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Background: To date, single-agent immune checkpoint inhibitor (CPI) therapy has proven to be ineffective against biomarker-unselected extrapulmonary poorly differentiated neuroendocrine carcinomas (EP-PDNECs). The efficacy of CPI in combination with chemotherapy remains under investigation. Methods: Patients with advanced, progressive EP-PDNECs were enrolled in a two-part study of pembrolizumab-based therapy. In Part A, patients received pembrolizumab alone. In Part B, patients received pembrolizumab plus chemotherapy. Primary endpoint: objective response rate (ORR). Secondary endpoints: safety, progression-free survival (PFS) and overall survival (OS). Tumours were profiled for programmed death-ligand 1 expression, microsatellite-high/mismatch repair deficient status, mutational burden (TMB), genomic correlates. Tumour growth rate was evaluated. Results: Part A (N = 14): ORR (pembrolizumab alone) 7% (95% CI, 0.2–33.9%), median PFS 1.8 months (95% CI, 1.7–21.4), median OS 7.8 months (95% CI, 3.1–not reached); 14% of patients (N = 2) had grade 3/4 treatment-related adverse events (TRAEs). Part B (N = 22): ORR (pembrolizumab plus chemotherapy) 5% (95% CI, 0–22.8%), median PFS 2.0 months (95% CI, 1.9–3.4), median OS 4.8 months (95% CI, 4.1–8.2); 45% of patients (N = 10) had grade 3/4 TRAEs. The two patients with objective response had high-TMB tumours. Discussion: Treatment with pembrolizumab alone and pembrolizumab plus chemotherapy was ineffective in advanced, progressive EP-PDNECs. Clinical trial registration: ClinicalTrials.gov NCT03136055. [ABSTRACT FROM AUTHOR]

The article discusses a study on the impact of diabetes mellitus on the collection of hematopoietic stem cells and hematologic recovery post-transplantation in a group of patients. The study examined patient data from Washington University School of Medicine in Saint Louis, Missouri. Hierarchical logistic multivariate regression was performed to develop a model of optimal stem cell collection. The results showed the association of DM with stem cell mobilization.

Clinical and research efforts have focused on promoting functional recovery after stroke. Brain stimulation strategies are particularly promising because they allow direct manipulation of the target area's excitability. However, elucidating the cell type and mechanisms mediating recovery has been difficult because existing stimulation techniques nonspecifically target all cell types near the stimulated site. To circumvent these barriers, we used optoge-netics to selectively activate neurons that express channelrhodop-sin 2 and demonstrated that selective neuronal stimulations in the ipsilesional primary motor cortex (iM1) can promote functional recovery. Stroke mice that received repeated neuronal stimulations exhibited significant improvement in cerebral blood flow and the neurovascular coupling response, as well as increased expression of activity-dependent neurotrophins in the contralesional cortex, including brain-derived neurotrophic factor, nerve growth factor, and neurotrophin 3. Western analysis also indicated that stimulated mice exhibited a significant increase in the expression of a plasticity marker growth-associated protein 43. Moreover, iM1 neuronal stimulations promoted functional recovery, as stimulated stroke mice showed faster weight gain and performed significantly better in sensory-motor behavior tests. Interestingly, stimulations in normal nonstroke mice did not alter motor behavior or neurotrophin expression, suggesting that the prorecovery effect of selective neuronal stimulations is dependent on the poststroke environment. These results demonstrate that stimulation of neurons in the stroke hemisphere is sufficient to promote recovery. [ABSTRACT FROM AUTHOR]

