Field Evidence on Individual Behavior & Performance in Rank-Order Tournaments

Economic analysis of rank-order tournaments has shown that intensified competition leads to declining performance. Empirical research demonstrates that individuals in tournament-type contests perform less well on average in the presence of larger number of competitors in total and superstars. Particularly in field settings, studies often lack direct evidence about the underlying mechanisms, such as the amount of effort, that might account for these results. Here we exploit a novel dataset on algorithmic programming contests that contains data on individual effort, risk taking, and cognitive errors that may underlie tournament performance outcomes. We find that competitors on average react negatively to an increase in the total number of competitors, and react more negatively to an increase in the number of superstars than non-superstars. We also find that the most negative reactions come from a particular subgroup of competitors: those that are highly skilled, but whose abilities put them near to the top of the ability distribution. For these competitors, we find no evidence that the decline in performance outcomes stems from reduced effort or increased risk taking. Instead, errors in logic lead to a decline in performance, which suggests a cognitive explanation for the negative response to increased competition. We also find that a small group of competitors, who are at the very top of the ability distribution (non-superstars), react positively to increased competition from superstars. For them, we find some evidence of increased effort and no increase in errors of logic, consistent with both economic and psychological explanations

Electrophysiological Correlates of Changes in Reaction Time Based on Stimulus Intensity

Background: Although reaction time is commonly used as an indicator of central nervous system integrity, little is currently understood about the mechanisms that determine processing time. In the current study, we are interested in determining the differences in electrophysiological events associated with significant changes in reaction time that could be elicited by changes in stimulus intensity. The primary objective is to assess the effect of increasing stimulus intensity on the latency and amplitude of afferent inputs to the somatosensory cortex, and their relation to reaction time. Methods: Median nerve stimulation was applied to the non-dominant hand of 12 healthy young adults at two different stimulus intensities (HIGH & LOW). Participants were asked to either press a button as fast as possible with their dominant hand or remain quiet following the stimulus. Electroencephalography was used to measure somatosensory evoked potentials (SEPs) and event related potentials (ERPs). Electromyography from the flexor digitorum superficialis of the button-pressing hand was used to assess reaction time. Response time was the time of button press. Results: Reaction time and response time were significantly shorter following the HIGH intensity stimulus compared to the LOW intensity stimulus. There were no differences in SEP (N20 & P24) peak latencies and peak-to-peak amplitude for the two stimulus intensities. ERPs, locked to response time, demonstrated a significantly larger pre-movement negativity to positivity following the HIGH intensity stimulus over the Cz electrode

Landscape of Epidermal Growth Factor Receptor Heterodimers in Brain Metastases

HER2+ breast cancer patients have an elevated risk of developing brain metastases (BM), despite adjuvant HER2-targeted therapy. The mechanisms underpinning this reduced intracranial efficacy are unclear. We optimised the in situ proximity ligation assay (PLA) for detection of the high-affinity neuregulin-1 receptor, HER2-HER3 (a key target of pertuzumab), in archival tissue samples and developed a pipeline for high throughput extraction of PLA data from fluorescent microscope image files. Applying this to a large BM sample cohort (n = 159) showed that BM from breast, ovarian, lung and kidney cancers have higher HER2-HER3 levels than other primary tumour types (melanoma, colorectal and prostate cancers). HER2 status, and tumour cell membrane expression of pHER2(Y1221/1222) and pHER3(Y1222) were positively, but not exclusively, associated with HER2-HER3 frequency. In an independent cohort (n = 78), BM had significantly higher HER2-HER3 levels than matching primary tumours (p = 0.0002). For patients who had two craniotomy procedures, HER2-HER3 dimer levels were lower in the consecutive lesion (n = 7; p = 0.006). We also investigated the effects of trastuzumab and pertuzumab on five different heterodimers in vitro: HER2-EGFR, HER2-HER4, HER2-HER3, HER3-HER4, HER3-EGFR. Treatment significantly altered the absolute frequencies of individual complexes in SKBr3 and/or MDA-MB-361 cells, but in the presence of neuregulin-1, the overall distribution was not markedly altered, with HER2-HER3 and HER2-HER4 remaining predominant. Together, these findings suggest that markers of HER2 and HER3 expression are not always indicative of dimerization, and that pertuzumab may be less effective at reducing HER2-HER3 dimerization in the context of excess neuregulin

