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A recent study suggested that proton pump inhibitor (PPI) use in patients with advanced non-small-cell lung cancer (NSCLC) receiving immune checkpoint inhibitors (ICIs) was associated with poor clinical outcomes. However, the clinical impact of PPI use on the outcome of patients receiving ICIs for postoperative recurrent NSCLC is unknown. The outcomes of 95 patients with postoperative recurrence of NSCLC receiving ICIs at 3 medical centers in Japan were analyzed. We conducted adjusted Kaplan-Meier survival analyses with the log-rank test, a Cox proportional hazards regression analysis, and a logistic regression analysis using inverse probability of treatment weighting (IPTW) to minimize the bias arising from the patients' backgrounds. The IPTW-adjusted Kaplan-Meier curves revealed that the progression-free survival (PFS), but not the overall survival (OS), was significantly longer in patients who did not receive PPIs than in those who did receive them. The IPTW-adjusted Cox regression analysis revealed that PPI use was an independent poor prognostic factor for the PFS and OS. Furthermore, in the IPTW-adjusted logistic regression analysis, PPI non-use was an independent predictor of disease control. In this multicenter and retrospective study, PPI use was associated with poor clinical outcomes in patients with postoperative recurrence of NSCLC who were receiving ICIs. PPIs should not be prescribed indiscriminately to patients with postoperative recurrence of NSCLC who intend to receive ICIs. These findings should be validated in a future prospective study.

Abstract Background Epidermal growth factor receptor (EGFR)-sensitizing mutation, exon 19 deletion consists of several molecular variants. Influences of these variants on clinical response to EGFR tyrosine kinase inhibitors remain elusive. Methods West Japan Oncology Group 8114LTR is a prospective, multi-institutional biomarker study. Treatment naïve, advanced non-small-cell lung cancer patients with EGFR-sensitizing mutation received afatinib monotherapy. We conducted a preplanned subset analysis of patients harboring exon 19 deletion. Tumor tissue exon 19 deletion molecular variants were identified by blocking-oligo-dependent polymerase chain reaction (PCR) and by Luminex Technology. Plasma cfDNA was also obtained before and after the treatment and EGFR mutations were detected with multiplexed, pico-droplet digital PCR assay. Results Among 57 registered patients, twenty-nine patients were exon 19 deletion. Tissue DNA and cfDNA were available in 26 patients. Among the detected seven molecular variants, the most frequent was p.E746_A750delELREA (65.4%). According to the various classifications of molecular variants, twenty one (80.8%) were classified into 15-nucleotide deletion, one (3.8%) into 18-nucleotide deletion, and four patients (15.4%) into other insertion/substitution variant subgroups. The patient subgroup with 15-nucleotide deletion showed significantly longer progression-free survival than patients in other mixed insertion/substitution variant subgroup (p = 0.0244). Conclusions The clinical significance of molecular variants of exon 19 deletion on the first line afatinib monotherapy is reported here for the first time. Further investigation is needed for development of better therapeutic strategies. Trial registration This trial was registered at UMIN Clinical Trials Registry at 2014/12/4 (UMIN000015847).

Many practitioners as well as researchers explore promoting environmentally conscious behavior in the context of public goods systems. Numerous experimental studies revealed various types of incentives to increase cooperation on public goods. There is ample evidence that monetary and non-monetary incentives, such as donations, have a positive effect on cooperation in public goods games that exceeds fully rational and optimal economic decision making. Despite an accumulation of these studies, in the typical setting of these experiments participants decide on an allocation of resources to a public pool, but they never exert actual effort. However, in reality, we often observe that players' real effort is required in these public goods game situations. Therefore, more analysis is needed to draw conclusions for a wider set of incentive possibilities in situations similar to yet deviating from resource allocation games. Here we construct a real effort public goods game in an online experiment and statistically analyze the effect different types of incentives have on cooperation. In our experiment, we examine combinations of monetary and social incentives in a setting aimed closer to practical realities, such as financial costs and real effort forming part of the decision to cooperate on a public good. In our real effort public goods game participants cooperate and defect on image-scoring tasks. We find that in our setting economic and social incentives produce an asymmetric effect. Interestingly economic incentives decreased the share of highly uncooperative participants, while social incentives raised the share of highly cooperative participants.