Although skin cancer is less common in Hispanics, they are at higher risk for presenting with more advanced stage skin cancer. We performed semi-structured interviews with Hispanic women that found high concern for photoaging from sun exposure. Based on these results, we developed two short Spanish-language films. The first emphasized photoaging benefits of sun protection, while the second focused on its benefits for skin cancer prevention. Our hypothesis was that the reduction of photoaging would be a more persuasive argument than skin cancer prevention for the adoption of sunscreen use by Hispanic women. Study participants were recruited from beauty salons located in predominantly Hispanic neighborhoods. Each of the two Spanish-language films was approximately 3 min long. A pre-intervention questionnaire assessed subjects' general knowledge and sunscreen habits, and a second questionnaire administered after viewing both films assessed for improvements in risk perception and inquired about which film was more persuasive. Eighty Hispanics participated ranging in age from 19 to 75. The pre-education survey found that 54 out of 80 believed that fair-skin Hispanics (FS) were at risk for skin cancer, and 44 out of 80 believed that dark-skin Hispanics (DS) were at risk. These numbers increased to 72 (FS) and 69 (DS) after the intervention ( p value: <0.0002 FS, <0.0001 DS). Hispanics overwhelmingly selected the video emphasizing the benefits of sun protection for skin cancer prevention as the more persuasive film (74 out of 80). A Spanish-language video has the potential to make an impact in healthy sun-protective behaviors, and information on how to properly apply sunscreen should be included in educational messages. [ABSTRACT FROM AUTHOR]

The lateral-flow immunoassay (LFA) is an inexpensive point-of-care (POC) paper-based diagnostic device with the potential to rapidly detect disease biomarkers in resource-poor settings. Although LFA is inexpensive, easy to use, and requires no laboratory equipment, it is limited by its sensitivity, which remains inferior to that of gold standard laboratory-based assays. Our group is the only one to have previously utilized various aqueous two-phase systems (ATPSs) to enhance LFA detection. In those studies, the sample was concentrated by an ATPS in a test tube and could only be applied to LFA after it had been extracted manually. Here, we bypass the extraction step by seamlessly integrating a polyethylene glycol–potassium phosphate ATPS with downstream LFA detection in a simple, inexpensive, power-free, and portable all-in-one diagnostic device. We discovered a new phenomenon in which the target biomarkers simultaneously concentrate as the ATPS solution flows through the paper membranes, and our device features a 3-D paper well that was designed to exploit this phenomenon. Studies with this device, which were performed at room temperature in under 25 min, demonstrated a 10-fold improvement in the detection limit of a model protein, transferrin. Our next-generation LFA technology is rapid, affordable, easy-to-use, and can be applied to existing LFA products, thereby providing a new platform for revolutionizing the current state of disease diagnosis in resource-poor settings. [ABSTRACT FROM AUTHOR]

Scholars studying the ethical, legal, and social issues (ELSI) associated with emerging technologies maintain the importance of considering these issues throughout the research and development cycle, even during the earliest stages of basic research. Embedding these considerations within the scientific process requires communication between ELSI scholars and the community of physical scientists who are conducting that basic research. We posit that this communication can be effective on a broad scale only if it links societal issues directly to characteristics of the emerging technology that are relevant to the physical and natural scientists involved in research and development. In this article, we examine nano-ELSI literature from 2003 to 2010 to discern the degree to which it makes these types of explicit connections. We find that, while the literature identifies a wide range of issues of societal concern, it generally does so in a non-specific manner. It neither links societal issues to particular forms or characteristics of widely divergent nanotechnologies nor to any of the many potential uses to which those nanotechnologies may be put. We believe that these kinds of specificity are essential to those engaged in nano-scale research. We also compare the literature-based findings to observations from interviews we conducted with nanoscientists and conclude that ELSI scholars should add technical- and application-related forms of specificity to their work and their writings to enhance effectiveness and impact in communicating with one important target audience-members of the nanoscale science community. [ABSTRACT FROM AUTHOR]

To understand the thinking process in private information games, we use “Mousetracking” to record which payoffs subjects attend to. The games have three information states and vary in strategic complexity. Subjects consistently deviate from Nash equilibrium choices and often fail to look at payoffs which they need to in order to compute an equilibrium response. Choices and lookups are similar when stakes are higher. When cluster analysis is used to group subjects according to lookup patterns and choices, three clusters appear to correspond approximately to level-3, level-2, and level-1 thinking in level-k models, and a fourth cluster is consistent with inferential mistakes (as, for example, in QRE or Cursed Equilibrium theories). Deviations from Nash play are associated with failure to look at the necessary payoffs. The time durations of looking at key payoffs can predict choices, to some extent, at the individual level and at the trial-by-trial level. [ABSTRACT FROM AUTHOR]

