-mediated signal transduction and marked tumor regression (≥30%) in a subset of KRAS G12D -mutant cell-line-derived and patient-derived xenograft models, including eight of 11 (73%) pancreatic ductal adenocarcinoma (PDAC) models. Pharmacological and CRISPR-based screens demonstrated that co-targeting KRAS G12D with putative feedback or bypass pathways, including EGFR or PI3Kα, led to enhanced anti-tumor activity. Together, these data indicate the feasibility of selectively targeting KRAS mutants with non-covalent, high-affinity small molecules and illustrate the therapeutic susceptibility and broad dependence of KRAS G12D mutation-positive tumors on mutant KRAS for tumor cell growth and survival. A potent and selective inhibitor of KRAS G12D , the most common mutant form of the KRAS oncoprotein, has anti-tumor efficacy in multiple pre-clinical cancer models, opening the possibility to therapeutically target this highly prevalent oncogenic driver.

Psoriasis is a common, chronic, immune-mediated inflammatory skin disease with increased epidermal proliferation. The objective of this review was to systematically identify the evidence and perform a network meta-analysis (NMA) to estimate the relative efficacy of secukinumab (SEC) against adalimumab (ADA) and infliximab (INF) for the treatment of moderate-to-severe plaque psoriasis. A systematic literature review (SLR) was conducted according to a pre-specified protocol to identify relevant studies. Initially, the databases were searched from database inception till June 2013, and the SLR was updated in April 2020. The eligibility criteria included adult patients (≥18 years old) with moderate-to-severe plaque psoriasis, and the SLR included randomized controlled trials (RCTs). The comparators of interest were SEC, ADA, INF, and placebo (PLA), while outcomes of interest were Psoriasis Area and Severity Index (PASI) (50, 75, and 90) at weeks 12, 16, and 24. A Bayesian NMA for PASI was utilized with a framework that evaluated the probability of PASI responses in different categories of PASI thresholds within a single model. A total of 23 RCTs that assessed the efficacy of SEC, ADA, and INF in patients with moderate-to-severe plaque psoriasis were identified. At 12 weeks, SEC was associated with a significantly better response compared with PLA and ADA for PASI 75 and 90, while response results were comparable against INF. At 12 weeks, risk ratio (95% confidence interval) derived from NMA for SEC vs. ADA and INF for PASI 75 was 1.35 (1.19, 1.57) and 1.01 (0.90, 1.18), respectively. At the 16-week and 24-week time interval, SEC was significantly better than PLA, ADA, and INF for PASI 75 and 90. Efficacy of SEC in the treatment of patient populations with moderate-to-severe plaque psoriasis is well demonstrated through NMA.

Acetyl-CoA carboxylase (ACC) catalyzes the rate-limiting step in de novo lipogenesis, which is increased in the livers of patients with nonalcoholic steatohepatitis. GS-0976 (firsocostat), an inhibitor of isoforms ACC1 and ACC2, reduced hepatic steatosis and serum fibrosis biomarkers such as tissue inhibitor of metalloproteinase 1 in patients with nonalcoholic steatohepatitis in a randomized controlled trial, although the impact of this improvement on fibrosis has not fully been evaluated in preclinical models. Here, we used Western diet-fed melanocortin 4 receptor-deficient mice that have similar phenotypes to nonalcoholic steatohepatitis patients including progressively developed hepatic steatosis as well as fibrosis. We evaluated the effects of ACC1/2 inhibition on hepatic fibrosis. After the confirmation of significant hepatic fibrosis with a 13-week pre-feeding, GS-0976 (4 and 16 mg/kg/day) treatment for 9 weeks lowered malonyl-CoA and triglyceride content in the liver and improved steatosis, histologically. Furthermore, GS-0976 reduced the histological area of hepatic fibrosis, hydroxyproline content, mRNA expression level of type I collagen in the liver, and plasma tissue metalloproteinase inhibitor 1, suggesting an improvement of hepatic fibrosis. The treatment with GS-0976 was also accompanied by reductions of plasma ALT and AST levels. These data demonstrate that improvement of hepatic lipid metabolism by ACC1/2 inhibition could be a new option to suppress fibrosis progression as well as to improve hepatic steatosis in nonalcoholic steatohepatitis.