Objectives We conducted a subanalysis of data from the multicentre, retrospective observational Nivolumab Japan Real World (CA209-9CR) study to evaluate nivolumab effectiveness and safety in elderly patients (aged ≥75 years) with advanced/metastatic non-small cell lung cancer.Materials and methods Medical record data of patients initiating nivolumab treatment between April 2016 and December 2016 were collected using electronic data capture from 23 cancer hospitals in Japan between March 2017 and August 2018. Nivolumab treatment data were collected to investigate the treatment patterns by age group (

Localized malignant pleural mesothelioma (LMPM) is an extremely rare tumor. We report the case of a 40-year-old Japanese male with an LMPM mimicking an anterior mediastinal tumor due to invasion to the anterior mediastinum, and we discuss mainly the differentiation of LMPM from an anterior mediastinal tumor. The present tumor had a long shape along the pleura, and LMPM could be one of the differential diagnoses. Keywords: Pleural mesothelioma, Localized, Pleural tumor, Radiology, LMPM

Abstract Reputation-based cooperation is often observed in modern society. People gain several types of information by assessing others. Among these, the most important information is the actions of people and those of their recipients. However, almost all studies assume that people consider all of the information they receive. This assumption is extreme, and people engaging in reputation-based cooperation may not pay attention to some information, i.e., they may display selective inattention. We demonstrate that subjects’ decision-making in relation to cooperative action depends on the content of the information they receive about their recipients. Our results show that subjects either consider or ignore information depending on the content of that information. When their recipients had cooperated previously, subjects cooperated without considering the information they received. When the recipients had played before with those who had bad reputations, subjects did not use that information, regardless of whether it was disclosed proactively. In other cases, subjects considered information on both the previous actions of recipients and those of the recipients’ own recipients. We found that subjects did not always use the information to make decisions, although they willingly received information about their recipients. This supports the proposition that selective inattention occurs in reputation-based cooperation.

Afatinib is an ErbB family blocker that is approved for the treatment of epidermal growth factor receptor ( EGFR) mutation-positive non-small-cell lung cancer (NSCLC). Pivotal randomized clinical studies demonstrated that afatinib significantly prolonged progression-free survival compared with platinum-based chemotherapy (LUX-Lung 3, LUX-Lung 6), and with gefitinib (LUX-Lung 7), with manageable side effects. However, these results were derived from controlled studies conducted in selected patients and are not necessarily representative of real-world use of afatinib. To gain a broader understanding of the effectiveness and safety of first-line afatinib, we have undertaken a literature review of real-world studies that have assessed its use in a variety of patient populations. We focused on patients with uncommon EGFR mutations, brain metastases, or those of advanced age, as these patients are often excluded from clinical studies but are regularly seen in routine clinical practice. The available real-world studies suggest that afatinib has clinical activity, and is tolerable, in diverse patient populations in an everyday clinical practice setting. Moreover, consistent with LUX-Lung 7, several real-world comparative studies indicate that afatinib might confer better efficacy than first-generation EGFR tyrosine kinase inhibitors. Tolerability-guided dose adjustment, undertaken in 21–68% of patients in clinical practice, did not appear to reduce the efficacy of afatinib. Taken together, these findings provide further support for the use of afatinib as a treatment option in patients with EGFR mutation-positive NSCLC.

English proficiency has become essential for Japanese people in today's globalized society. However, since the structure of the Japanese language is very different from that of English, it has proven difficult for Japanese people to create natural and fluent English sentences without specialized training. We developed a support system for English composition using a new method which addresses this issue. The main characteristic of the system is the use of a dictionary of similar sentence patterns. This dictionary was developed by defining a new distance measurement between sentences that emphasize expressions at the end of a sentence in a Japanese text due to the head finality of Japanese. Our experiment revealed that in terms of fluency of translation, higher scores were obtained with this system, in comparison with the singular use of a word dictionary. Also, in terms of both adequacy and fluency, the average values with this system exceeded those with traditional support systems for English composition considered in this study.

Small-cell lung cancer (SCLC) is an aggressive malignant cancer that is classified into four subtypes based on the expression of the following key transcription and co-transcription factors: ASCL1, NEUROD1, YAP1, and POU2F3. The protein expression levels of these key molecules may be important for the formation of SCLC characteristics in a molecular subtype-specific manner. We expect that immunohistochemistry (IHC) of these molecules may facilitate the diagnosis of the specific SCLC molecular subtype and aid in the appropriate selection of individualized treatments. We attempted IHC of the four key factors and 26 candidate SCLC target molecules selected from the gene expression omnibus datasets of 47 SCLC samples, which were grouped based on positive or negative results for the four key molecules. We examined differences in the expression levels of the candidate targets and key molecules. ASCL1 showed the highest positive rate in SCLC samples, and significant differences were observed in the expression levels of some target molecules between the ASCL1-positive and ASCL1-negative groups. Furthermore, the four key molecules were coordinately and simultaneously expressed in SCLC cells. An IHC study of ASCL1-positive samples showed many candidate SCLC target molecules, and IHC could become an essential method for determining SCLC molecular subtypes.