Immune Mechanisms of Resistance to Cediranib in Ovarian Cancer

This paper investigates mechanisms of resistance to the VEGF receptor inhibitor cediranib in high-grade serous ovarian cancer, HGSOC, and defines rational combination therapies. We used three different syngeneic orthotopic mouse HGSOC models that replicated the human tumor microenvironment, TME. After 4-5 weeks treatment of established tumors, cediranib had anti-tumor activity with increased tumor T cell infiltrates and alterations in myeloid cells. However, continued cediranib treatment did not change overall survival or the immune microenvironment in two of the three models. Moreover, treated mice developed additional peritoneal metastases not seen in controls. Cediranib-resistant tumors had intrinsically high levels of IL-6 and JAK/STAT signaling and treatment increased endothelial STAT3 activation. Combination of cediranib with a murine anti-IL-6 antibody was superior to monotherapy, increasing mouse survival, reducing blood vessel density and pSTAT3, with increased T cell infiltrates in both models. In a third HGSOC model, that had lower inherent IL-6 JAK/STAT3 signaling in the TME but high PD1 signaling, long-term cediranib treatment significantly increased overall survival. When the mice eventually relapsed, pSTAT3 was still reduced in the tumors but there were high levels of immune cell PD1 and PDL1. Combining cediranib with an anti-PD1 antibody was superior to monotherapy in this model, increasing T cells and decreasing blood vessel densities. Bioinformatics analysis of two human HGSOC transcriptional datasets revealed distinct clusters of tumors with IL-6 and PD-1 pathway expression patterns that replicated the mouse tumors. Combination of anti-IL-6 or anti-PD1 in these patients may increase activity of VEGFR inhibitors and prolong disease-free survival

Basal-like grade III invasive ductal carcinoma of the breast: patterns of metastasis and long-term survival.

INTRODUCTION: Cytokeratin (CK) 14, one of several markers expressed in normal myoepithelial/basal cells, is also expressed in a proportion of breast carcinomas. Previous studies have suggested that expression of such 'basal' markers predicts different biological behaviour, with more frequent lung and brain metastases and poorer prognosis than other carcinomas. METHODS: We performed CK14 immunohistochemistry on 443 grade III invasive ductal carcinomas with extended clinical follow-up (mean 116 months), and we correlated CK14 immunopositivity (basal-like phenotype) with clinicopathological criteria. RESULTS: Eighty-eight of 443 (20%) tumours showed CK14 expression. CK14-positive tumours were more likely to be oestrogen receptor-negative (p < 0.0001) and axillary node-negative (p = 0.001) than were CK14-negative cases. CK14-positive cases developed less bone and liver metastases (hazard ratio [HR] 0.49, p = 0.01, and HR 0.53, p = 0.035, respectively) but more frequent brain metastases (HR 1.92, p = 0.051). In patients without metastatic disease, disease-free survival in CK14-positive cases was significantly better than in CK14-negative cases (HR 0.65, p = 0.005). In patients with metastatic disease, however, CK14 positivity was associated with a poorer prognosis (HR 1.84, p = 0.001). The overall survival in CK14-positive and -negative patients was similar at 5 years (60% and 59%, respectively), but the long-term survival was better in CK14-positive patients (HR 0.69, p = 0.02). CONCLUSION: These results demonstrate that basal-like tumours differ in their biological behaviour from other tumours, with a distinct pattern of metastatic spread. Compared to other grade III tumours, basal-like tumours appear to have a relatively good long-term survival but survival after metastases is poor.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

The effects of neo-adjuvant chemotherapy on myeloid cells in high-grade serous ovarian cancer metastases

PhD Thesi

Enhanced anti-tumour activity of carmustine (BCNU) with tumour necrosis factor in vitro and in vivo.

