Retinoblastoma pathway dysregulation causes DNA methyltransferase 1 overexpression in cancer via MAD2-mediated inhibition of the anaphase-promoting complex

We have examined the mechanism of normal DNA methyltransferase 1 (DNMT1) degradation as well as its mechanism of dysregulation in cancer. We have previously reported that DNMT1 protein levels were elevated and abnormally stabilized because of defective degradation through its N-terminal destruction domain. Here, we report that DNMT1 was abnormally stabilized in several cancer cell lines and that, in cells with normal DNMT1 destruction, depletion of CDC20 or FZR1 (two substrate recognition adaptor components of the anaphase-promoting complex) resulted in stabilization of DNMT1 that was partially dependent on the N-terminal destruction domain, thus implicating this cell cycle regulator in the destruction of DNMT1. MAD2, an inhibitor of CDC20, was shown to stabilize DNMT1 levels, and overexpression of MAD2, a consequence of retinoblastoma (RB) pathway dysregulation, was shown to correlate with impaired G(1) phase DNMT1 destruction and RB inactivation by hyperphosphorylation in several normal and cancer cell lines. Furthermore, in a series of 85 cases of human breast cancer, a moderately strong, but highly significant, correlation between MAD2 and DNMT1 immunohistochemical staining was observed, yielding a Spearman rank order correlation coefficient of 0.37 (P<0.001). This suggests that RB pathway inactivation, a common dysfunction in cancer cells, may be the underlying cause of DNMT1 dysregulation.     

The potential role of pretransplant MIBG diagnostic scintigraphy in targeted administration of 131I‐MIBG accompanied by ASCT for high‐risk and relapsed neuroblastoma: A pilot study

MIBG is an effective component in treatment of neuroblastoma. Furthermore, MIBG scintigraphy is an imaging modality in primary assessments. None of the previous studies have evaluated the role of pretransplant MIBG scintigraphy in decision making for neuroblastoma treatment. We selected therapeutic regimen based on pretransplant ¹³¹I‐MIBG scintigraphy. Twenty high‐risk patients were enrolled. On day ?30, patients underwent diagnostic MIBG scintigraphy. Patients were then subdivided into two groups (10 cases in each arm). MIBG‐avid subgroup received MIBG (12 mCi/kg), etoposide (1200 mg/m²), carboplatin (1500 mg/m²), and melphalan (210 mg/m²). Non‐MIBG‐avid subgroup received etoposide (600 mg/m²), carboplatin (1200 mg/m²), and melphalan (150 mg/m²). Patients received CRA after ASCT. Mean age at diagnosis was 42.5 months (range, 17–65) in MIBG‐avid and 38.9 months (range, 18–65) in non‐MIBG‐avid patients. Mean age at diagnosis and transplantation did not reveal significant difference between two subgroups. In MIBG‐avid patients, the three‐yr OS was 66 ± 21%. In MIBG‐non‐avid subgroup, the three‐yr OS was 53 ± 20%. In MIBG‐avid and non‐MIBG‐avid subgroups, the three‐yr EFS were 66 ± 21% and 47 ± 19%, respectively. These findings may suggest an effective role in selecting the therapeutic strategy for pre‐ASCT MIBG scintigraphy in high‐risk neuroblastoma. MIBG‐avid subset may benefit from the combination of therapeutic MIBG and high dose of chemotherapy.     

Assessment of smoking behaviour in a dental setting: a 1-year follow-up study using self-reported questionnaire data and exhaled carbon monoxide levels

Objectives

This study analyses the changes in smoking habits over the course of 1 year in a group of patients referred to an oral medicine unit.

Materials and methods

Smoking history and behaviour were analysed at baseline and after 1 year based on a self-reported questionnaire and on exhaled carbon monoxide levels [in parts per million (ppm)]. During the initial examination, all smokers underwent tobacco use prevention and cessation counselling.

Results

Of the initial group of 121 patients, 98 were examined at the follow-up visit. At the baseline examination, 33 patients (33.67 %) indicated that they were current smokers. One year later, 14 patients (42.24 % out of the 33 smokers of the initial examination) indicated that they had attempted to stop smoking at least once over the follow-up period and 15.15 % (5 patients) had quit smoking. The mean number of cigarettes smoked per day by current smokers decreased from 13.10 to 12.18 (p?=?0.04). The exhaled CO level measurements showed very good correlation with a Spearman's coefficient 0.9880 for the initial visit, and 0.9909 for the follow-up examination. For current smokers, the consumption of one additional cigarette per day elevated the CO measurements by 0.77 ppm (p?<?0.0001) at the baseline examination and by 0.84 ppm (p?<?0.0001) at the 1-year follow-up.

Conclusions

In oral health care, where smoking cessation is an important aspect of the treatment strategy, the measurement of exhaled carbon monoxide shows a very good correlation with a self-reported smoking habit.

Clinical relevance

Measurement of exhaled carbon monoxide is a non-invasive, simple and objective measurement technique for documenting and monitoring smoking cessation and reduction.     

Unusual renal pathology associated with a Wilms tumor in a 15-month-old infant

Beckwith-Wiedemann syndrome is an overgrowth dis-order that predisposes to the development of a variety of malignancies including Wilms tumor. Pathologists may suspect the presence of Beckwith-Wiedemann syndrome, which may be clinically subtle, on the basis of the histopathology of the renal parenchyma adjacent to a Wilms tumor. These kidneys typically harbor multiple nephrogenic rests (especially perilobar nephrogenic rests), and their medullas have blunted papillae resulting from excessive fibromyxoid stroma, decreased collecting ducts, and decreased Henle loops. This complex of findings constitutes the so-called Beckwith Medulla. Extensions of this stroma-rich medulla into the cortex results in characteristic dysplastic medullary-ray nodules. Identification of these histologic abnormalities by the pathologist should prompt the clinician to evaluate the child for Beckwith-Wiedemann syndrome. Proper screening of these children can allow for early detection of cancers and treatment while these cancers are curable.