The angiogenic factor midkine is regulated by dexamethasone and retinoic acid during alveolarization and in alveolar epithelial cells

<p>Abstract</p> <p>Background</p> <p>A precise balance exists between the actions of endogenous glucocorticoids (GC) and retinoids to promote normal lung development, in particular during alveolarization. The mechanisms controlling this balance are largely unknown, but recent evidence suggests that midkine (MK), a retinoic acid-regulated, pro-angiogenic growth factor, may function as a critical regulator. The purpose of this study was to examine regulation of MK by GC and RA during postnatal alveolar formation in rats.</p> <p>Methods</p> <p>Newborn rats were treated with dexamethasone (DEX) and/or all-trans-retinoic acid (RA) during the first two weeks of life. Lung morphology was assessed by light microscopy and radial alveolar counts. MK mRNA and protein expression in response to different treatment were determined by Northern and Western blots. In addition, MK protein expression in cultured human alveolar type 2-like cells treated with DEX and RA was also determined.</p> <p>Results</p> <p>Lung histology confirmed that DEX treatment inhibited and RA treatment stimulated alveolar formation, whereas concurrent administration of RA with DEX prevented the DEX effects. During normal development, MK expression was maximal during the period of alveolarization from postnatal day 5 (PN5) to PN15. DEX treatment of rat pups decreased, and RA treatment increased lung MK expression, whereas concurrent DEX+RA treatment prevented the DEX-induced decrease in MK expression. Using human alveolar type 2 (AT2)-like cells differentiated in culture, we confirmed that DEX and cAMP decreased, and RA increased MK expression.</p> <p>Conclusion</p> <p>We conclude that MK is expressed by AT2 cells, and is differentially regulated by corticosteroid and retinoid treatment in a manner consistent with hormonal effects on alveolarization during postnatal lung development.</p

Molecular effects of Lapatinib in the treatment of HER2 overexpressing oesophago-gastric adenocarcinoma.

BACKGROUND: Lapatinib, a dual EGFR and HER2 inhibitor has shown disappointing results in clinical trials of metastatic oesophago-gastric adenocarcinomas (OGAs), and in vitro studies suggest that MET, IGFR, and HER3 confer resistance. This trial applied Lapatinib in the curative neoadjuvant setting and investigated the feasibility and utility of additional endoscopy and biopsy for assessment of resistance mechanisms ex vivo and in vivo. METHODS: Patients with HER2 overexpressing OGA were treated for 10 days with Lapatinib monotherapy, and then in combination with three cycles of Oxaliplatin and Capecitabine before surgery. Endoscopic samples were taken for molecular analysis at: baseline including for ex vivo culture +/- Lapatinib to predict in vivo response, post-Lapatinib monotherapy and at surgery. Immunohistochemistry (IHC) and proteomic analysis was performed to assess cell kinetics and signalling activity. RESULTS: The trial closed early (n=10) due to an anastomotic leak in two patients for which a causative effect of Lapatinib could not be excluded. The reduction in Phosphorylated-HER2 (P-HER2) and P-EGFR in the ex vivo-treated biopsy demonstrated good correlation with the in vivo response at day 10. Proteomic analysis pre and post-Lapatinib demonstrated target inhibition (P-ERBB2, P-EGFR, P-PI3K, P-AKT, and P-ERK) that persisted until surgery. There was also significant correlation between the activation of MET with the level of P-Erk (P=0.0005) and P-PI3K : T-PI3K (total PI3K) ratio (P=0.0037). There was no significant correlation between the activation status of IGFR and HER3 with downstream signalling molecules. CONCLUSIONS: Additional endoscopy and biopsy sampling for multiple biomarker endpoints was feasible and confirmed in vitro data that MET is likely to be a significant mechanism of Lapatinib resistance in vivo.This research was funded by the Medical Research Council [Grant SK002].This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/bjc.2015.34

Routine management, healthcare resource use and patient and carer‐reported outcomes of patients with transfusion‐dependent β‐thalassaemia in the United Kingdom: A mixed methods observational study

Abstract Objectives We evaluated routine healthcare management, clinical status and patient‐ and carer‐reported outcomes in UK paediatric and adult patients with transfusion‐dependent β‐thalassaemia (TDT). Methods A multi‐centre, observational mixed‐methodology study evaluated 165 patients (50% male; median age 24.1 [interquartile range (IQR)] 11.8–37.2] years) from nine UK centres. Results Patients had a mean of 13.7 (standard deviation [SD] ±3.2) transfusion episodes/year (mean retrospective observation period 4.7 [±0.7] years). The median (IQR) for iron overload parameters at the last assessment during the observation period were: serum ferritin (n = 165) 1961.0 (1090.0–3003.0) μg/L (38% > 2500 μg/L); R2 liver iron (n = 119) 5.4 (2.9–11.6) mg/g (16% ≥15 mg/g); T2* cardiac iron (n = 132) 30.3 (22.0–37.1) ms (10% < 10 ms). All patients received ≥1 iron chelator during the observation period; 21% received combination therapy. Patients had a mean of 7.8 (±8.1) non‐transfusion‐related hospital attendances or admissions/year. Adult patients’ mean EQ‐5D utility score was 0.69 (±0.33; n = 94 [≥16 years]) and mean Transfusion‐dependent quality of life score was 58.6 (±18.4; n = 94 [≥18 years]). For Work Productivity and Activity impairment, mean activity impairment for patients ≥18 years (n = 88) was 48% (±32%) and for carers (n = 29) was 28% (±23%). Conclusions TDT presents significant burden on patients, carers and healthcare resources