Monitoring growth in asthmatic children treated with high dose inhaled glucocorticoids does not predict adrenal suppression

Aims: To determine whether routine outpatient monitoring of growth predicts adrenal suppression in prepubertal children treated with high dose inhaled glucocorticoid.

Methods: Observational study of 35 prepubertal children (aged 4–10 years) treated with at least 1000 µg/day of inhaled budesonide or equivalent potency glucocorticoid for at least six months. Main outcome measures were: changes in HtSDS over 6 and 12 month periods preceding adrenal function testing, and increment and peak cortisol after stimulation by low dose tetracosactrin test. Adrenal suppression was defined as a peak cortisol 500 nmol/l.

Results: The areas under the receiver operator characteristic curves for a decrease in HtSDS as a predictor of adrenal insufficiency 6 and 12 months prior to adrenal testing were 0.50 (SE 0.10) and 0.59 (SE 0.10). Prediction values of an HtSDS change of –0.5 for adrenal insufficiency at 12 months prior to testing were: sensitivity 13%, specificity 95%, and positive likelihood ratio of 2.4. Peak cortisol reached correlated poorly with change in HtSDS ( = 0.23, p = 0.19 at 6 months; = 0.33, p = 0.06 at 12 months).

Conclusions: Monitoring growth does not enable prediction of which children treated with high dose inhaled glucocorticoids are at risk of potentially serious adrenal suppression. Both growth and adrenal function should be monitored in patients on high dose inhaled glucocorticoids. Further research is required to determine the optimal frequency of monitoring adrenal function.

The PD-1/PD-L1 Axis: An Immune-Mediated Mechanism of Chemoresistance in Cancer

The ability of tumour cells to avoid immune destruction (immune escape) and their acquired resistance to anti-cancer drugs constitute important barriers to the successful management of cancer. The interaction between specific molecules on the surface of tumour cells with their corresponding receptors on immune effector cells can result in inhibition of these effector cells, consequently allowing tumour cells to evade the host’s anti-tumour immune response. The interaction of the Programmed Death Ligand 1 (PD-L1) on the surface of tumour cells with the Programmed Death-1 (PD-1) receptor on cytotoxic T lymphocytes leads to inactivation of these immune effectors, and is a specific example of an immune escape mechanism tumour cells use to avoid immune destruction. Clinically, antibodies capable of blocking the PD-1/PD-L1 interaction have demonstrated significant therapeutic benefit, and are currently being used to help bolster patients’ immune response against malignant cells in a variety of cancer types. Here we show that the PD-1/PD-L1 interaction also leads to tumour cell resistance to conventional chemotherapeutic agents. Incubation of PD-L1-expressing human and mouse tumour cells with PD-1-expressing Jurkat T cells or purified recombinant PD-1 resulted in tumour cell resistance to doxorubicin and docetaxel. Interference with the PD-1/PD-L1 interaction using blocking anti-PD-1 or anti-PD-L1 antibody or shRNA-mediated gene silencing resulted in attenuation of PD-1/PD-L1-mediated drug resistance. Moreover, inhibition of the PD-1/PD-L1 signalling axis using anti-PD-1 antibody enhanced the effect of doxorubicin chemotherapy to inhibit 4T1 tumour cell metastasis in an in vivo mouse model of mammary carcinoma. These findings indicate that blockade of the PD-1/PD-L1 axis may be a useful approach to immunosensitize and chemosensitize tumours in cancer patients and provide a rationale for the use of anti-PD-1/PD-L1 antibodies as adjuvants to chemotherapy.

Pubertal impairment in Nhlh2

Pubertal development is impaired in mice lacking the basic helix-loop-helix transcription factor Nhlh2. The mechanisms underlying changes in reproduction in Nhlh2-deficient mice (Nhlh2-/-) are unclear. Here we show that hypothalamic gonadotropin-releasing hormone-1 (GnRH-1) content is reduced in adult Nhlh2-/- mice as is the number of GnRH-1 neurons localized to mid- and caudal hypothalamic regions. This reduction was detected postnatally after normal migration of GnRH-1 neurons within nasal regions had occurred. Phenotype rescue experiments showed that female Nhlh2-/- mice were responsive to estrogen treatment. In contrast, puberty could not be primed in female Nhlh2-/- mice with a GnRH-1 regimen. The adenohypophysis of Nhlh2-/- mice was hypoplastic although it contained a full complement of the five anterior pituitary cell types. GnRH-1 receptors (GnRHRs) were reduced in Nhlh2-/- pituitary gonadotropes as compared to wild type. In vitro assays indicated that Nhlh2 expression is regulated in parallel with GnRHR expression. However, direct transcriptional activity of Nhlh2 on the GnRHR promoter was not found. These results indicate that Nhlh2 plays a role in the development and functional maintenance of the hypothalamic-pituitarygonadal axis at least at two levels: 1) in the hypothalamus by regulating the number and distribution of GnRH-1 neurons and, 2) in the developing and mature adenohypophysis.

