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BackgroundTo determine the safety and efficacy of the anti-colony-stimulating factor 1 receptor (anti-CSF1R) monoclonal antibody AMG 820 in combination with pembrolizumab in patients with select solid tumors.Patients and methodsPatients had advanced, refractory mismatch repair-proficient colorectal cancer, pancreatic cancer, or non-small cell lung cancer (NSCLC) with low (<50%) programmed cell death-ligand 1 (PD-L1) expression and were naïve to anti-programmed cell death-1 (PD-1)/PD-L1 or had relapsed/refractory NSCLC after anti-PD-1/PD-L1 treatment with low or high (≥50%) PD-L1 expression; all were anti-CSF1/CSF1R naïve. Patients received 1100 mg or 1400 mg AMG 820 plus 200 mg pembrolizumab intravenously every 3 weeks. The primary endpoints were incidence of dose-limiting toxicities (DLTs) and adverse events (AEs) and objective response rate per immune-related Response Evaluation Criteria in Solid Tumours at the recommended combination dose.ResultsOverall, 116 patients received ≥1 dose of AMG 820 plus pembrolizumab (18 at 1400 mg AMG 820; 98 at 1100 mg AMG 820). Most patients (64%) were male; the median age was 64 (range 30–86) years. Seven patients had DLTs (1 at 1400 mg AMG 820; 6 at 1100 mg AMG 820). Almost all patients (99.1%) had AEs, 87.9% with grade ≥3 AEs. The most common AEs were increased aspartate aminotransferase (59.5%), fatigue (48.3%), periorbital/face edema (48.3%), and rash/maculopapular rash (37.1%). The best response was immune-related partial response in 3 patients (3%; duration of response 9.2, 10.0, 12.5 months) and immune-related stable disease in 39 patients (34%). None of the completed phase II cohorts met the predefined threshold for efficacy. Post-treatment there was accumulation of serum colony-stimulating factor 1 (CSF1) and interleukin-34, reduction in CSF1-dependent CD16-expressing monocytes, and increased PD-L1 expression and CD4 and CD8 cell numbers in tumor biopsies.ConclusionsThe recommended combination dose of 1100 mg AMG 820 plus 200 mg pembrolizumab had an acceptable safety profile. Although pharmacodynamic effects were observed, antitumor activity was insufficient for further evaluation of this combination in selected patient populations.Trial registration number NCT02713529

Purpose This study aims to address the following questions: What is enduring about consumer behavior on social media given that digital and social media (DSM) technologies change rapidly? Why do millennials use social media to the extent they do? The authors’ review revealed that a prevailing theoretical approach that may help answer these questions is inadequate. The technology acceptance model (TAM) from information systems was grafted into marketing to explain consumer technology adoption. TAM predicts Facebook adoption effectively, as demonstrated in the authors’ first study, but does not go beyond that in explaining the why’s behind its use. In a second study, the authors used the means-end approach (MEC) complementarily to unearth the why’s of millennials’ use of Facebook. Design/methodology/approach The authors used a mixed-methods design combining the structural modeling of TAM with the probing one-on-one interviews and laddering of MEC. Findings The authors found that the laddering process both widened and deepened TAM’s scope. It not only confirmed the importance of the TAM attributes, perceived ease of use and perceived usefulness, but it also revealed others, in determining adoption. It was also able to dig deeper from these to uncover a mesh of fundamental values that millennials used Facebook to satisfy, such as belongingness, pleasure, social acceptance and inner harmony, in their quest for inner and relational contentment. The authors also found negative aspects that kept consumers away, such as its lack of privacy and the overwhelming nature of unwanted video in its feed, tying these back to important values. Research limitations/implications The authors build on prior exploratory work relating to DSM use and uncover psychological drivers of consumer behavior on social media, by blending TAM in a consumer context, and the MEC approach. The TAM-MEC framework used here offers a technology-independent template for other DSM research, by focusing on how and why consumers use media socially. Practical implications Managerially, the authors discuss the building of sustainable marketing strategy on enduring consumer values rather than on transient attributes or technologies. The authors also discuss potential areas of vulnerability for Facebook, such as its increasing use of video and live content, which creates negative consumer sentiment and which may drive consumers to competitors. Originality/value By blending the quantitative TAM and the qualitative MEC, something that has not been done before in marketing, this research provides trustworthy answers to the research questions. In so doing, this study also contributes some cohesion to the fragmented DSM research field, as called for recently in prominent journals, by anchoring DSM study in well-established theories in marketing.