Despite the accumulation of research on indirect reciprocity over the past 30 years and the publication of over 100,000 related papers, there are still many issues to be addressed. Here, we look back on the research that has been done on indirect reciprocity and identify the issues that have been resolved and the ones that remain to be resolved. This manuscript introduces indirect reciprocity in the context of the evolution of cooperation, basic models of social dilemma situations, the path taken in the elaboration of mathematical analysis using evolutionary game theory, the discovery of image scoring norms, and the breakthroughs brought about by the analysis of the evolutionary instability of the norms. Moreover, it presents key results obtained by refining the assessment function, resolving the punishment dilemma, and presenting a complete solution to the social dilemma problem. Finally, it discusses the application of indirect reciprocity in various disciplines.

We sought to identify peripheral blood markers associated with two immune-related factors-programmed cell death-ligand-2 (PD-L2) and indoleamine 2,3-dioxygenase-1 (IDO1)-that are expressed on tumor cells in primary lung adenocarcinoma (AD) specimens. We randomly selected 448 patients (70%) from 640 consecutive patients with resected stage I-III primary lung AD, who had been treated at that point with surgery alone. Expression of PD-L2 and IDO1 in these patients was assessed by immunohistochemistry, and evaluated with respect to peripheral blood markers measured before surgery, including white blood cells, absolute neutrophil count, absolute lymphocyte count, absolute monocyte count (AMC), absolute eosinophil count (AEC), serum C-reactive protein, and serum lactate dehydrogenase levels. Membrane PD-L2 expression and cytoplasmic IDO1 expression were defined by tumor proportion score (TPS); samples with TPS < 1% were considered negative. Logistic regression models were used to identify variables associated with the immune-related factors. Advanced stage (P = 0.0090), higher AMC (P = 0.0195), and higher AEC (P = 0.0015) were independent predictors of IDO1 expression. PD-L2 expression was not associated with any tested peripheral blood markers. Peripheral blood markers, especially AMC and AEC, could potential predict IDO1 expression in lung AD. This study should be replicated in another cohort; further efforts to explore other biomarkers that predict PD-L2 or IDO1 expression are also warranted.

Although exploring the principles of resource allocation is still important in many fields, little is known about appropriate methods for optimal resource allocation thus far. This is because we should consider many issues including opposing interests between many types of stakeholders. Here, we develop a new allocation method to resolve budget conflicts. To do so, we consider two points—minimizing assessment costs and satisfying allocational efficiency. In our method, an evaluator’s assessment is restricted to one’s own projects in one’s own department, and both an executive’s and mid-level executives’ assessments are also restricted to each representative project in each branch or department they manage. At the same time, we develop a calculation method to integrate such assessments by using a multi-branch tree structure, where a set of leaf nodes represents projects and a set of non-leaf nodes represents either directors or executives. Our method is incentive-compatible because no director has any incentive to make fallacious assessments.

Theoretical and empirical studies have generally weighed the effect of peer punishment and pool punishment for sanctioning free riders separately. However, these sanctioning mechanisms often pose a puzzling tradeoff between efficiency and stability in detecting and punishing free riders. Here, we combine the key aspects of these qualitatively different mechanisms in terms of evolutionary game theory. Based on the dilemmatic donation game, we introduce a strategy of commitment to both cooperation and peer punishment. To make the commitment credible, we assume that those willing to commit have to make a certain deposit. The deposit will be refunded as long as the committers faithfully cooperate in the donation game and punish free riders and non-committers. It turns out that the deposit-based commitment offers both the efficiency of peer punishment and the stability of pool punishment and that the replicator dynamics lead to transitions of different systems: pool punishment to commitment to peer punishment.

Indirect reciprocity is one of the basic mechanisms to sustain mutual cooperation, by which beneficial acts are returned, not by the recipient, but by third parties. This mechanism relies on the ability of individuals to know the past actions of others, and to assess those actions. There are many different systems of assessing others, which can be interpreted as rudimentary social norms (i.e., views on what is “good” or “bad”). In this paper, impacts of different adaptive architectures, i.e., ways for individuals to adapt to environments, on indirect reciprocity are investigated. We examine two representative architectures: one based on replicator dynamics and the other on genetic algorithm. Different from the replicator dynamics, the genetic algorithm requires describing the mixture of all possible norms in the norm space under consideration. Therefore, we also propose an analytic method to study norm ecosystems in which all possible second order social norms potentially exist and compete. The analysis reveals that the different adaptive architectures show different paths to the evolution of cooperation. Especially we find that so called Stern-Judging, one of the best studied norms in the literature, exhibits distinct behaviors in both architectures. On one hand, in the replicator dynamics, Stern-Judging remains alive and gets a majority steadily when the population reaches a cooperative state. On the other hand, in the genetic algorithm, it gets a majority only temporarily and becomes extinct in the end.

