Effect of antenatal corticosteroids on fetal growth and gestational age at birth.

OBJECTIVE: To estimate the effect of multiple courses of antenatal corticosteroids on neonatal size, controlling for gestational age at birth and other confounders, and to determine whether there was a dose-response relationship between number of courses of antenatal corticosteroids and neonatal size. METHODS: This is a secondary analysis of the Multiple Courses of Antenatal Corticosteroids for Preterm Birth Study, a double-blind randomized controlled trial of single compared with multiple courses of antenatal corticosteroids in women at risk for preterm birth and in which fetuses administered multiple courses of antenatal corticosteroids weighed less, were shorter, and had smaller head circumferences at birth. All women (n=1,858) and children (n=2,304) enrolled in the Multiple Courses of Antenatal Corticosteroids for Preterm Birth Study were included in the current analysis. Multiple linear regression analyses were undertaken. RESULTS: Compared with placebo, neonates in the antenatal corticosteroids group were born earlier (estimated difference and confidence interval [CI]: -0.428 weeks, CI -0.10264 to -0.75336; P=.01). Controlling for gestational age at birth and confounding factors, multiple courses of antenatal corticosteroids were associated with a decrease in birth weight (-33.50 g, CI -66.27120 to -0.72880; P=.045), length (-0.339 cm, CI -0.6212 to -0.05676]; P=.019), and head circumference (-0.296 cm, -0.45672 to -0.13528; P<.001). For each additional course of antenatal corticosteroids, there was a trend toward an incremental decrease in birth weight, length, and head circumference. CONCLUSION: Fetuses exposed to multiple courses of antenatal corticosteroids were smaller at birth. The reduction in size was partially attributed to being born at an earlier gestational age but also was attributed to decreased fetal growth. Finally, a dose-response relationship exists between the number of corticosteroid courses and a decrease in fetal growth. The long-term effect of these findings is unknown. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00187382. LEVEL OF EVIDENCE: II.

Oral epidermal growth factor receptor tyrosine kinase inhibitors for the treatment of non-small cell lung cancer: comparative pharmacokinetics and drug-drug interactions.

The development of orally active small molecule inhibitors of the epidermal growth factor receptor (EGFR) has led to new treatment options for non-small cell lung cancer (NSCLC). Patients with activating mutations of the EGFR gene show sensitivity to, and clinical benefit from, treatment with EGFR tyrosine kinase inhibitors (EGFR-TKls). First generation reversible ATP-competitive EGFR-TKls, gefitinib and erlotinib, are effective as first, second-line or maintenance therapy. Despite initial benefit, most patients develop resistance within a year, 50-60% of cases being related to the appearance of a T790M gatekeeper mutation. Newer, irreversible EGFR-TKls - afatinib and dacomitinib - covalently bind to and inhibit multiple receptors in the ErbB family (EGFR, HER2 and HER4). These agents have been mainly evaluated for first-line treatment but also in the setting of acquired resistance to first-generation EGFR-TKls. Afatinib is the first ErbB family blocker approved for patients with NSCLC with activating EGFR mutations; dacomitinib is in late stage clinical development. Mutant-selective EGFR inhibitors (AZD9291, CO-1686, HM61713) that specifically target the T790M resistance mutation are in early development. The EGFR-TKIs differ in their spectrum of target kinases, reversibility of binding to EGFR receptor, pharmacokinetics and potential for drug-drug interactions, as discussed in this review. For the clinician, these differences are relevant in the setting of polymedicated patients with NSCLC, as well as from the perspective of innovative anticancer drug combination strategies.

Leukemic cluster growth in culture is an independent risk factor for acute myeloid leukemia and short survival in patients with myelodysplastic syndrome.

In patients with myelodysplastic syndrome (MDS) precursor cell cultures (colony-forming unit cells, CFU-C) can provide an insight into the growth potential of malignant myeloid cells. In a retrospective single-center study of 73 untreated MDS patients we assessed whether CFU-C growth patterns were of prognostic value in addition to established criteria. Abnormalities were classified as qualitative (i.e. leukemic cluster growth) or quantitative (i.e. strongly reduced/absent growth). Thirty-nine patients (53%) showed leukemic growth, 26 patients (36%) had strongly reduced/absent colony growth, and 12 patients showed both. In a univariate analysis the presence of leukemic growth was associated with strongly reduced survival (at 10 years 4 vs. 34%, p = 0.004), and a high incidence of transformation to AML (76 vs. 32%, p = 0.01). Multivariate analysis identified leukemic growth as a strong and independent predictor of early death (relative risk 2.12, p = 0.03) and transformation to AML (relative risk 2.63, p = 0.04). Quantitative abnormalities had no significant impact on the disease course. CFU-C assays have a significant predictive value in addition to established prognostic factors in MDS. Leukemic growth identifies a subpopulation of MDS patients with poor prognosis.