Responses of calves to acute stress: Individual consistency and relations between behavioral and physiological measures

The present study examined the consistency over time of individual differences in behavioral and physiological responsiveness of calves to intuitively alarming test situations as well as the relationships between behavioral and physiological measures. Twenty Holstein Friesian heifer calves were individually subjected to the same series of two behavioral and two hypothalamo-pituitary-adrenocortical (HPA) axis reactivity tests at 3, 13 and 26 weeks of age. Novel environment (open field, OF) and novel object (NO) tests involved measurement of behavioral, plasma cortisol and heart rate responses. Plasma ACTH and/or cortisol response profiles were determined after administration of exogenous CRH and ACTH, respectively, in the HPA axis reactivity tests. Principal component analysis (PCA) was used to condense correlated measures within ages into principal components reflecting independent dimensions underlying the calves' reactivity. Cortisol responses to the OF and NO tests were positively associated with the latency to contact and negatively related to the time spent in contact with the NO. Individual differences in scores of a principal component summarizing this pattern of inter-correlations, as well as differences in separate measures of adrenocortical and behavioral reactivity in the OF and NO tests proved highly consistent over time. The cardiac response to confinement in a start box prior to the OF test was positively associated with the cortisol responses to the OF and NO tests at 26 weeks of age. HPA axis reactivity to ACTH or CRH was unrelated to adrenocortical and behavioral responses to novelty. These findings strongly suggest that the responsiveness of calves was mediated by stable individual characteristics. Correlated adrenocortical and behavioral responses to novelty may reflect underlying fearfulness, defining the individual's susceptibility to the elicitation of fear. Other independent characteristics mediating reactivity may include activity or coping style (related to locomotion) and underlying sociality (associated with vocalization). (c) 2005 Elsevier Inc. All rights reserved.

A Population-Based Study of IGF Axis Polymorphisms and the Esophageal Inflammation, Metaplasia, Adenocarcinoma Sequence

BACKGROUND & AIMS: Insulin-like growth factor (IGF) axis plays a key role in cell development, proliferation, and survival and is implicated in the etiology of several cancers. Few studies have examined the relationship between genetic variation of this axis and esophageal adenocarcinoma (EAC) or its precursors. METHODS: In a population-based case-control study, we investigated the association of common polymorphisms of IGF-1, IGF-2, IGF-1 receptor, IGF binding protein -3, growth hormones (GH) 1 and GH2, and GH receptor with reflux esophagitis (RE), Barrett esophagus (BE), and EAC. Two hundred and thirty RE, 224 BE, 227 EAC cases, and 260 controls were studied. Gene polymorphisms were identified using publicly available online resources; 102 IGF axis tag and putatively functional single-nucleotide polymorphisms (SNPs) were analyzed using MassARRAY iPLEX and Taqman assays. Results were analyzed using Haploview.
RESULTS: Three polymorphisms were disease-associated. IGF1 SNP rs6214 was associated with BE (adjusted P = .039). Using GG genotype as reference, odds ratio for BE in AA (wild-type) was 0.43 (95% confidence interval [CI], 0.24-0.75). GH receptor SNP rs6898743 was associated with EAC (adjusted P = .0112). With GG as reference, odds ratio for EAC in CC (wildtype) genotype was 0.42 (95% CI, 0.23-0.76). IGF1 (CA)(17) 185-bp allele was associated with RE (adjusted P = .0116). Using IGF1(non17) as reference, odds ratio for RE in IGF1(17) carriers was 7.29 (95% CI, 1.57-46.7).
CONCLUSIONS: In this study, 3 polymorphisms of IGF genes were associated with EAC or its precursors. These polymorphisms may be markers of disease risk; independent validation of our findings is required. These results suggest the IGF pathway is involved in EAC development.