This article theoretically proposes and empirically verifies an understudied issue in the business ethics (BE) and corporate social responsibility (CSR) literature-how moral degradation (MD) in a society influences the relationship between BE or CSR and firm performance (i.e., corporate legitimacy and competitive advantage). Building on strategic choice theory, we propose that both BE and CSR become more important in enhancing business success when the perceived MD is heightened. Our analysis of 300 firms operating in China statistically confirms our hypotheses: first, under high MD, firms' engagement in CSR results in higher corporate legitimacy and competitive advantage, and second, their adherence to ethical business codes leads to higher corporate legitimacy. We conclude the article by outlining the implications for both theory and practice. [ABSTRACT FROM AUTHOR]

Current theory on foreign subsidiary autonomy is insufficient to examine a situation where a multinational lacks experience to organize global operations, and yet intends to compete extensively with established multinational enterprises (MNEs) from advanced economies. By building on theoretical perspectives developed for emerging-market multinational enterprises (EMNEs), we advance the idea that foreign subsidiary autonomy is a strategic mechanism to overcome the EMNE's weaknesses in managing globally dispersed businesses and their home-country disadvantages after foreign entry. Subsidiary autonomy delegation assists in performing the learning functions necessary for overcoming resource and capability voids, as well as for distancing the subsidiary administratively from the parent's negative home-country institutional heritage. Analyses of survey data collected from headquarter senior executives of 240 Chinese MNEs suggest that subsidiary autonomy delegation is higher among firms relying on foreign markets as a springboard to acquire strategic assets, whose top managers at the headquarters perceive high domestic institutional constraints, and which do not count on government assistance to expand internationally. Further, we demonstrate that these relationships are strengthened with greater inward foreign direct investment cooperative experience, and with the use of merger and acquisition entry modes. These findings have important implications for theories on subsidiary autonomy. [ABSTRACT FROM AUTHOR]

Valley of death describes the metaphorical depths to which promising science and technology too often plunge, never to emerge and reach their full potential. Behavioral and institutional perspectives help in understanding the implications of choices-characterized by Field of Dreams imagery-that inadvertently lead into rather than over the valley of death. A workshop conducted among a diverse set of scientists, managers, and technology-transfer staff at a US national laboratory is a point of departure for discussing behavioral and institutional elements that promote or impede the pathway between research and use and for suggesting actionable measures that can facilitate the flow of information and products from research toward use. In the complex systems that constitute research institutions, where competing pressures can create barriers to information or technology transfer, one recommendation is to reframe the process as a more active ushering toward use. [ABSTRACT FROM AUTHOR]

In this paper, we derive and experimentally test a theoretical model of speculation in multiperiod asset markets with public information flows. The speculation arises from the traders' heterogeneous posteriors as they make different inferences from sequences of public information. This leads to overpricing in the sense that price exceeds the most optimistic belief about the real value of the asset. We find evidence of speculative overpricing in both incomplete and complete markets, where the information flow is a gradually revealed sequence of imperfect public signals about the state of the world. We also find evidence of asymmetric price reaction to good news and bad news, another feature of equilibrium price dynamics under our model. Markets with a relaxed short-sale constraint exhibit less overpricing. [ABSTRACT FROM AUTHOR]

This study addresses an important issue in designing and managing business process offshoring (BPO): process integration between an offshore service provider and its global BPO client. We applied the information-processing lens in global BPO and developed the logic that internationally disaggregated process integration requires a fit between process integration and BPO's task characteristics (i.e., task complexity and security) and task interdependence (task connectivity, stickiness, and dependency). This alignment is further moderated by the task context, such as the geographic dispersion of the global client's end-customers and the type of offshore provider (independent vendor vs captive and joint venture). Finally, we suggest that process integration has a positive but curvilinear relationship with the economic returns achieved by offshore providers. Our analysis of 308 BPO companies in India and China supports our propositions. We conclude that international managers monitoring and integrating globally disaggregated activities in BPO should establish a proper alignment with the BPO project's task traits and task interdependence, and look closely at the conditioning effect of external complexity. By redressing the paucity of research on governing global BPO, this study offers some insights into the integration--externalization dynamics for growing business/knowledge process offshoring. [ABSTRACT FROM AUTHOR]

