Radiative equilibrium models of the Jovian atmosphere calculated by Hogan, Rasool, and Encrenaz (1969) and by Cess and Khetan (1973) are shown to be in conflict. A new calculation is presented which agrees closely with that of Cess and Khetan. This model, however, fails to predict the observed intensity in the 7.8-micron methane band by about a factor of 8. It is shown that the observed emission intensity in the 7.8-micron band is a critical test of these models. The Pioneer 10 occultation profile is at variance with the models. The emission intensity at 7.8 microns implied by the Pioneer 10 result is shown to be 100 times greater than observed. It is concluded that the Pioneer 10 temperature profile is not representative of the global average.-

Introduction

Patients with advanced-stage non-small cell lung cancer (NSCLC) and borderline performance status (performance status 2 [PS2]) are often excluded from clinical trials and platinum-based therapy. In light of the potential role for serum proteomics in predicting the benefit of erlotinib beyond that of epidermal growth factor receptor gene (EGFR) mutational status, we conducted a trial in which the Veristrat proteomics assay was used for data enrichment when selecting a cohort of patients with NSCLC and PS2 to receive erlotinib with and without chemotherapy.

Methods

Patients with metastatic NSCLC, PS2, acceptable end-organ function, and Veristrat-good status were randomly assigned to receive either 150 mg of erlotinib orally daily (arm 1) or 150 mg of erlotinib orally daily on days 2 through16 plus four cycles of carboplatin (area under the curve = 5 on day 1) and paclitaxel (200 mg/m(2) intravenously on day 1) followed by 150 mg of erlotinib orally (arm 2). The arm 2 agents were pharmacodynamically separated to mitigate potential antagonism. The arm with superior observed median progression-free survival (PFS) would be selected for further evaluation, but only if PFS lasted for at least 3 months.

Results

The trial terminated before the planned accrual of 98 patients for regulatory reasons. A total of 156 patients were screened. Of the 83 (59%) who were classified as Veristrat good, 59 met the trial eligibility criteria and were randomly assigned to one of two arms (33 patients in arm 1 and 26 in arm 2). The patients in arm 2 patients had a higher response rate (23% versus 6%, p = 0.06), disease control rate (77% versus 41%, p = 0.0046), median PFS (4.6 versus 1.6 months, p = 0.06), and median overall survival (11 versus 6 months, p = 0.27). Treatment-related grade 4 adverse events were seen in two patients in arm 1 (thrombosis and hypomagnesemia) and in five patients in arm 2 (neutropenia in five, febrile neutropenia in one, and leukopenia in one).

Conclusions

In a proteomics-enriched cohort of patients with NSCLC and PS2, pharmacodynamically separated erlotinib plus chemotherapy had better efficacy than did erlotinib alone and surpassed the protocol-specified benchmark of PFS of at least 3 months required for further study.

Cholangiocytes, bile duct lining cells, actively adjust the amount of cholesterol and bile acids in bile through expression of enzymes and channels involved in transportation and metabolism of the cholesterol and bile acids. Herein, we report molecular mechanisms regulating bile acid biosynthesis in cholangiocytes. Among the cytochrome p450 (Cyp) enzymes involved in bile acid biosynthesis, sterol 27-hydroxylase (Cyp27) that is the rate-limiting enzyme for the acidic pathway of bile acid biosynthesis expressed in cholangiocytes. Expression of other Cyp enzymes for the basic bile acid biosynthesis was hardly detected. The Cyp27 expression was negatively regulated by a hydrophobic bile acid through farnesoid X receptor (FXR), a nuclear receptor activated by bile acid ligands. Activated FXR exerted the negative effects by inducing an expression of fibroblast growth factor 15/19 (FGF15/19). Similar to its repressive function against cholesterol 7α-hydroxylase (Cyp7a1) expression in hepatocytes, secreted FGF15/19 triggered Cyp27 repression in cholangiocytes through interaction with its cognate receptor fibroblast growth factor receptor 4 (FGFR4). The involvements of FXR and FGFR4 for the bile acid-induced Cyp27 repression were confirmed in vivo using knockout mouse models. Different from the signaling in hepatocytes, wherein the FGF15/19-induced repression signaling is mediated by c-Jun N-terminal kinase (JNK), FGF15/19-induced Cyp27 repression in cholangiocytes was mediated by p38 kinase. Thus, the results collectively suggest that cholangiocytes may be able to actively regulate bile acid biosynthesis in cholangiocytes and even hepatocyte by secreting FGF15/19. We suggest the presence of cholangiocyte-mediated intrahepatic feedback loop in addition to the enterohepatic feedback loop against bile acid biosynthesis in the liver.

Introduction

The TIGER-3 (NCT02322281) study was initiated to compare the efficacy and safety of rociletinib, a third-generation EGFR tyrosine kinase inhibitor (TKI) that targets EGFR T790M and common EGFR-activating mutations, versus chemotherapy in patients with NSCLC who progressed on first- or second-generation EGFR TKIs.

Methods

Patients with advanced or metastatic EGFR-mutated NSCLC with disease progression on standard therapy (previous EGFR TKI and platinum-based chemotherapy) were randomized to oral rociletinib (500 or 625 mg twice daily) or single-agent chemotherapy (pemetrexed, gemcitabine, docetaxel, or paclitaxel).