Background This open-label, first-in-human, phase 1 study evaluated the safety, pharmacokinetics, pharmacodynamics, and maximum tolerated dose (MTD) of AMG 228, an agonistic human IgG1 monoclonal antibody targeting glucocorticoid-induced tumor necrosis factor receptor−related protein (GITR), in patients with refractory advanced solid tumors. Methods AMG 228 was administered intravenously every 3 weeks (Q3W). Dose escalation was in two stages: single-patient cohorts (3, 9, 30, and 90 mg), followed by “rolling six” design ( n  = 2–6; 180, 360, 600, 900, and 1200 mg). Primary endpoints included incidence of dose-limiting toxicities (DLTs), AEs, and pharmacokinetics. Additional endpoints were objective response and pharmacodynamic response. Results Thirty patients received AMG 228, which was well tolerated up to the maximum planned dose (1200 mg). No DLTs occurred; the MTD was not reached. The most common treatment-related AEs were fatigue (13%), infusion-related reaction (7%), pyrexia (7%), decreased appetite (7%), and hypophosphatemia (7%). Two patients had binding anti−AMG 228 antibodies (one at baseline); no neutralizing antibodies were detected. AMG 228 exhibited target-mediated drug disposition, and serum exposure was approximately dose proportional at 180–1200 mg and greater than dose proportional at 3–1200 mg. Doses > 360 mg Q3W achieved serum trough coverage for 95% in vitro GITR occupancy. Despite GITR coverage in peripheral blood and tumor biopsies, there was no evidence of T-cell activation or anti-tumor activity. Conclusions In patients with advanced solid tumors, AMG 228 Q3W was tolerable up to the highest tested dose (1200 mg), exhibited favorable pharmacokinetics, and provided target coverage indicating a pharmacokinetic profile appropriate for longer intervals. However, there was no evidence of T-cell activation or anti-tumor activity with AMG 228 monotherapy. Trial registration ClinicalTrials.gov, NCT02437916 .

Advanced human cancers are invariably aneuploid, in that they harbour cells with abnormal chromosome numbers 1 , 2 . However, the molecular defects underlying this trait, and whether they are a cause or a consequence of the malignant phenotype, are not clear. Mutations that disable the retinoblastoma (Rb) pathway are also common in human cancers 1 . These mutations promote tumour development by deregulating the E2F family of transcription factors leading to uncontrolled cell cycle progression 3 . We show that the mitotic checkpoint protein Mad2 is a direct E2F target and, as a consequence, is aberrantly expressed in cells with Rb pathway defects. Concordantly, Mad2 is overexpressed in several tumour types, where it correlates with high E2F activity and poor patient prognosis. Generation of Rb pathway lesions in normal and transformed cells produces aberrant Mad2 expression and mitotic defects leading to aneuploidy, such that elevated Mad2 contributes directly to these defects. These results demonstrate how chromosome instability can arise as a by-product of defects in cell cycle control that compromise the accuracy of mitosis, and suggest a new model to explain the frequent appearance of aneuploidy in human cancer.

Gastrointestinal (GI) tract damage by chemotherapy or radiation limits their efficacy in cancer treatment. Radiation has been postulated to target epithelial stem cells within the crypts of Lieberkühn to initiate the lethal GI syndrome. Here, we show in mouse models that microvascular endothelial apoptosis is the primary lesion leading to stem cell dysfunction. Radiation-induced crypt damage, organ failure, and death from the GI syndrome were prevented when endothelial apoptosis was inhibited pharmacologically by intravenous basic fibroblast growth factor (bFGF) or genetically by deletion of the acid sphingomyelinase gene. Endothelial, but not crypt, cells express FGF receptor transcripts, suggesting that the endothelial lesion occurs before crypt stem cell damage in the evolution of the GI syndrome. This study provides a basis for new approaches to prevent radiation damage to the bowel.

Purpose This research aims to examine how source of funds (paying with company’s funds versus personal funds) affects buyer’s judgments of price fairness and via these judgments, buyer’s response to prices. Design/methodology/approach A scenario-based experiment is used (N = 200). To test the hypotheses, the authors run moderated mediation regression analyses with the help of the PROCESS macro. Findings Drawing on fairness heuristics theory, the authors hypothesize and find that relative to when paying with personal funds, when paying with company’s funds, the perceived price difference plays a less significant role, whereas the perceived social acceptability of the pricing practice underlying the price difference plays a more important role in shaping price fairness judgments and, via these judgments, buyer’s response to prices. Practical implications The findings generate advice for companies that serve both the business and personal segments (e.g. airlines and hotels). Buyers in the personal segment typically pay with their own money. To persuade these buyers that a price is fair, it is crucial to show that the price represents a good deal for them. Buyers in the business segment often pay with company’s fund. Companies have more flexibility in charging different prices, but they should make sure that the reasons for the price difference are socially acceptable. Originality/value This research shows how the relative role of price difference versus social acceptability in price fairness judgments varies as a function of source of funds and how an inconsistency between price difference and its economic impact affects price fairness judgments.