abstract Guanxi, a social network tie drawing on connections in business relations, has been identified as a powerful strategic tool helping organizations maintain competitive advantages and achieve superior performance. However, prior empirical studies on the guanxi-performance link provide indefinite conclusions. The purpose of this study is to systematically review and quantify the guanxi-performance link in a meta-analytic framework by decomposing guanxi into business ties (i.e., guanxi with business partners) and government ties (i.e., guanxi with government authorities) and organizational performance into economic performance and operational performance. Based on effect sizes from fifty-three studies encompassing 20,212 organizations, we estimate that the overall effect size of the guanxi-performance relationship is positive and significant, thus endorsing the argument that guanxi does enhance organizational performance. Specifically, our meta-analysis results demonstrate that both business and government ties lead to both economic and operational performance. However, business ties have a bigger impact on operational performance, whereas government ties exert larger effects on economic performance. Further meta-analytic regression results suggest that ownership (state-owned vs. non-state-owned) and location (Mainland vs. overseas China) explain some of the variations of the guanxi-performance link. Both business and government ties are more important to organizations in Mainland China than to those in overseas China. Government ties are more important to state-owned than to non-state-owned organizations. Lastly, while business ties remain a valuable strategic tool in China, the importance of government ties is time-variant and has been declining with the development of the institutional environment in China. [ABSTRACT FROM AUTHOR]

Evolving lineages face a constant intracellular threat: most new coding sequence mutations destabilize the folding of the encoded protein. Misfolded proteins form insoluble aggregates and are hypothesized to be intrinsically cytotoxic. Here, we experimentally isolate a fitness cost caused by toxicity of misfolded proteins. We exclude other costs of protein misfolding. such as loss of functional protein or attenuation of growth-limiting protein synthesis resources, by comparing growth rates of budding yeast expressing folded or misfolded variants of a gratuitous protein, YFP, at equal levels. We quantify a fitness cost that increases with misfolded protein abundance, up to as much as a 3.2% growth rate reduction when misfolded YFP represents less than 0.1% of total cellular protein. Comparable experiments on variants of the yeast gene orotidine- 5'-phosphate decarboxylase (URA3) produce similar results. Quan- titative proteomic measurements reveal that, within the cell, misfolded YFP induces coordinated synthesis of interacting cytosolic chaperone proteins in the absence of a wider stress response, pro- viding evidence for an evolved modular response to misfolded proteins in the cytosol. These results underscore the distinct and evolutionarily relevant molecular threat of protein misfolding, independent of protein function. Assuming that most misfolded proteins impose similar costs, yeast cells express almost all proteins at steady-state levels sufficient to expose their encoding genes to selection against misfolding. lending- credibility to the recent suggestion that such selection imposes a global constraint on molecular evolution. [ABSTRACT FROM AUTHOR]

Administrative monopolies are a rampant problem in China. The Anti-Monopoly Law of the People's Republic of China (AML) attempts to deal with this problem by prohibiting government entities from abusing administrative power in anti-competitive ways. This article explores the effectiveness and enforcement of the administrative monopoly provisions by first looking at the treatment of administrative monopoly cases under the AML. The cases highlight not only the weaknesses of China's legal and judicial enforcement mechanisms, but also the important role of extra-legal mechanisms, such as the public pressure for rectification of violations. Second, China's situation is compared to that of Ukraine. The Ukrainian experience shows that the key elements to effective enforcement are providing for clear legislative penalties and having a strong and independent enforcement authority. Therefore, this article finds that, while the AML appears to have had some effect on reining in administrative monopolies, enforcement can be vastly improved by establishing an anti-monopoly enforcement agency that is independent, well resourced and empowered to take direct action against contraventions. Accordingly, the article concludes with some recommendations for short term and long term reform. [ABSTRACT FROM AUTHOR]

We investigate theoretically and experimentally the crisis bargaining model, a dynamic game of two-sided incomplete information with player types drawn from a commonly known distribution. Little work has been done to analyze whether and how players update their beliefs in such games. Within the experiment we elicited beliefs from players about their opponent's type using a proper scoring rule. We implement two treatments that vary the cost of backing down to the first mover after initial entry, generating sharp comparative static predictions in both beliefs and strategies. We find that players do update their beliefs in the predicted directions after observing some of the action choices. However, we highlight evidence of conservative updating relative to rational expectations. [ABSTRACT FROM AUTHOR]