The effects on experimental melanoma of a combination of recombinant human tumour necrosis factor alpha (rhTNF alpha) and carmustine (BCNU) were studied in vitro and in vivo. In vitro, BCNU alone was cytotoxic to murine B16 melanoma cells, and at all concentrations of BCNU this toxicity was increased by the addition of TNF. In vivo, BCNU and TNF, when given separately, caused tumour growth delay of B16 melanoma and of human melanoma xenografts in immune-deprived mice. The combination of TNF at low dose 2.5 x 10(5) U kg-1 = 122 ng kg-1) with BCNU (35 mg kg-1) resulted in significant growth delay (compared with either drug alone) in B16 melanoma (P = 0.005). There was no significant increase in toxicity as assessed by weight loss and peripheral blood counts. Experiments with human melanoma xenografts yielded similar results (P = 0.001) but only at higher doses of TNF (1 x 10(6) U kg-1 = 489 ng kg-1). The enhancement of BCNU cytotoxicity by TNF may be important if it can be translated into patients with melanoma. A randomised study is now underway to investigate the clinical potential of this observation

The Secret to Successful User Communities: An Analysis of Computer Associates’ User Groups

This paper provides the first large scale study that examines the impact of both individual- and group-specific factors on the benefits users obtain from their user communities. By empirically analysing 924 survey responses from individuals in 161 Computer Associates' user groups, this paper aims to identify the determinants of successful user communities. To measure success, the amount of time individual members save through having access to their user networks is used. As firms can significantly profit from successful user communities, this study proposes four key implications of the empirical results for the management of user communities

Risk of diabetes mellitus among users of immune checkpoint inhibitors: A population‐based cohort study

Background Immune checkpoint inhibitors (ICIs) are increasingly established cancer therapeutics, but they are associated with new-onset diabetes mellitus (DM). Such risks have not been adequately quantified, and between-class and -sex differences remain unexplored. Methods This was a prospective cohort study of cancer patients receiving any ICI in Hong Kong between 2013 and 2021. Patients with known DM were excluded. Due to few patients using other ICIs, only programmed cell death 1 inhibitors (PD-1i) and programmed death ligand 1 inhibitors (PD-L1i) were compared, alongside between-sex comparison. When comparing PD-1i against PD-L1i, patients with the use of other ICIs or both PD-1i and PD-L1 were further excluded. Inverse probability treatment weighting (IPTW) was used to minimize between-group covariate imbalances. Results Altogether, 3375 patients were analyzed (65.2% males, median age 62.2 [interquartile range 53.8–69.5] years old). Over a median follow-up of 1.0 [0.4–2.4] years, new-onset DM occurred in 457 patients (13.5%), with a 3-year risk of 14.5% [95% confidence interval 13.3%, 15.8%]. IPTW achieve acceptable covariate balance between sexes, and between PD-1i (N = 622) and PD-L1i (N = 2426) users. Males had significantly higher risk of new-onset DM (hazard ratio 1.35 [1.09, 1.67], p = 0.006), while PD-1i and PD-L1i users did not have significantly different risks (hazard ratio vs PD-L1i 0.81 [0.59, 1.11], p = 0.182). These were consistent in those with at least 1 year of follow-up, and on competing risk regression. Conclusion Users of ICI may have a substantial risk of new-onset DM, which may be higher in males but did not differ between PD-1i and PD-L1i

Are estrogen receptor-positive breast cancers in BRCA1 mutation carriers sporadic?

There is a strong association between BRCA1 mutation carrier status and estrogen receptor-negative breast cancer. This has led to the idea that estrogen receptor-positive breast cancers in BRCA1 mutation carriers may be incidental or sporadic in nature and not as a direct result of BRCA1 dysfunction. A recent paper in Breast Cancer Research challenges this view