Results

Enrollment was halted when rociletinib development was discontinued in 2016. Of 149 enrolled patients, 75 were randomized to rociletinib (n = 53: 500 mg twice daily; n = 22: 625 mg twice daily) and 74 to chemotherapy. The median investigator-assessed progression-free survival (PFS) was 4.1 months (95% confidence interval [CI]: 2.6-5.4) in the rociletinib 500-mg group and 5.5 months (95% CI: 1.8-8.1) in the 625-mg group versus 2.5 months (95% CI: 1.4-2.9) in the chemotherapy group. An improved PFS was observed in patients with T790M-positive NSCLC treated with rociletinib (n = 25; 500 mg and 625 mg twice daily) versus chemotherapy (n = 20; 6.8 versus 2.7 mo; hazard ratio = 0.55, 95% CI: 0.28-1.07, p = 0.074). Grade 3 or higher hyperglycemia (24.0%), corrected QT prolongation (6.7%), diarrhea (2.7%), and vomiting (1.3%) were more frequent with rociletinib than chemotherapy (0%, 0%, 1.4%, and 0%, respectively).

Conclusions

Rociletinib had a more favorable median PFS versus chemotherapy but had higher rates of hyperglycemia and corrected QT prolongation in patients with advanced EGFR-mutated NSCLC who progressed on previous EGFR TKI. Incomplete enrollment prevented evaluation of the primary efficacy end point.

After sequential treatment with first- and third-generation EGFR tyrosine kinase inhibitors (TKIs), EGFR-mutant non-small cell lung cancers frequently harbor multiple resistance mutations in exon 20 of EGFR including T790M, mediating resistance to first-generation TKIs, and at codons 792, 796, or 797 mediating resistance to third-generation TKIs. However, whether these resistance mutations are in cis or trans has therapeutic implications for patients. We analyzed a cohort of 29 patients with NSCLC harboring EGFR mutations at codons 792, 796, or 797 to establish the configuration of these mutations. We performed hybrid capture-based, next-generation sequencing on formalin-fixed paraffin-embedded biopsy tissue or liquid biopsy. 27 samples had both a T790M mutation and a mutation at codons 792, 796, or 797. In all of these cases, the mutations were found in the cis configuration; the trans configuration was not observed. Two patients' samples harbored a mutation at codon 797 but no T790M mutation. In these two cases, longitudinal analysis showed earlier biopsies harbored EGFR T790M, which was undetectable following osimertinib treatment. Treatment of one these patients with both first- and third-generation EGFR TKIs resulted in a mixed response. Here we describe multiple configurations of EGFR T790M and third-generation TKI resistance mutations at codons 792, 796, and 797. These mutations are most commonly found in cis, which confers resistance to all current EGFR TKIs. We also describe two patients that exhibited T790M loss with acquisition of a mutation at codon 797. In addition, one of these patients, with an EGFR C797S in a lung biopsy was subsequently found to have EGFR C797N in a later biopsy of pleural fluid, highlighting the dynamic multiclonal nature of advanced NSCLC.

Purpose Concurrent chemoradiotherapy is standard treatment for patients with stage III non-small-cell lung cancer. Elderly patients may experience increased rates of adverse events (AEs) or less benefit from concurrent chemoradiotherapy. Patients and Methods Individual patient data were collected from 16 phase II or III trials conducted by US National Cancer Institute-supported cooperative groups of concurrent chemoradiotherapy alone or with consolidation or induction chemotherapy for stage III non-small-cell lung cancer from 1990 to 2012. Overall survival (OS), progression-free survival, and AEs were compared between patients age ≥ 70 (elderly) and those younger than 70 years (younger). Unadjusted and adjusted hazard ratios (HRs) for survival time and CIs were estimated by single-predictor and multivariable frailty Cox models. Unadjusted and adjusted odds ratio (ORs) for AEs and CIs were obtained from single-predictor and multivariable generalized linear mixed-effect models. Results A total of 2,768 patients were classified as younger and 832 as elderly. In unadjusted and multivariable models, elderly patients had worse OS (HR, 1.20; 95% CI, 1.09 to 1.31 and HR, 1.17; 95% CI, 1.07 to 1.29, respectively). In unadjusted and multivariable models, elderly and younger patients had similar progression-free survival (HR, 1.01; 95% CI, 0.93 to 1.10 and HR, 1.00; 95% CI, 0.91 to 1.09, respectively). Elderly patients had a higher rate of grade ≥ 3 AEs in unadjusted and multivariable models (OR, 1.35; 95% CI, 1.07 to 1.70 and OR, 1.38; 95% CI, 1.10 to 1.74, respectively). Grade 5 AEs were significantly higher in elderly compared with younger patients (9% v 4%; P < .01). Fewer elderly compared with younger patients completed treatment (47% v 57%; P < .01), and more discontinued treatment because of AEs (20% v 13%; P < .01), died during treatment (7.8% v 2.9%; P < .01), and refused further treatment (5.8% v 3.9%; P = .02). Conclusion Elderly patients in concurrent chemoradiotherapy trials experienced worse OS, more toxicity, and had a higher rate of death during treatment than younger patients.

During the Laser Interferometer Gravitational-wave Observatory and Virgo joint science runs in 2009-2010, gravitational wave (GW) data from three interferometer detectors were analyzed within minutes to select GW candidate events and infer their apparent sky positions. Target coordinates were transmitted to several telescopes for follow-up observations aimed at the detection of an associated optical transient. Images were obtained for eight such GW candidates. We present the methods used to analyze the image data as well as the transient search results. No optical transient was identified with a convincing association with any of these candidates, and none of the GW triggers showed strong evidence for being astrophysical in nature. We compare the sensitivities of these observations to several model light curves from possible sources of interest, and discuss prospects for future joint GW-optical observations of this type. © 2014. The American Astronomical Society. All rights reserved.