Introduction of Trojan sex chromosomes to boost population growth.

Conservation programs that deal with small or declining populations often aim at a rapid increase of population size to above-critical levels in order to avoid the negative effects of demographic stochasticity and genetic problems like inbreeding depression, fixation of deleterious alleles, or a general loss of genetic variability and hence of evolutionary potential. In some situations, population growth is determined by the number of females available for reproduction, and manipulation of family sex ratios towards more daughters has beneficial effects. If sex determination is predominantly genetic but environmentally reversible, as is the case in many amphibia, reptiles, and fish, Trojan sex chromosomes could be introduced into populations in order to change sex ratios towards more females. We analyse the possible consequences for the introduction of XX-males (XX individuals that have been changed to phenotypic males in a XY/XX sex determination system) and ZW males, WW males, or WW females (in a ZZ/ZW sex determination system). We find that the introduction of WW individuals can be most effective for an increase of population growth, especially if the induced sex change has little or no effect on viability.

Absence of mTOR Inhibitor Effect on Hepatic Cyst Growth: A Case Report of a Kidney Transplant Recipient with Autosomal Dominant Polycystic Kidney Disease.

Some experimental studies have suggested a beneficial effect of the mammalian target of rapamycin (mTOR) inhibitor use on hepatic and renal cyst growth in patients with autosomal dominant polycystic kidney disease (ADPKD). However, the results of clinical studies are conflicting and the role of mTOR inhibitors is still uncertain. We report the case of a patient with ADPKD who underwent deceased kidney transplantation because of an end-stage renal disease. The evolution was uneventful with an excellent graft function under cyclosporine (CsA) monotherapy. Some years later, the patient developed a symptomatic hepatomegaly due to growth of cysts. CsA was replaced by sirolimus, an mTOR inhibitor, in order to reduce or control the increase in the cyst and liver volume. Despite the switch, the hepatic volume increased by 25% in two years. Finally sirolimus was stopped because of the lack of effect on hepatic cyst growth and the presence of sirolimus side effects. The interest of our case resides in the followup by MRI imaging during the mTOR inhibitor treatment and 15 months after the restart of the initial immunosuppressive therapy. This observation indicates that mTOR inhibitors did not have significant effect on cyst-associated hepatic growth in our patient, which is consistent with some results of recent large clinical studies.

The nuclear receptor DHR3 modulates dS6 kinase-dependent growth in Drosophila.

S6 kinases (S6Ks) act to integrate nutrient and insulin signaling pathways and, as such, function as positive effectors in cell growth and organismal development. However, they also have been shown to play a key role in limiting insulin signaling and in mediating the autophagic response. To identify novel regulators of S6K signaling, we have used a Drosophila-based, sensitized, gain-of-function genetic screen. Unexpectedly, one of the strongest enhancers to emerge from this screen was the nuclear receptor (NR), Drosophila hormone receptor 3 (DHR3), a critical constituent in the coordination of Drosophila metamorphosis. Here we demonstrate that DHR3, through dS6K, also acts to regulate cell-autonomous growth. Moreover, we show that the ligand-binding domain (LBD) of DHR3 is essential for mediating this response. Consistent with these findings, we have identified an endogenous DHR3 isoform that lacks the DBD. These results provide the first molecular link between the dS6K pathway, critical in controlling nutrient-dependent growth, and that of DHR3, a major mediator of ecdysone signaling, which, acting together, coordinate metamorphosis.

Fas ligand-induced proinflammatory transcriptional responses in reconstructed human epidermis. Recruitment of the epidermal growth factor receptor and activation of MAP kinases.

