SHH pathway inhibition is protumourigenic in adamantinomatous craniopharyngioma.

Pharmacological inhibition of the sonic hedgehog (SHH) pathway can be beneficial against certain cancers but detrimental in others. Adamantinomatous craniopharyngioma (ACP) is a relevant pituitary tumour, affecting children and adults, that is associated with high morbidity and increased mortality in long-term follow-up. We have previously demonstrated overactivation of the SHH pathway in both human and mouse ACP. Here, we show that this activation is ligand dependent and induced by the expression of SHH protein in a small proportion of tumour cells. We investigate the functional relevance of SHH signalling in ACP through MRI-guided preclinical studies using an ACP mouse model. Treatment with vismodegib, a clinically approved SHH pathway inhibitor, results in a significant reduction in median survival due to premature development of highly proliferative and vascularised undifferentiated tumours. Reinforcing the mouse data, SHH pathway inhibition in human ACP leads to a significant increase in tumour cell proliferation both ex vivo, in explant cultures, and in vivo, in a patient-derived xenograft model. Together, our results demonstrate a protumourigenic effect of vismodegib-mediated SHH pathway inhibition in ACP.

Harnessing engineered antibodies of the IgE class to combat malignancy: initial assessment of FcɛRI-mediated basophil activation by a tumour-specific IgE antibody to evaluate the risk of type I hypersensitivity.

BACKGROUND: IgE antibodies, sequestered into tissues and retained locally by the high-affinity IgE receptor, FcɛRI, on powerful effector cells such as mast cells, macrophages and eosinophils, may offer improvements in the therapy of solid tumours. The chimeric antibody, MOv18 IgE, against the human ovarian carcinoma antigen, folate receptor α (FRα), is more effective than its IgG1 counterpart in xenograft models of ovarian cancer. Although MOv18 IgE binds to a single epitope on FRα and cannot cross-link IgE receptors on basophils, there remains a risk that components in the circulation of ovarian cancer patients might cross-link FRα-MOv18-IgE-receptor-FcɛRI complexes on basophils to cause type I hypersensitivity. OBJECTIVE: To assess the propensity for MOv18 used in a therapeutic setting to cause FcɛRI-mediated type I hypersensitivity. METHODS: As validated readouts of the potential for MOv18 to cause FcɛRI-mediated type I hypersensitivity we measured release of a granule-stored mediator from a rat basophilic leukaemia cell line RBL SX-38 stably transfected with human tetrameric (αßγ2) FcɛRI, and induction of CD63 on blood basophils from patients with ovarian carcinoma and healthy controls ex vivo. RESULTS: Serum FRα levels were increased in ovarian cancer patients compared with healthy controls. MOv18 IgE alone, or in the presence of its antigen recombinant human FRα, or of healthy volunteer (n=14) or ovarian carcinoma patient (n=32) sera, did not induce RBL SX-38 cell degranulation. Exposure to FRα-expressing ovarian tumour cells at target-to-effector ratios expected within tumours induced degranulation. MOv18 IgE did not induce expression of CD63 in blood basophils from either healthy volunteers (n=6), or cancer patients, despite detectable levels of circulating FRα (n=5). CONCLUSION AND CLINICAL RELEVANCE: These encouraging data are compatible with the hypothesis that, when ovarian carcinoma patients are treated with MOv18, FcɛRI-mediated activation of effector cells occurs within the tumour mass but not in the circulation mandating, with due caution, further pre-clinical studies.

Parental hostility and its sources in psychologically abusive mothers: a test of the three-factor theory.

A revised version of the three-factor theory of child abuse (Lesnik-Oberstein, Cohen, & Koers, 1982) is presented. Further, we report on a research designed to test three main hypotheses derived from Factor I (1) (a high level of hostility in abusive parents) and its sources. The three main hypotheses are: (1) that psychologically abusive mothers have a high level of hostile feelings (Factor I); (2) that the high level of hostile feelings in abusive mothers is associated with low marital coping skills (resulting in affectionless, violent marriages), a negative childhood upbringing (punitive, uncaring, over controlling), a high level of stress (objective stress), and a high level of strain (low self-esteem, depression, neurotic symptoms, social anxiety, feelings of being wronged); and (3) that maternal psychological child abuse is associated with low marital coping skills, a negative childhood upbringing, a high level of stress and a high level of strain. Forty-four psychologically abusing mothers were compared with 128 nonabusing mothers on a variety of measures and were matched for age and educational level. All the mothers had children who were hospitalized for medical symptoms. The three hypotheses were supported, with the exception of the component of hypothesis 2 concerning the association between objective stress and maternal hostility. The positive results are consistent with the three-factor theory.

Research in the Netherlands on a theory of child abuse: a preliminary report.

A three-factor theory of child abuse has been developed which includes: (1) a high level of parental aggression; (2) a low level of parental inhibition of overt aggression; and (3) the focusing of parental aggression on the child. In the theory each factor is the outcome of a subfactor "path." A high level of parental aggression is the outcome of seven subfactors. A low level of parental inhibition of overt aggression is the outcome of three subfactors. The focusing of parental aggression on the child is the outcome of ten subfactors. The theory posits that the type of child abuse that occurs is determined by the ratio of total parental aggression to total parental inhibition of overt aggression. High numerical values of the ratio result in battering. Lower numerical values result, in descending order, in non-organic failure to thrive, physical neglect and emotional abuse. The theory and 50 hypotheses derivable from it are being tested on a sample of 150 child-abuse families and 150 control families.