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In this article, we propose a new data-analytic approach to measure firms’ dyadic business proximity. Specifically, our method analyzes the unstructured texts that describe firms’ businesses using the statistical learning technique of topic modeling, and constructs a novel business proximity measure based on the output. When compared with existent methods, our approach is scalable for large datasets and provides finer granularity on quantifying firms’ positions in the spaces of product, market, and technology. We then validate our business proximity measure in the context of industry intelligence and show the measure’s effectiveness in an empirical application of analyzing mergers and acquisitions in the U.S. high technology industry. Based on the research, we also build a cloud-based information system to facilitate competitive intelligence on the high technology industry.

An unmet medical need exists for patients with metastatic renal cell carcinoma who have progressed on VEGF-targeted and mTOR-inhibitor therapies. Fibroblast growth factor (FGF) pathway activation has been proposed as a mechanism of escape from VEGF-targeted therapies. Dovitinib is an oral tyrosine-kinase inhibitor that inhibits VEGF and FGF receptors. We therefore compared dovitinib with sorafenib as third-line targeted therapies in patients with metastatic renal cell carcinoma. In this multicentre phase 3 study, patients with clear cell metastatic renal cell carcinoma who received one previous VEGF-targeted therapy and one previous mTOR inhibitor were randomly assigned through an interactive voice and web response system to receive open-label dovitinib (500 mg orally according to a 5-days-on and 2-days-off schedule) or sorafenib (400 mg orally twice daily) in a 1:1 ratio. Randomisation was stratified by risk group and region. The primary endpoint was progression-free survival (PFS) assessed by masked central review. Efficacy was assessed in all patients who were randomly assigned and safety was assessed in patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01223027. 284 patients were randomly assigned to the dovitinib group and 286 to the sorafenib group. Median follow-up was 11·3 months (IQR 7·9–14·6). Median PFS was 3·7 months (95% CI 3·5–3·9) in the dovitinib group and 3·6 months (3·5–3·7) in the sorafenib group (hazard ratio 0·86, 95% CI 0·72–1·04; one-sided p=0·063). 280 patients in the dovitinib group and 284 in the sorafenib group received at least one dose of study drug. Common grade 3 or 4 adverse events included hypertriglyceridaemia (38 [14%]), fatigue (28 [10%]), hypertension (22 [8%]), and diarrhoea (20 [7%]) in the dovitinib group, and hypertension (47 [17%]), fatigue (24 [8%]), dyspnoea (21 [7%]), and palmar-plantar erythrodysaesthesia (18 [6%]) in the sorafenib group. The most common serious adverse event was dyspnoea (16 [6%] and 15 [5%] in the dovitinib and sorafenib groups, respectively). Dovitinib showed activity, but this was no better than that of sorafenib in patients with renal cell carcinoma who had progressed on previous VEGF-targeted therapies and mTOR inhibitors. This trial provides reference outcome data for future studies of targeted inhibitors in the third-line setting. Novartis Pharmaceuticals Corporation.

Spontaneously hypertensive rats (SHR) are the most widely used animal model for the study of attention deficit hyperactivity disorder (ADHD). Here we sought to reveal the neuronal circuits and molecular basis of ADHD and its potential treatment using SHR. Combined electrophysiological, biochemical, pharmacological, chemicogenetic, and behavioral approaches were utilized. We found that AMPAR-mediated synaptic transmission in pyramidal neurons of prefrontal cortex (PFC) was diminished in SHR, which was correlated with the decreased surface expression of AMPAR subunits. Administration of methylphenidate (a psychostimulant drug used to treat ADHD), which blocks dopamine transporters and norepinephrine transporters, ameliorated the behavioral deficits of adolescent SHR and restored AMPAR-mediated synaptic function. Activation of PFC pyramidal neurons with a CaMKII-driven Gq-coupled designer receptor exclusively activated by designer drug also led to the elevation of AMPAR function and the normalization of ADHD-like behaviors in SHR. These results suggest that the disrupted function of AMPARs in PFC may underlie the behavioral deficits in adolescent SHR and enhancing PFC activity could be a treatment strategy for ADHD.