Purpose - The purpose of this paper is to review and understand the underlying structure of price perception, to recognize how cultural factors influence price perception, and to develop and empirically test a model of cultural differences and price perception.Design methodology approach - This project gathered data from both China and the USA. Using the LISREL 8.52 program, a proposed model was tested and modified in order to obtain a parsimonious underlying structure explaining cultural influences on consumers' price perceptions.Findings - Results of the data analysis show that culture factors do have significant effects on price perception. Internal reference price has a consistent and negative effect on the overall price perception of both goods and services purchase and durable and non-durable goods purchase. However, the significant associations between price perception factors and overall price perception were only found in the services and non-durable goods purchase but not in the durable goods purchase.Practical implications - This study helps international marketers understand the cross-cultural consumer behavioral differences in general and the price perception differences in particular. It also provides a series of guidelines for international pricing strategy and international promotion strategy on an operational level.Originality value - Theoretically, the paper integrates the solid base of work on domestic pricing from the Lichtenstein et al. study on price perception as well as work on culture from anthropology and sociology, international business, international marketing, and Hofstede's culture theory.

Purpose - This paper seeks to use the consumer-perceived levels of internet shopping skills and challenges, to cluster the young Chinese customers and to compare the quality perceptions of customers from the different clusters.Design methodology approach - A survey of 237 college students from Beijing with the average age of 20.2 was conducted via a paper-and-pencil questionnaire. All the constructs were measured using established scales. The students completed the questionnaire in their native language.Findings - The paper finds that, at the present level of internet development in China, online consumers can be segmented on the basis of their self-rated internet skills and their perception of the challenges involved in online shopping.Practical implications - Online customer segments obtained through internet skill and challenge level perceptions are demonstrated to explain some of the differences in the online shopping behaviors and service quality perceptions. The managers of online stores in China could segment young Chinese consumers based on this conceptual background.Originality value - The online shopping environment in China is characterized by a relatively low level of participation, but a rapid rate of growth, especially among young consumers. This is one of the first studies which evaluated the young Chinese consumers' online shopping behaviors and provided a conceptual basis for segmenting this market.

Purpose - The purpose of this paper is to apply Lichtenstein et al.'s price perception model to American, Chinese and Japanese cultures, to test the measurement equivalence across three cultures, and to compare the price perception constructs across three cultures using equivalent instruments.Design methodology approach - A questionnaire is used to collect information on more than 500 student respondents from America, China, and Japan.Findings - Utilizing structural equation modeling, a 21-item version of Lichtenstein et al.'s scale is created that has good fit across the three cultures. In progressively constraining tests, good model fit is found when constraining or partially constraining the factor loadings, error correlations, factor variances, and correlations between factors to be equal across three cultures tested. In addition, after creating price perception subscales, no significant differences emerge between Chinese, Japanese, and US consumers on value consciousness or price quality schemas. Significant differences emerge on price consciousness, prestige sensitivity, and sales proneness.Practical implications - The 21-item scale of Lichtenstein et al.'s price perception model can be generalized to both China and Japan. The primary conclusions (i.e. that Chinese consumers reported significantly higher price and prestige sensitivity, compared to USA and Japanese consumers, while US consumers showed higher levels of sales proneness than Chinese and Japanese consumers) provide a rationale for international retailers to develop different pricing and promotional strategies when expanding their business into these three cultures.Originality value - A 21-item scale to measure five of Lichtenstein et al.'s price perception constructs that has been validated through measurement invariance tests and compared across consumers in China, Japan, and the USA is provided.

Recent advances in automotive automation technology have made self-driving vehicles technically feasible. As automotive technology continues to evolve, self-driving vehicles are projected to be available for purchase within the United States by 2030. This study proposes and tests an integrated consumer adoption model in an effort to better understand factors that may influence a consumer's intention to use a self-driving vehicle. An 18-item questionnaire was developed for this study. A survey was then conducted using Qualtrics (n = 1,050). Results show that facilitating conditions significantly impact both performance expectancy and effort expectancy of self-driving vehicles. The resulting performance expectancy and effort expectancy subsequently have a strong influence on attitude towards a self-driving vehicle. Attitude then directly impacts the intention to use a self-driving vehicle. Implications are discussed that should be beneficial to marketers of self-driving vehicles.