Increased coronary blood vessel development could potentially benefit patients with ischemic heart disease. In a model of stress-induced myocardial ischemia, intracoronary injection of a recombinant adenovirus expressing human fibroblast growth factor-5 (FGF-5) resulted in messenger RNA and protein expression of the transferred gene. Two weeks after gene transfer, regional abnormalities in stress-induced function and blood flow were improved, effects that persisted for 12 weeks. Improved blood flow and function were associated with evidence of angiogenesis. This report documents, for the first time, successful amelioration of abnormalities in myocardial blood flow and function following in vivo gene transfer.

Purpose In a recent phase II study of onartuzumab (MetMAb), patients whose non–small cell lung cancer (NSCLC) tissue scored as positive for MET protein by immunohistochemistry (IHC) experienced a significant benefit with onartuzumab plus erlotinib (O+E) versus erlotinib. We describe development and validation of a standardized MET IHC assay and, retrospectively, evaluate multiple biomarkers as predictors of patient benefit. Experimental Design Biomarkers related to MET and/or EGF receptor (EGFR) signaling were measured by IHC, FISH, quantitative reverse transcription PCR, mutation detection techniques, and ELISA. Results A positive correlation between IHC, Western blotting, and MET mRNA expression was observed in NSCLC cell lines/tissues. An IHC scoring system of MET expression taking proportional and intensity-based thresholds into consideration was applied in an analysis of the phase II study and resulted in the best differentiation of outcomes. Further analyses revealed a nonsignificant overall survival (OS) improvement with O+E in patients with high MET copy number (mean ≥5 copies/cell by FISH); however, benefit was maintained in “MET IHC-positive”/MET FISH-negative patients (HR, 0.37; P = 0.01). MET, EGFR, amphiregulin, epiregulin, or HGF mRNA expression did not predict a significant benefit with onartuzumab; a nonsignificant OS improvement was observed in patients with high tumor MET mRNA levels (HR, 0.59; P = 0.23). Patients with low baseline plasma hepatocyte growth factor (HGF) exhibited an HR for OS of 0.519 (P = 0.09) in favor of onartuzumab treatment. Conclusions MET IHC remains the most robust predictor of OS and progression-free survival benefit from O+E relative to all examined exploratory markers.

PurposeTumors with oncogenic dependencies on the HER family of receptor tyrosine kinases (RTKs) often respond well to targeted inhibition. Our previous work suggested that many cell lines derived from squamous cell carcinomas of the head and neck (SCCHNs) depend on autocrine signaling driven by HER2/3 dimerization and high-level co-expression of HRG. Additionally, results from a Phase I trial of MEHD7495A, a dual-action antibody that blocks ligand binding to EGFR and HER3, suggest that high-level HRG expression was associated with clinical response in SCCHN patients. Here we explore the hypothesis that high-level HRG expression defines a subpopulation of SCCHNs with activated HER3.Experimental DesignqRT-PCR expression profiling was performed on >750 tumors of diverse origin, including >150 therapy-naïve, primary, and recurrent SCCHNs. Activated HER3, defined by immunoprecipitation of phospho-HER3, was compared to HRG expression in SCCHN samples. Paracrine versus autocrine expression was evaluated using RNA-in situ hybridization.ResultsSCCHN tumors express the highest levels of HRG compared to a diverse collection of other tumor types. We show that high HRG expression is associated with activated HER3, whereas low HRG expression is associated with low HER3 activation in SCCHN tumors. Furthermore, HRG expression is higher in recurrent SCCHN compared to patient-matched therapy naïve specimens.Conclusions HRG expression levels define a biologically distinct subset of SCCHN patients. We propose that high-level expression of HRG is associated with constitutive activation of HER3 in SCCHN and thus defines an actionable biomarker for interventions targeting HER3.

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Aims In order to determine acute cardiac involvement in patients with COVID-19, we quantitatively evaluated tissue characteristics and mechanics by non-invasive cardiac magnetic resonance (CMR) in a cohort of patients within the first 10 days of the onset of COVID symptoms. Methods and results Twenty-five patients with reverse transcription polymerase chain reaction confirmed COVID-19 and at least one marker of cardiac involvement [cardiac symptoms, abnormal electrocardiograph (ECG), or abnormal cardiac biomarkers] and 25 healthy age- and gender-matched control subjects were recruited to the study. Patients were divided into those with elevated (n = 8) or normal TnI (n = 17). There were significant differences in global longitudinal strain among patients who were positive and negative for hs-TnI, and controls [−12.3 (−13.3, −11.5)%, −13.1 (−14.2, −9.8)%, and −15.7 (−18.3, −12.7)%, P = 0.004]. Native myocardial T1 relaxation times in patients with positive and negative hs-TnI manifestation (1169.8 ± 12.9 and 1113.2 ± 31.2 ms) were significantly higher than the normal (1065 ± 57 ms) subjects, respectively (P < 0.001). The extracellular volume (ECV) of patients who were positive and negative for hs-TnI was higher than that of the normal controls [32 (31, 33)%, 29 (27, 30)%, and 26 (24, 27.5)%, P < 0.001]. In our study, quantitative T2 mapping in patients who were positive and negative for hs-TnI [51 (47.9, 52.8) and 48 (47, 49.4) ms] was significantly higher than the normal [42 (41, 45.2) ms] subjects (P < 0.001). Conclusion In patients with early-stage COVID-19, myocardial oedema, and functional abnormalities are a frequent finding, while irreversible regional injury such as necrosis may be infrequent.