ObjectiveGastric cancer is a major gastrointestinal malignancy for which targeted therapies are emerging as treatment options. This study sought to identify the most prevalent molecular targets in gastric cancer and to elucidate systematic patterns of exclusivity and co-occurrence among these targets, through comprehensive genomic analysis of a large panel of gastric cancers.DesignUsing high-resolution single nucleotide polymorphism arrays, copy number alterations were profiled in a panel of 233 gastric cancers (193 primary tumours, 40 cell lines) and 98 primary matched gastric non-malignant samples. For selected alterations, their impact on gene expression and clinical outcome were evaluated.Results22 recurrent focal alterations (13 amplifications and nine deletions) were identified. These included both known targets (FGFR2, ERBB2) and also novel genes in gastric cancer (KLF5, GATA6). Receptor tyrosine kinase (RTK)/RAS alterations were found to be frequent in gastric cancer. This study also demonstrates, for the first time, that these alterations occur in a mutually exclusive fashion, with KRAS gene amplifications highlighting a clinically relevant but previously underappreciated gastric cancer subgroup. FGFR2-amplified gastric cancers were also shown to be sensitive to dovitinib, an orally bioavailable FGFR/VEGFR targeting agent, potentially representing a subtype-specific therapy for FGFR2-amplified gastric cancers.ConclusionThe study demonstrates the existence of five distinct gastric cancer patient subgroups, defined by the signature genomic alterations FGFR2 (9% of tumours), KRAS (9%), EGFR (8%), ERBB2 (7%) and MET (4%). Collectively, these subgroups suggest that at least 37% of gastric cancer patients may be potentially treatable by RTK/RAS directed therapies.

Savolitinib combined with osimertinib is a potential novel therapy for patients with EGFR mutation-positive non-small-cell lung cancer (NSCLC) harbouring MET amplification after progression on EGFR tyrosine kinase inhibitor (TKI) therapy. We aimed to evaluate the efficacy and safety of savolitinib–osimertinib versus standard of care platinum-based doublet chemotherapy in this patient population. SACHI was a multicentre, randomised, active-controlled, open-label, phase 3 trial conducted across 68 Chinese hospitals. Eligible adults with locally advanced or metastatic EGFR mutation-positive NSCLC and MET amplification after EGFR TKI failure were randomly assigned (1:1) to once daily oral savolitinib–osimertinib or intravenous chemotherapy (pemetrexed plus either cisplatin or carboplatin), both in 21-day cycles. Central randomisation was implemented through an interactive web-response system with stratification based on the presence of brain metastases, previous exposure to third-generation EGFR TKIs, and EGFR mutation subtype, using a mixed block-size methodology. The primary endpoint, investigator-assessed progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumours version 1.1, was tested using a hierarchical procedure: first in the third-generation EGFR TKI-naive population, and if positive, the intention-to-treat (ITT) population. Safety analysis was performed in all patients who received at least one dose of the study treatment. Interim analysis data cutoff was Aug 30, 2024. This study is registered with ClinicalTrials.gov (NCT05015608) and is complete. Between Oct 15, 2021, and Aug 30, 2024, 211 patients were enrolled, 106 were randomly assigned to savolitinib–osimertinib and 105 were randomly assigned to chemotherapy, including 137 (65%) of 211 who were third-generation EGFR TKI-naive (69 in the savolitinib–osimertinib group; 68 in the chemotherapy group). In 106 patients in the savolitinib–osimertinib group, the median age was 59·4 years (IQR 54·3–65·8), 62 (58%) were female, and 44 (42%) were male. In 105 patients in the chemotherapy group, the median age was 61·9 years (IQR 56·3–69·1), 55 (52%) were female, and 50 (48%) were male. All participants were Asian. Median PFS was significantly prolonged with savolitinib–osimertinib versus chemotherapy in the third-generation EGFR TKI-naive (9·8 months [95% CI 6·9–12·5] vs 5·4 months [4·2–6·0]; hazard ratio 0·34 [0·21–0·56]; p<0·0001) and ITT populations (8·2 months [6·9–11·2] vs 4·5 months [3·0–5·4]; 0·34 [0·23–0·49]; p<0·0001). Grade 3 or worse treatment-emergent adverse events occurred in the same proportion of patients in both groups who received the study drugs (60 [57%] of 106 patients in the savolitinib–osimertinib group and 55 [57%] of 96 patients in the chemotherapy group). The savolitinib–osimertinib combination improved PFS versus chemotherapy in patients with EGFR mutation-positive, MET-amplified NSCLC that had progressed on EGFR TKI therapy, while maintaining a favourable tolerability profile. This regimen offers a potential oral treatment option for this biomarker-selected population. HUTCHMED and AstraZeneca.

