hTR repressor-related gene on human chromosome 10p15.1.

Somatic cells express genes that suppress telomerase activity and these genes may be inactivated in tumour cells. We postulated that cancer cells acquire immortality by activation of telomerase by the loss of such a gene. We have reported recently that a telomerase repressor gene may be located on 10p15.1 by deletion mapping using microcell-mediated chromosome transfer (MMCT), radiated microcell fusion (RMF), fluorescent in situ hybridization (FISH) and STS analysis. To independently confirm this result, we correlated expression of RNA component of telomerase (hTR) as a marker of telomerase expression by in situ hybridization with allelic loss in pulmonary carcinoid tumours. Unlike most malignant tumours, pulmonary carcinoids (which are low-grade malignant tumours) are heterogeneous for telomerase expression. Loss of 5 closely spaced polymorphic markers on 10p15.1, especially D10S1728, were highly correlated with hTR expression. In an additional experiment, 10p15.1 showed higher and more significant correlation than any region of 3p where it has been predicted as another chromosomal location of telomerase repressor with allelic loss of the region. Our findings strongly suggest that 10p15.1 harbours a gene involved in repression of telomerase RNA component in human somatic cells and each putative repressor (on 3p and 10p) may act independently.

Dissociation of chronotropic and inotropic responses in the rat heart during sympathetic stimulation.

It is not fully resolved how the chronotropic and inotropic responses alter depending on the strength or duration of stimulation, and how the alpha-vasoconstrictor effect competes with metabolic vasodilation during sympathetic stimulation. The present study investigated the effects of differential frequency stimuli on these responses in rat hearts during sympathetic stimulation while keeping the left ventricular end-diastolic volume constant. The heart was perfused at a constant flow or pressure with a modified Krebs-Henseleit solution. Electrical stimulation of sympathetic nerves (SNS) was performed at 4 frequencies (0.2, 0.5, 1 and 3 Hz) for 90 s in pithed rats without or with an a or alpha2 adrenergic receptor antagonist. The heart rate progressively increased during 3-Hz SNS (33+/-10% at 30s, 38+/-14% at 90s), whereas the inotropic action peaked at about 30s and then decreased (left ventricular systolic pressure +23+/-8% at 30s, -1+/-13% at 90s). This phenomenon indicates a negative staircase, in spite of a gradual increase in norepinephrine release. The reduction of contractility did not differ from that shown by constant atrial pacing with an equivalent rate. The coronary alpha1-vasoconstrictor response was competitive with metabolic vasodilation only in the early phase of stimulation and the alpha2-vasoconstrictor action had little contribution to the regulation of coronary circulation. The fact that these results differ from previous findings suggests that sympathetic regulation of the heart should be reconsidered, although direct application of the present results to humans is not clear because of species differences.

Genetic changes in the spectrum of neuroendocrine lung tumors.

BACKGROUND: Recent classifications identify four categories of neuroendocrine (NE) tumors of the lung: low grade typical carcinoid (TC), intermediate grade atypical carcinoid (AC), and high grade large cell neuroendocrine carcinoma (LC-NEC) and small cell lung carcinoma (SCLC). METHODS: The authors studied the molecular changes present in 59 archival NE tumors (10TCs, 11 ACs, 18 LNECs, and 20 SCLCs). Utilizing microdissection and polymerase chain reaction-based assays, the authors examined loss of heterozygosity (LOH) at ten chromosomal regions frequently deleted in lung tumors (3p, 5q, 11q, 13q, and 17p) and for mutations at the p53 and ras genes. RESULTS: With the exception of ras gene mutations, the majority of these changes frequently were present in carcinomas and were present at lower frequencies in carcinoids. LOH at one or more 3p regions was the most frequent change found in the carcinoids. A relatively high incidence of LOH at the MEN1 gene was common in all NE lung tumors. The incidence of LOH and p53 gene abnormalities progressively increased with increasing severity of tumor type. The patterns of p53 gene mutations were different between AC and high grade NE tumors. LOH at 5q21 was correlated with poor survival in the carcinoid group. CONCLUSIONS: Although NE lung tumors have varied etiologies, the results of the current study support the clinicopathologic concept that they represent a spectrum ranging from low grade TC to the highly malignant NE carcinomas.

Molecular abnormalities associated with endocrine tumors of the uterine cervix.

Objective. We studied the molecular abnormalities involved in the pathogenesis of endocrine tumors of the uterine cervix. Methods. We obtained DNA from precisely microdissected archival tissue from 15 endocrine tumors of the uterine cervix, consisting of 5 carcinoids (1 typical, 4 atypical), 2 large cell neuroendocrine carcinomas, and 8 small cell carcinomas. We investigated the presence of high-risk (types 16 and 18) and intermediate-risk (types 31 and 33) human papilloma virus (HPV) sequences, TP53 and K-ras gene mutations, and loss of heterozygosity (LOH) at 9 genes/chromosomal regions, including 3p14.2/FHIT, 3p14-p21, 3p21, 3p22-p24, 5q21-q22/APC-MCC region, 9p21/CDKN2, 11q23/MEN1, 13q/RB, and 17p/TP53. Results. HPV sequences were detected in 8 (53%) tumors, HPV 16 in 2 cases, and HPV 18 in 2 cases. LOH at 9p21 (43%) and localized 3p deletions (47%) were the most frequent allelic losses found. Allelic losses at 5q21-q22/APC-MCC region, 11q23/MEN1, and 13q/RB were infrequent. TP53 gene mutations were detected in 7 (47%) tumors (1 atypical carcinoid and 6 carcinomas). HPV sequences were demonstrated in 4 of the 7 cases with TP53 gene mutations. No K-ras mutations were detected. Conclusion. The molecular changes present in endocrine tumors of the uterine cervix have distinct features. They incorporate those present in the neuroendocrine tumors of the lung (high frequency of TP53 gene abnormalities and 9p21 deletions) with those detected in squamous cell carcinomas of the cervix (high-risk HPV sequences and localized 3p deletions).

[Pleural fibroma with a cavity-like air space].

A 45-year-old man was admitted to the hospital because of an increase in the size of an abnormal shadow on chest X-ray films over the preceding 5 years. A chest X-ray film on admission revealed a round air space in a mass-like shadow in the right upper lung field. Results of physical examination, sputum cytologic examination, and Ziehl-Neelsen staining were negative. Histopathological examination of a percutaneous lung biopsy specimen revealed a benign fibrous tumor of the pleura. Thoracotomy revealed a pedunculated tumor arising from the visceral pleura at the apical segment of the right upper lobe. A wedge resection was done. Histological examination revealed that the tumor consisted of regularly-shaped spindle cells with densely collagenous tissue. Normal lung tissue was found to be invaginated into the tumor tissue. These findings are consistent with the radiologic findings.