Pharmacological reactivation of p53 as a strategy to treat cancer

It has been confirmed through studies using the technique of unbiased sequencing that the TP53 tumour suppressor is the most frequently inactivated gene in cancer. This finding, together with results from earlier studies, provides compelling evidence for the idea that p53 ablation is required for the development and maintenance of tumours. Genetic reconstitution of the function of p53 leads to the suppression of established tumours as shown in mouse models. This strongly supports the notion that p53 reactivation by small molecules could provide an efficient strategy to treat cancer. In this review, we summarize recent advances in the development of small molecules that restore the function of mutant p53 by different mechanisms, including stabilization of its folding by Apr‐246, which is currently being tested in a Phase II clinical trial. We discuss several classes of compounds that reactivate wild‐type p53, such as Mdm2 inhibitors, which are currently undergoing clinical testing, MdmX inhibitors and molecules targeting factors upstream of Mdm2/X or p53 itself. Finally, we consider the clinical applications of compounds targeting p53 and the p53 pathway.     

The Cancer and Deity Questionnaire: A New Religion and Cancer Measure

We evaluated a new measure, the Cancer and Deity Questionnaire (CDQ), which assesses perceived relations with God after a cancer diagnosis. Based on object relations theory, the 12-item CDQ assesses benevolent and abandoning God representations. Sixty-one older participants with recent cancer diagnoses completed the questionnaire at baseline, and 52 of these participants completed the same questionnaire at follow-up. Internal consistency was excellent for the Benevolence scale (α = .97) and good for the Abandonment scale (α = .80). Moderate correlations with the Spiritual Well-Being Scale support divergent validity. Correlations between CDQ scales and the Styles of Religious Coping scales support convergent validity. The CDQ is brief, easily scored, practical for psycho-oncology research, and adaptable for use with other illnesses.     

Correlation of the Epworth Sleepiness Scale with respiratory sleep parameters in patients with sleep-related breathing disorders and upper airway pathology

The aim of the study was to test whether a correlation between the Epworth Sleepiness Scale (ESS) and respiratory sleep parameters recorded by polysomnography (PSG) in patients with sleep-related breathing disorders and upper airway pathology exists. The PSG records of 130 patients (average age 52.6 ± 10.7 years) with upper airway pathology suspected of having obstructive sleep apnea (OSA) have been retrospectively evaluated. Upper airway pathology included deviation of the nasal septum, inferior nasal turbinate hypertrophy, soft palate webbing, elongated uvula, tonsillar hypertrophy, macroglossia, hypertrophy of the tongue base, unfavorable palate position relative to the tongue base. To test for a possible correlation in this patient population between ESS score and arithmetic values of AHI, SPO₂, ODI and Arousal Index, the Spearman’s correlation coefficient was calculated. No correlation between ESS and AHI, minimal SpO₂ and ODI was proven and only a weak positive correlation between Arousal Index and ESS was found in this particular patient population. We concluded that in patients with upper airway pathology, it is not possible to predict solely on the basis of the ESS score the existence of OSA or of other disturbances in Arousal Index, minimal SpO₂ and ODI. Nevertheless, historical data evaluated by questionnaires, such as the ESS provide for additional information combined with the clinical findings to select patients who are candidates for further detailed sleep studies.     

Thyrotropin receptor-DNA vaccination of transgenic mice expressing HLA-DR3 or HLA-DQ6b.

Graves' disease in Caucasians is associated with the major histocompatibility (MHC) antigen HLA-DR3. One approach to studying the role of susceptibility genes involves the use of mice that lack murine MHC and instead express human HLA antigens. Although Graves' disease does not arise spontaneously in animals, thyrotropin receptor (TSHR) antibodies can be induced in mice by vaccination with TSHR-DNA in a plasmid. In the present study, we characterized TSHR antibodies and thyroiditis developing in HLA-DR3 transgenic mice vaccinated with TSHR-DNA. As controls, we used mice transgenic for HLA-DQ6b, an MHC antigen rarely associated with Graves' disease. We observed that approximately 30% of DR3-, but none of DQ6b-transgenic mice, developed TSHR antibodies detectable by enzyme-linked immunosorbent assay (ELISA). The cysteine-rich amino terminal peptide was the dominant linear antibody epitope in DR3 mice, as in other strains vaccinated with TSHR-DNA. Sera from some vaccinated DR3 mice were positive on flow cytometry using intact cells expressing the TSHR, demonstrating recognition of the native TSHR on the cell surface. Although none of the these mice had thyroid stimulating antibodies or were hyperthyroid, a few developed lymphocytic infiltration of the thyroid. These data, together with information for other mouse strains, demonstrate that MHC (human and murine) and non-MHC genes contribute to the outcome of TSHR-DNA vaccination and indicate the potential value of DR3 transgenic mice for dissecting immune responses to the TSHR.     

Disruption of the NHR4 domain structure in AML1-ETO abrogates SON binding and promotes leukemogenesis

AML1-ETO is generated from t(8;21)(q22;q22), which is a common form of chromosomal translocation associated with development of acute myeloid leukemia (AML). Although full-length AML1-ETO alone fails to promote leukemia because of its detrimental effects on cell proliferation, an alternatively spliced isoform, AML1-ETO9a, without its C-terminal NHR3/NHR4 domains, strongly induces leukemia. However, full-length AML1-ETO is a major form of fusion product in many t(8;21) AML patients, suggesting additional molecular mechanisms of t(8;21)-related leukemogenesis. Here, we report that disruption of the zinc-chelating structure in the NHR4 domain of AML1-ETO by replacing only one critical amino acid leads to rapid onset of leukemia, demonstrating that the NHR4 domain with the intact structure generates inhibitory effects on leukemogenesis. Furthermore, we identified SON, a DNA/RNA-binding domain containing protein, as a novel NHR4-interacting protein. Knock-down of SON by siRNA resulted in significant growth arrest, and disruption of the interaction between AML1-ETO and endogenous SON rescued cells from AML1-ETO-induced growth arrest, suggesting that SON is an indispensable factor for cell growth, and AML1-ETO binding to SON may trigger signals inhibiting leukemogenesis. In t(8;21) AML patient-derived primary leukemic cells and cell lines, abnormal cytoplasmic localization of SON was detected, which may keep cells proliferating in the presence of full-length AML1-ETO. These results uncovered the crucial role of the NHR4 domain in determination of cellular fate during AML1-ETO-associated leukemogenesis.     

Optical monitoring of stress-related changes in the brain tissues and vessels associated with hemorrhagic stroke in newborn rats

Stress is a major factor for a risk of cerebrovascular catastrophes. Studying of mechanisms underlying stress-related brain-injures in neonates is crucial for development of strategy to prevent of neonatal stroke. Here, using a model of sound-stress-induced intracranial hemorrhages in newborn rats and optical methods, we found that cerebral veins are more sensitive to the deleterious effect of stress than arteries and microvessels. The development of venous insufficiency with decreased blood outflow from the brain accompanied by hypoxia, reduction of complexity of venous blood flow and high production of beta-arrestin-1 are possible mechanisms responsible for a risk of neonatal hemorrhagic stroke.OCIS codes: (170.0170) Medical optics and biotechnology, (170.3880) Medical and biological imaging, (170.1470) Blood or tissue constituent monitoring, (170.2655) Functional monitoring and imaging