Fas ligand (FasL) exerts potent proapoptotic and proinflammatory actions on epidermal keratinocytes and has been implicated in the pathogenesis of eczema, toxic epidermal necrolysis, and drug-induced skin eruptions. We used reconstructed human epidermis to investigate the mechanisms of FasL-induced inflammatory responses and their relationships with FasL-triggered caspase activity. Caspase activity was a potent antagonist of the pro-inflammatory gene expression triggered by FasL prior to the onset of cell death. Furthermore, we found that FasL-stimulated autocrine production of epidermal growth factor receptor (EGFR) ligands, and the subsequent activation of EGFR and ERK1 and ERK2 mitogen-activated protein kinases, were obligatory extracellular steps for the FasL-induced expression of a subset of inflammatory mediators, including CXCL8/interleukin (IL)-8, ICAM-1, IL-1alpha, IL-1beta, CCL20/MIP-3alpha, and thymic stromal lymphopoietin. These results expand the known physiological role of EGFR and its ligands from promoting keratinocyte mitogenesis and survival to mediating FasL-induced epidermal inflammation.

Fingermark detection based on the in situ growth of luminescent nanoparticles: towards a new generation of multimetal deposition

The in situ deposition of zinc oxide on gold nanoparticles in aqueous solution has been here successfully applied in the field of fingermark detection on various non-porous surfaces. In this article, we present the improvement of the multimetal deposition, an existing technique limited up to now to non-luminescent results, by obtaining luminescent fingermarks with very good contrast and details. This is seen as a major improvement in the field in terms of selectivity and sensitivity of detection, especially on black surfaces.

Enhanced production of indole-3-acetic acid by a genetically modified strain of Pseudomonas fluorescens CHA0 affects root growth of cucumber but does not improve protection of the plant against Pythium root rot

The biocontrol strain CHA0 of Pseudomonas fluorescens produces small amounts of indole-3-acetic acid via the tryptophan side chain oxidase and the tryptophan transaminase pathways. A recombinant plasmid (pME3468) expressing the tryptophan monooxygenase pathway was introduced into strain CHA0; this resulted in elevated synthesis of indole-3-acetic acid in vitro, especially after addition of -tryptophan. In natural soil, strain CHA0/pME3468 increased fresh root weight of cucumber by 17-36%, compared to the effect of strain CHA0; root colonization was about 106 cells per g of root. However, both strains gave similar protection of cucumber against Pythium ultimum. In autoclaved soil, at 6×107 cells per g of root, strain CHA0 stimulated growth of roots and shoots, whereas strain CHA0/pME3468 caused root stunting and strong reduction of plant weight. These results are in agreement with the known effects of exogenous indole-3-acetic acid on plant roots and suggest that in the system examined, indole-3-acetic acid does not contribute to the biocontrol properties of strain CHA0.

Notch signaling in the integrated control of keratinocyte growth/differentiation and tumor suppression.

Oncogenesis is closely linked to abnormalities in cell differentiation. Notch signaling provides an important form of intercellular communication involved in cell fate determination, stem cell potential and differentiation. Here we review the role of this pathway in the integrated growth/differentiation control of the keratinocyte cell type, and the maintenance of normal skin homeostasis. In parallel with the pro-differentiation function of Notch1 in keratinocytes, we discuss recent evidence pointing to a tumor suppressor function of this gene in both mouse skin and human cervical carcinogenesis. The possibility that Notch signaling elicits signals with a duality of growth positive and negative function will be discussed.

Myocardial angiogenesis induction with bone protein derived growth factors (animal experiment).

Myocardial angiogenesis induction with vascular growth factors constitutes a potential strategy for patients whose coronary artery disease is refractory to conventional treatment. The importance of angiogenesis in bone formation has led to the development of growth factors derived from bovine bone protein. Twelve pigs (mean weight, 73 +/- 3 kg) were chosen for the study. In the first group (n = 6, growth factor group) five 100 micrograms boluses of growth factors derived from bovine bone protein, diluted in Povidone 5%, were injected in the lateral wall of the left ventricle. In the second group (n = 6, control group), the same operation was performed but only the diluting agent was injected. All the animals were sacrificed after 28 days and the vascular density of the left lateral wall (expressed as the number of vascular structures per mm2) as well as the area of blood vessel profiles per myocardial area analysed were determined histologically with a computerised system. The growth factor group had a capillary density which was significantly higher than that of the control group: 12.6 +/- 0.9/mm2 vs 4.8 +/- 0.5/mm2 (p < 0.01). The same holds true for the arteriolar density: 1 +/- 0.2/mm2 vs 0.3 +/- 0.1/mm2 (p < 0.01). The surface ratios of blood vessel profiles per myocardial area were 4900 +/- 800 micron 2/mm2 and 1550 +/- 400 micron 2/mm2 (p < 0.01) respectively. In this experimental model, bovine bone protein derived growth factors induce a significant neovascularisation in healthy myocardium, and appear therefore as promising candidates for therapeutic angiogenesis.