As emerging approaches, IT-based applications designed for encouraging pro-environmental behaviors have shown great potential. By focusing on Ant Forest, this study attempts to explore the embedded gamification design to identify key elements that lead to users’ long-term game participation which eventually fosters pro-environmental behaviors. First, a focus group interview was conducted to identify twenty-one gamification design elements in four modules: task design, social interaction, feedback, and reward. Furthermore, this study employed the Two-Dimensional Kano Model and better–worse analysis to classify and prioritize the gamification design elements that impact users’ attitudes toward Ant Forest. Five Attractive elements, five One-Dimensional elements, four Must-Be elements, and seven Indifferent elements were identified in Ant Forest from 207 questionnaires. The results emphasize the significant impact of gamification design elements that are highly correlated with environmental sustainability (i.e., green context, pro-environmental behaviors, plant a tree) in Ant Forest. In addition, users who are rewarded by both virtual medals and official certificates demonstrate higher satisfaction, whereas elements associated with social interaction and competition show trivial importance. This study has profound theoretical implications as an interdisciplinary study, and yields helpful insights for practice to improve Ant Forest design, promote Ant Forest usage and finally fuel pro-environmental behaviors.

Purpose The purpose of this paper is to explain the “good-to-good” app switching phenomenon that has not been specifically addressed in the prior switching literature. Drawing on the consumer learning theory, this study explores how external social word of mouth (WOM) and internal satisfaction influence app users’ switching intention through social learning route and analogical learning route. This study also examines the moderating effect of app heterogeneity. Design/methodology/approach An online survey was used to collect data. Two categories of mobile apps with different levels of within-category heterogeneity were targeted in survey questions. A total of 525 valid survey responses were collected. Findings Social WOM about a competing app increases users’ switching intention through both social norm influence and social information influence, resulting in a direct effect on switching intention and an indirect effect through the perceived attractiveness of a competing app. Users’ satisfaction with an adopted app positively influences the perceived attractiveness of an unadopted competing app, offering evidence for analogical learning in user switching. Meanwhile, users’ satisfaction imposes a direct negative effect on switching intention. A higher level of within-category heterogeneity strengthens (weakens) the positive effect of social WOM (satisfaction) on users’ perceived attractiveness of a competing app. Originality/value This study complements the existing switching literature by disentangling the “good-to-good” switching phenomenon in the mobile app market from the consumer learning perspective. This study extends the understanding of cross-category user switching by considering different levels of product heterogeneity.

PurposeWhile anonymous online interactions could be helpful and less risky, they are usually not enough for LGBTQ+ people to satisfy the need of expressing their marginalized identity to networks of known ties (i.e. on identified social media like Facebook, WeChat, and TikTok). However, identified social media bring LGBTQ+ people both sources and challenges like “context collapse” that flattens diverse networks or audiences that are originally separated. Previous studies focus on LGBTQ+ people's disclosure and responses to context collapse, few studies investigate how their perceptions of context collapse are shaped and their privacy management beyond regulating disclosure on social media. Drawing on identity theory and communication privacy management (CPM), this study aims to investigate how the need of LGBTQ+ people for self-identity affects their perceived context collapse and results in privacy management on identified social media.Design/methodology/approachGiven the target population is LGBTQ+ people, The authors recruited participants through active LGBTQ+ online communities, influential LGBTQ+ activists, and the snowballing sampling. The authors empirically examined the proposed model using the PLS-SEM technique with a valid sample of 232 respondents concerning their identity practices and privacy management on WeChat, a typical and popular identified social media in China.FindingsThe results suggested that the need for expressing the self and the need for maintaining continuity of self-identity have significant influences on perceived context collapse, but vary in directions. The perceived context collapse will motivate LGBTQ+ individuals to engage in privacy management to readjust rules on ownership, access, and extension. However, only ownership management helps them regain the perceived privacy control on social media.Originality/valueThis study incorporated and highlighted the influence of LGBTQ+ identity in shaping context collapse and online privacy management. This study contributes to the literature on privacy and information communication and yields practical implications, especially on improving privacy-related interactive design for identified social media services.