Interleukin 18 function in atherosclerosis is mediated by the interleukin 18 receptor and the Na-Cl co-transporter. Interleukin-18 (IL18) participates in atherogenesis through several putative mechanisms 1 , 2 . Interruption of IL18 action reduces atherosclerosis in mice 3 , 4 . Here, we show that absence of the IL18 receptor (IL18r) does not affect atherosclerosis in apolipoprotein E–deficient ( Apoe −/− ) mice, nor does it affect IL18 cell surface binding to or signaling in endothelial cells. As identified initially by co-immunoprecipitation with IL18, we found that IL18 interacts with the Na-Cl co-transporter (NCC; also known as SLC12A3), a 12-transmembrane-domain ion transporter protein preferentially expressed in the kidney 5 . NCC is expressed in atherosclerotic lesions, where it colocalizes with IL18r. In Apoe −/− mice, combined deficiency of IL18r and NCC, but not single deficiency of either protein, protects mice from atherosclerosis. Peritoneal macrophages from Apoe −/− mice or from Apoe −/− mice lacking IL18r or NCC show IL18 binding and induction of cell signaling and cytokine and chemokine expression, but macrophages from Apoe −/− mice with combined deficiency of IL18r and NCC have a blunted response. An interaction between NCC and IL18r on macrophages was detected by co-immunoprecipitation. IL18 binds to the cell surface of NCC-transfected COS-7 cells, which do not express IL18r, and induces cell signaling and cytokine expression. This study identifies NCC as an IL18-binding protein that collaborates with IL18r in cell signaling, inflammatory molecule expression, and experimental atherogenesis.

Recently, mobile applications have offered users the option to share their location information with friends. Using data from a major location-based social networking application in China, we estimate an empirical model of restaurant discovery and observational learning. The unique feature of repeat customer visits in the data allows us to examine observational learning in trials and repeats and to separate it from non-informational confounding mechanisms, such as homophily, using a novel test based on the empirical model. The empirical evidence supports a strong observational learning effect. We also find that the moderating role of the geographical locations of users and their friends on the magnitude of observational learning is critical. These findings suggest a nuanced view for local merchants to boost observational learning with the advancement of location-based technology. The online appendix is available at https://doi.org/10.1287/isre.2017.0769 .

Immunoglobulin E (IgE) activates mast cells (MCs). It remains unknown whether IgE also activates other inflammatory cells, and contributes to the pathogenesis of abdominal aortic aneurysms (AAAs). This study demonstrates that CD4 + T cells express IgE receptor FcεR1, at much higher levels than do CD8 + T cells. IgE induces CD4 + T‐cell production of IL6 and IFN‐γ, but reduces their production of IL10. FcεR1 deficiency ( Fcer1a −/− ) protects apolipoprotein E‐deficient ( Apoe −/− ) mice from angiotensin‐II infusion‐induced AAAs and reduces plasma IL6 levels. Adoptive transfer of CD4 + T cells (but not CD8 + T cells), MCs, and macrophages from Apoe −/− mice, but not those from Apoe −/− Fcer1a −/− mice, increases AAA size and plasma IL6 in Apoe −/− Fcer1a −/− recipient mice. Biweekly intravenous administration of an anti‐IgE monoclonal antibody ablated plasma IgE and reduced AAAs in Apoe −/− mice. Patients with AAAs had significantly higher plasma IgE levels than those without AAAs. This study establishes an important role of IgE in AAA pathogenesis by activating CD4 + T cells, MCs, and macrophages and supports consideration of neutralizing plasma IgE in the therapeutics of human AAAs. Synopsis This study demonstrates the pathologic role of IgE and its high affinity receptor FcεR1 in AAAs by activating MCs, macrophages but also CD4 and CD8 T cells and suggests anti‐IgE antibodies as future putative therapeutics for treatment. IgE is expressed in MCs, macrophages, and CD4 + and CD8 + T cells in human AAA lesions. Genetic depletion of IgE high affinity receptor FcεR1 protects mice from AAA formation. Reduced AAAs in FcεR1‐deficient mice can be reversed to different extent after mice receiving donor MCs, macrophages, and CD4 + T cells from wild‐type mice but not those from FcεR1‐deficient mice. Interruption of IgE‐FcεR1 interaction with an anti‐IgE antibody achieves similar AAA inhibitory effect to that from FcεR1‐deficient mice. Graphical Abstract This study demonstrates the pathologic role of IgE and its high affinity receptor FcεR1 in AAAs by activating MCs, macrophages but also CD4 and CD8 T cells and suggests anti‐IgE antibodies as future putative therapeutics for treatment.