Intensive studies on indirect reciprocity have explored rational assessment rules for maintaining cooperation and several have demonstrated the effects of the stern-judging rule. Uchida and Sasaki demonstrated that the stern-judging rule is not suitable for maintaining cooperative regimes in private assessment conditions while a public assessment system has been assumed in most studies. Although both assessment systems are oversimplified and society is most accurately represented by a mixture of these systems, little analysis has been reported on their mixture. Here, we investigated how much weight on the use of information originating from a public source is needed to maintain cooperative regimes for players adopting the stern-judging rule when players get information from both public and private sources. We did this by considering a hybrid-assessment scheme in which players use both assessment systems and by using evolutionary game theory. We calculated replicator equations using the expected payoffs of three strategies: unconditional cooperation, unconditional defection, and stern-judging rule adoption. Our analysis shows that the use of the rule helps to maintain cooperation if reputation information from a unique public notice board is used with more than a threshold probability. This hybrid-assessment scheme can be applied to other rules, including the simple-standing rule and the staying rule.

Abstract We hypothesized that elucidating the interactome of epidermal growth factor receptor (EGFR) forms that are mutated in lung cancer, via global analysis of protein–protein interactions, phosphorylation, and systematically perturbing the ensuing network nodes, should offer a new, more systems‐level perspective of the molecular etiology. Here, we describe an EGFR interactome of 263 proteins and offer a 14‐protein core network critical to the viability of multiple EGFR‐mutated lung cancer cells. Cells with acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) had differential dependence of the core network proteins based on the underlying molecular mechanisms of resistance. Of the 14 proteins, 9 are shown to be specifically associated with survival of EGFR‐mutated lung cancer cell lines. This included EGFR, GRB2, MK12, SHC1, ARAF, CD11B, ARHG5, GLU2B, and CD11A. With the use of a drug network associated with the core network proteins, we identified two compounds, midostaurin and lestaurtinib, that could overcome drug resistance through direct EGFR inhibition when combined with erlotinib. Our results, enabled by interactome mapping, suggest new targets and combination therapies that could circumvent EGFR TKI resistance.

Social dilemmas are among the most puzzling issues in the biological and social sciences. Extensive theoretical efforts have been made in various realms such as economics, biology, mathematics, and even physics to figure out solution mechanisms to the dilemma in recent decades. Although punishment is thought to be a key mechanism, evolutionary game theory has revealed that the simplest form of punishment called peer punishment is useless to solve the dilemma, since peer punishment itself is costly. In the literature, more complex types of punishment, such as pool punishment or institutional punishment, have been exploited as effective mechanisms. So far, mechanisms that enable peer punishment to function as a solution to the social dilemma remain unclear. In this paper, we propose a theoretical way for peer punishment to work as a solution mechanism for the dilemma by incorporating prospect theory into evolutionary game theory. Prospect theory models human beings as agents that estimate small probabilities and loss of profit as greater than they actually are; thus, those agents feel that punishments are more frequent and harsher than they really are. We show that this kind of cognitive distortion makes players decide to cooperate to avoid being punished and that the cooperative state achieved by this mechanism is globally stable as well as evolutionarily stable in a wide range of parameter values.

Although positive incentives for cooperators and/or negative incentives for free-riders in social dilemmas play an important role in maintaining cooperation, there is still the outstanding issue of who should pay the cost of incentives. The second-order free-rider problem, in which players who do not provide the incentives dominate in a game, is a well-known academic challenge. In order to meet this challenge, we devise and analyze a meta-incentive game that integrates positive incentives (rewards) and negative incentives (punishments) with second-order incentives, which are incentives for other players' incentives. The critical assumption of our model is that players who tend to provide incentives to other players for their cooperative or non-cooperative behavior also tend to provide incentives to their incentive behaviors. In this paper, we solve the replicator dynamics for a simple version of the game and analytically categorize the game types into four groups. We find that the second-order free-rider problem is completely resolved without any third-order or higher (meta) incentive under the assumption. To do so, a second-order costly incentive, which is given individually (peer-to-peer) after playing donation games, is needed. The paper concludes that (1) second-order incentives for first-order reward are necessary for cooperative regimes, (2) a system without first-order rewards cannot maintain a cooperative regime, (3) a system with first-order rewards and no incentives for rewards is the worst because it never reaches cooperation, and (4) a system with rewards for incentives is more likely to be a cooperative regime than a system with punishments for incentives when the cost-effect ratio of incentives is sufficiently large. This solution is general and strong in the sense that the game does not need any centralized institution or proactive system for incentives.

