Duplications of proximal 16q flanked by heterochromatin are not euchromatic variants and show no evidence of heterochromatic position effect.

Extra euchromatic material was found within the major heterochromatic block of chromosome 16 (16qh) in one de novo case and seven members of two families. In contrast to the euchromatic variants of chromosome 9 (9qh), which are derived from pericentromeric euchromatin, molecular cytogenetics confirmed that these duplications were of 16q11.2-->q12.2 in the de novo case, of 16q11.2-->q13 in three members of family 1 and 16q11.2-->q12.1 in four members of family 2. The duplication had arisen as a post-zygotic mitotic event in the mother of family 1 and been transmitted paternally in family 2. An insertional mechanism of origin is proposed for the duplications in case 1 and family 1. Expression at the 16q13 matrix metalloproteinase-2 (MMP2)locus in families 1 and 2 was proportional to genomic copy number and not therefore consistent with position effect silencing due to the flanking blocks of heterochromatin. We conclude that proximal 16q duplications within 16qh are not novel euchromatic variants but associated with a variable phenotype including developmental delay, speech delay, learning difficulties and behavioural problems. The behavioural problems in families ascertained through affected children are much less severe than those encountered in previous patients ascertained as adults.

Mutagenic mucus in the cervix of smokers.

A pilot study was conducted to determine whether any relationship exists between mutagenicity of a women's uterine cervical mucus and her current smoking status. Cervical fluids obtained from 78 premenopausal women seen between July 1983 and March 1984 at the University of California, San Francisco Dysplasia (and diethylstilbestrol) Clinic or in a private practice were tested for mutagenicity by means of the Ames-Salmonella microsomal test. Of 36 current smokers, 14 (39%) had positive tests as compared to 5 of 42 nonsmokers (12%). The odds ratio (OR) estimate was 4.7 with 95% confidence limits (CL) of 1.6-14.2. Secretions from 14 of 32 (44%) women who had smoked during the day of the sample collection--within the previous 7 hours--were positive on the laboratory test, whereas none of the 4 women was positive who had smoked 8 hours or more before the specimens were obtained. Fluids from women with dysplasia or carcinoma in situ were more likely to be mutagenic than were those from other women, although this finding may be due to chance (OR = 2.0 with 95% CL of .70-5.9). This relationship between smoking and mutagenic cervical fluids offers evidence that might help to explain the association between cervical cancer and cigarette smoking noted in previous epidemiologic studies.

A step-wise logistic regression analysis of papillary carcinoma of the thyroid.

Fourteen cytologic features seen in fine needle aspirates of papillary carcinoma of the thyroid were subjected to a step-wise logistic regression analysis to determine which are predictive of papillary carcinoma. The study cases included 38 histologically proven papillary carcinomas and 54 other palpable thyroid nodules. The three most important variables in making the prediction of papillary carcinoma were intranuclear inclusions, papillary structures without vessels and cells with metaplastic cytoplasm.

Dissociation of antitumor potency from anthracycline cardiotoxicity in a doxorubicin analog.

The search for new congeners of the leading anticancer drug doxorubicin has led to an analog that is approximately 1000 times more potent, noncardiotoxic at therapeutic dose levels, and non-cross-resistant with doxorubicin. The new anthracycline, 3'-deamino-3'-(3-cyano-4-morpholinyl)doxorubicin (MRA-CN), is produced by incorporation of the 3' amino group of doxorubicin in a new cyanomorpholinyl ring. The marked increase in potency was observed against human ovarian and breast carcinomas in vitro; it was not accompanied by an increase in cardiotoxicity in fetal mouse heart cultures. Doxorubicin and MRA-CN both produced typical cardiac ultrastructural and biochemical changes, but at equimolar concentrations. In addition, MRA-CN was not cross-resistant with doxorubicin in a variant of the human sarcoma cell line MES-SA selected for resistance to doxorubicin. Thus antitumor efficacy was dissociated from both cardiotoxicity and cross-resistance by this modification of anthracycline structure.