Promising pre-clinical validation of targeted radionuclide therapy using a [131I] labelled iodoquinoxaline derivative for an effective melanoma treatment

Targeted internal radionuclide therapy (TRT) would be an effective alternative to current therapies for dissemi- nated melanoma treatment. At our institution, a class of iodobenzamides has been developed as potent melanoma- seeking agents. This review described the preclinical vali- dations of a quinoxaline derivative molecule (ICF01012) as tracer for TRT application. It was selected for its high, specific and long-lasting uptake in tumour with rapid clear- ance from non-target organs providing suitable dosimetry parameters for TRT. Extended in vivo study of metabolic profiles confirmed durable tumoural concentration of the unchanged molecule form. Moreover melanin specificity of ICF01012 was determined by binding assay with syn- thetic melanin and in vivo by SIMS imaging. Then, we showed in vivo that [131I] ICF01012 treatment drastically inhibited growth of B16F0, B16Bl6 and M4Beu tumours whereas [131I] NaI or unlabelled ICF01012 treatment was without significant effect. Histological analysis showed that residual tumour cells exhibit a significant loss of aggres- siveness after treatment. This anti-tumoural effect was associated with a lengthening of the treated-mice survival time and an inhibition of lung dissemination for B16Bl6 model. Results presented here support the concept of TRT using a [131I] labelled iodoquinoxaline derivative for an effective melanoma treatment.

Response of BRAF-mutant melanoma to BRAF inhibition is mediated by a network of transcriptional regulators of glycolysis.

Deregulated glucose metabolism fulfills the energetic and biosynthetic requirements for tumor growth driven by oncogenes. Because inhibition of oncogenic BRAF causes profound reductions in glucose uptake and a strong clinical benefit in BRAF-mutant melanoma, we examined the role of energy metabolism in responses to BRAF inhibition. We observed pronounced and consistent decreases in glycolytic activity in BRAF-mutant melanoma cells. Moreover, we identified a network of BRAF-regulated transcription factors that control glycolysis in melanoma cells. Remarkably, this network of transcription factors, including hypoxia-inducible factor-1α, MYC, and MONDOA (MLXIP), drives glycolysis downstream of BRAF(V600), is critical for responses to BRAF inhibition, and is modulated by BRAF inhibition in clinical melanoma specimens. Furthermore, we show that concurrent inhibition of BRAF and glycolysis induces cell death in BRAF inhibitor (BRAFi)-resistant melanoma cells. Thus, we provide a proof-of-principle for treatment of melanoma with combinations of BRAFis and glycolysis inhibitors.

The effect of chromate on the pitting susceptibility of AA7075-T651 studied using potentiostatic transients

The effect of chromate on metastable pitting of AA7075-T651 as determined via potentiostatic polarisation is reported. A systematic study of metastable pitting and its correlation with stable pits was conducted in various concentrations of sodium chromate (Na2CrO4), revealing the metastable pitting rate was able to provide a quantitative metric for pitting corrosion. The size and number of metastable pits decreased significantly in the presence of chromate. The present study is intended as a general baseline for the assessment of future chromate replacement technologies, as elaborated herein. © 2014 Elsevier Ltd.

Balloon cell melanoma: a case report with polarized and non-polarized dermatoscopy and dermatopathology

Balloon cell melanoma is a rare melanoma subtype, with only one previous case with dermatoscopy published. It is often non-pigmented, leading to diagnostic difficulty, and there is a tendency for lesions to be thick at diagnosis. We report a case of balloon cell melanoma on the forearm of a 61-year-old man with both polarized and non-polarized dermatoscopy and dermatopathology. It presented as a firm pale nodule with focal eccentric pigmentation. The clinical images evoke a differential diagnosis of dermatofibroma, dermal nevus, Spitz nevus and basal cell carcinoma as well as melanoma. This melanoma was partially pigmented due to a small, pigmented superficial spreading component on the edge of the non-pigmented balloon cell nodule, prompting further evaluation. In retrospect there was the clue to malignancy of polarizing-specific white lines (chrysalis structures) and polymorphous vessels, including a pattern of dot vessels. The reticular lines exclude basal cell carcinoma, polarizing-specific white lines are inconsistent with the diagnosis of dermal nevus and their eccentric location is inconsistent with both Spitz nevus and dermatofibroma. Excision biopsy was performed, revealing a superficial spreading melanoma with two distinct invasive components, one of atypical non-mature epithelioid cells and the other an amelanotic nodular component, comprising more than 50% of the lesion, characterized by markedly distended epithelioid melanocytes showing pseudo-xanthomatous cytoplasmic balloon cell morphology. A diagnosis of balloon cell melanoma, Breslow thickness 1.9 mm, mitotic rate 3 per square millimeter was rendered. Wide local excision was performed, as was sentinel lymph node biopsy, which was negative.

Gender differences in adolescent depression: Differential female susceptibility to stressors affecting family functioning

Objective: The aim of this study was to examine associations between family-based stressors and depressive symptoms in adolescents.

Method: Participants were 10-14 year olds who participated in a large Australian population study (n=6,552). Depressive symptoms and pubertal development were assessed using the self-report Short Mood and Feelings Questionnaire and the Pubertal Development Scale. Three indicators of stress exposure were examined-low emotional closeness to parents, residential and school transitions, and family conflict. The effect of gender, stress exposure and the interaction of gender and stress exposure on depressive symptoms was tested using multivariate logistic regression.

Results: High family conflict, residential instability and low emotional closeness with parents were independently associated with adolescent depressive symptoms. There was a significant gender by emotional closeness interaction; females reporting low emotional closeness to their parents were 2.3 times more likely to report high depressive symptoms than females reporting high emotional connections with parents.

Conclusions: Female adolescents may be more susceptible to particular types of stresses and particularly the quality of the parent-child relationship.

Susceptibility of reproduction in female pigs to impairment by stress and the role of the hypothalamo-pituitary-adrenal axis

Although it is generally considered that stress can impair reproduction, we suggest that the impact of acute or repeated acute stress or acute or repeated acute elevations of cortisol are of little consequence in female pigs, even if these occur during the series of endocrine events that induce oestrus and ovulation. It is important to understand the impact of acute stress on reproduction because, in the intensive production of livestock, animals are often subjected to short-term challenges. There seems little doubt that reproduction in a proportion of female pigs is susceptible to impairment by severe and prolonged stress or the sustained elevation of cortisol but only when this continues for a substantial period. In female pigs, where reproduction is susceptible to impairment by severe prolonged stress, it is possible that the mediators of this suppression are cortisol, corticotrophin-releasing factor and vasopressin but, in pigs, there is evidence to suggest that adrenocorticotrophic hormone is not involved. Other substances secreted during stress may be involved but these are not considered in this review. It is possible that the mediators of stress act at any level of the hypothalamo-pituitary-ovarian axis. Although a variety of experimental manipulations have provided potential mediators and mechanisms for the stress-induced suppression of reproduction, these experimental manipulations rarely represented physiological circumstances so it is not clear if such mechanisms would be important in a physiological context. The precise mediators and mechanisms by which hormones released during stress may inhibit reproductive processes during severe prolonged stress are yet to be determined.