Amphiregulin, a ligand of the epidermal growth factor receptor (EGFR), is associated with the efficacy of cetuximab, an antibody against EGFR, as treatment for colorectal cancer (CRC). In contrast, the HER3 ligand heregulin correlates with cetuximab resistance. In this study, we evaluated how the combined levels of circulating amphiregulin and heregulin affect clinical outcomes in patients who receive cetuximab as therapy against advanced CRC.Plasma levels of amphiregulin and heregulin were measured by enzyme-linked immunosorbent assay in 50 patients with CRC in a training cohort, and in 10 patients in a validation cohort. The combined expression was then assessed with clinical outcome after receiver operating characteristics analysis.Overall response rate was 26%, and median progression-free survival was 110 days in the training cohort. Patients with high amphiregulin and low heregulin had significantly higher objective response rate at 58% and significantly longer progression-free survival of 216 days. This result was confirmed in the validation cohort.A subgroup of CRC patients with high amphiregulin and low heregulin respond to cetuximab therapy better than other patients.

Despite recent advances in reputation technologies, it is not clear how reputation systems can affect human cooperation in social networks. Although it is known that two of the major mechanisms in the evolution of cooperation are spatial selection and reputation-based reciprocity, theoretical study of the interplay between both mechanisms remains almost uncharted. Here, we present a new individual-based model for the evolution of reciprocal cooperation between reputation and networks. We comparatively analyze four of the leading moral assessment rules—shunning, image scoring, stern judging, and simple standing—and base the model on the giving game in regular networks for Cooperators, Defectors, and Discriminators. Discriminators rely on a proper moral assessment rule. By using individual-based models, we show that the four assessment rules are differently characterized in terms of how cooperation evolves, depending on the benefit-to-cost ratio, the network-node degree, and the observation and error conditions. Our findings show that the most tolerant rule—simple standing—is the most robust among the four assessment rules in promoting cooperation in regular networks.

SRPX2 (Sushi repeat-containing protein, X-linked 2) has recently emerged as a multifunctional protein that is involved in seizure disorders, angiogenesis and cellular adhesion. Here, we analyzed this protein biochemically. SRPX2 protein was secreted with a highly posttranslational modification. Chondroitinase ABC treatment completely decreased the molecular mass of purified SRPX2 protein to its predicted size, whereas heparitinase, keratanase and hyaluroinidase did not. Secreted SRPX2 protein was also detected using an anti-chondroitin sulfate antibody. These results indicate that SRPX2 is a novel chondroitin sulfate proteoglycan (CSPG). Furthermore, a binding assay revealed that hepatocyte growth factor dose-dependently binds to SRPX2 protein, and a ligand-glycosaminoglycans interaction was speculated to be likely in proteoglycans. Regarding its molecular architecture, SRPX2 has sushi repeat modules similar to four other CSPGs/lecticans; however, the molecular architecture of SRPX2 seems to be quite different from that of the lecticans. Taken together, we found that SRPX2 is a novel CSPG that is overexpressed in gastrointestinal cancer cells. Our findings provide key glycobiological insight into SRPX2 in cancer cells and demonstrate that SRPX2 is a new member of the cancer-related proteoglycan family.

Gefitinib and erlotinib, small-molecule tyrosine kinase inhibitors (TKIs) of the epidermal growth factor receptor (EGFR), were the first molecularly targeted agents to become clinically available for the treatment of non-small cell lung cancer (NSCLC). During the course of their clinical development, it has become clear that the substantial clinical benefit associated with EGFR-TKIs is limited to patients harboring activating mutations of EGFR. Accumulating clinical outcomes in patients with EGFR mutation-positive NSCLC treated with EGFR-TKIs support the notion that this group of individuals constitutes a clinically distinct population. These findings have prompted investigations of the potential role of first-line treatment with EGFR-TKIs in molecularly selected patients, with platinum-based doublet chemotherapy currently being the standard of care for most individuals with advanced NSCLC. This review summarizes the results of recent clinical trials of EGFR-TKIs in selected patients and highlights the efficacy of these drugs in first-line treatment as a form of personalized medicine aimed at improving therapy for advanced NSCLC.