PurposeCustomization, a marketing strategy through providing personalized products, might be a new solution to motivate consumer feedbacks in electronic commerce (e-commerce) websites. Taking the dual-value of customization (emotional involvement and uniqueness expression) as the theoretical basis, this study aims to investigate the impact of customization on consumer's word-of-mouth (WOM) behaviors and contents by motivating: (1) more, (2) faster, (3) positive at first and then negative, (4) longer and (5) more helpful WOMs.Design/methodology/approachA field study was conducted with multi-sourced data: customer order data from a Chinese retailer and WOM data from Amazon.com. The two datasets were matched to filter out 463 online reviews among 6,892 customers who placed customized orders. Heckman's two-stage model, logistic regression, Ordinary least squares regression, Tobit regression, analysis of covariance and Lind–Mehlum U Test were used in the data analysis.Findings This study has found that (1) customization level motivates WOM behaviors including WOM posting and WOM speed, (2) an inverted U-shaped relationship exists between customization level and consumer rating and (3) customization level has a significantly positive impact on WOM helpfulness but not on WOM length.Originality/value This study advances theoretical development in the area of WOM motivators by proposing a new product-centric approach, customization, to stimulate voluntary WOMs. Empirical field research that analyzes consumer's real responses to customization is in scarcity. The dual-value of customized products is proposed as the underlying mechanism to explain the impact of customization level on consumer's WOM behaviors/contents. An interesting inverted U-shaped relationship is found between customization level and customer rating. This research provides nuanced practical guidance for websites, companies and consumers.

PurposeIn the online microloan market, the ability to evaluate the credit risk of borrowers is key to business success. Based on the general strain theory, this study proposes a contextualized two-stage model with stress factors, negative affects and constraint factors to explain the psychological mechanism of borrowers' default behaviors.Design/methodology/approachAn online survey is conducted to test the hypotheses. We collect and analyze 713 valid responses through a structural equation model.Findings(1) Economic and social strains experienced by borrowers can cause four types of negative affects: life dissatisfaction, perceived unfairness, inferiority feeling and loneliness; (2) Both strains and negative affects have a considerable effect on borrowers' default intention; (3) Moral norm plays a negative moderating role in the relationship between strains, negative affects and default behavior, whereas perceived deterrence shows a strong main effect.Originality/value(1) This study introduces the GST from sociology and criminology, and contextualizes it in the microloan context to explain default behavior; (2) This study provides a comprehensive and staged psychological mechanism to explain deviant behavior; (3) This study bears critical implications for the current practice in credit assessment and default prevention.

Supplemental Digital Content is available in the text AbstractBackground:Psoriasis is a common, chronic, immune-mediated inflammatory skin disease with increased epidermal proliferation. The objective of this review was to systematically identify the evidence and perform a network meta-analysis (NMA) to estimate the relative efficacy of secukinumab (SEC) against adalimumab (ADA) and infliximab (INF) for the treatment of moderate-to-severe plaque psoriasis.Methods:A systematic literature review (SLR) was conducted according to a pre-specified protocol to identify relevant studies. Initially, the databases were searched from database inception till June 2013, and the SLR was updated in April 2020. The eligibility criteria included adult patients (≥18 years old) with moderate-to-severe plaque psoriasis, and the SLR included randomized controlled trials (RCTs). The comparators of interest were SEC, ADA, INF, and placebo (PLA), while outcomes of interest were Psoriasis Area and Severity Index (PASI) (50, 75, and 90) at weeks 12, 16, and 24. A Bayesian NMA for PASI was utilized with a framework that evaluated the probability of PASI responses in different categories of PASI thresholds within a single model.Results:A total of 23 RCTs that assessed the efficacy of SEC, ADA, and INF in patients with moderate-to-severe plaque psoriasis were identified. At 12 weeks, SEC was associated with a significantly better response compared with PLA and ADA for PASI 75 and 90, while response results were comparable against INF. At 12 weeks, risk ratio (95% confidence interval) derived from NMA for SEC vs. ADA and INF for PASI 75 was 1.35 (1.19, 1.57) and 1.01 (0.90, 1.18), respectively. At the 16-week and 24-week time interval, SEC was significantly better than PLA, ADA, and INF for PASI 75 and 90.Conclusion:Efficacy of SEC in the treatment of patient populations with moderate-to-severe plaque psoriasis is well demonstrated through NMA.