Background Overexpression of fibroblast growth factor receptor 1 (FGFR1), found in ≤8% of hormone receptor–positive (HR + ), human epidermal growth factor receptor 2–negative (HER2 − ) breast cancer cases, is correlated with decreased overall survival and resistance to endocrine therapy (ET). Dovitinib, a potent FGFR inhibitor, has demonstrated antitumor activity in heavily pretreated patients with FGFR pathway–amplified breast cancer. Methods In this randomized, placebo-controlled phase II trial, we evaluated whether the addition of dovitinib to fulvestrant would improve outcomes in postmenopausal patients with HR + , HER2 − advanced breast cancer that had progressed during or after prior ET. Patients were stratified by FGF pathway amplification and presence of visceral disease, and they were randomized 1:1 to receive fulvestrant plus dovitinib or placebo. The primary endpoint was progression-free survival (PFS). Results From 15 May 2012 to 26 November 2014, 97 patients from 36 centers were enrolled. The frequency of FGF pathway amplification was lower than anticipated, and the study was terminated early owing to slow accrual of patients with FGF pathway amplification. The median PFS (95% CI) was 5.5 (3.8–14.0) months vs 5.5 (3.5–10.7) months in the dovitinib vs placebo arms, respectively (HR, 0.68; did not meet predefined efficacy criteria). For the FGF pathway–amplified subgroup ( n  = 31), the median PFS (95% CI) was 10.9 (3.5–16.5) months vs 5.5 (3.5–16.4) months in the dovitinib vs placebo arms, respectively (HR, 0.64; met the predefined superiority criteria). Frequently reported adverse events in the dovitinib (diarrhea, nausea, vomiting, asthenia, and headache) and placebo (diarrhea, fatigue, nausea, and asthenia) arms were mostly low grade. Conclusions The safety profile of dovitinib plus fulvestrant was consistent with the known safety profile of single-agent dovitinib. Dovitinib in combination with fulvestrant showed promising clinical activity in the FGF pathway – amplified subgroup. However, the data reported herein should be interpreted with caution, given that fewer PFS events occurred in the FGF pathway–amplified patients than was expected and that an effect of dovitinib regardless of FGR pathway amplification status cannot be excluded, because the population was smaller than expected. Trial registration ClinicalTrials.gov identifier: NCT01528345 . Registered 31 January 2012.

Background Combining the programmed death-1 inhibitor toripalimab and the angio-immuno kinase inhibitor surufatinib showed preliminary antitumor activity in patients with advanced solid tumors in a phase I study. Here, we report the efficacy and safety of this combination regimen in treatment-naive advanced or metastatic non-small-cell lung cancer (NSCLC) patients with a programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) of 1% or greater (PD-L1-positive) and patients with previously treated small-cell lung cancer (SCLC). Methods This open-label, single-arm phase II study included patients with treatment-naive advanced or metastatic PD-L1-positive NSCLC or previously treated SCLC in China. Patients received surufatinib (250 mg orally, once daily) plus toripalimab (240 mg intravenously, once every 3 weeks). Primary endpoint was investigator-assessed objective response rate (ORR) per RECIST v1.1. Secondary endpoints included duration of response (DoR), disease control rate, progression-free survival (PFS), overall survival (OS), and safety. Results Forty-three patients were treated (NSCLC cohort, n  = 23; SCLC cohort, n  = 20). ORRs (95% CIs) were 57.1% (34.0–78.2) in the NSCLC cohort and 15.8% (3.4–39.6) in the SCLC cohort. Median duration of response was not reached (NR) in both cohorts. Median PFS was 9.6 (5.5–NR) and 3.0 months (2.8–4.1), respectively, and median OS was 24.3 (10.8–NR) and 11.0 months (5.0–15.7), respectively. Grade ≥ 3 treatment-related adverse events were reported in 24 patients (55.8%) overall. Conclusion Surufatinib plus toripalimab showed encouraging antitumor activity and a tolerable safety profile in patients with treatment-naive advanced or metastatic PD-L1-positive NSCLC and previously treated SCLC.