Perfluorochemicals as US contrast agents for tumor imaging and hepatosplenography: preliminary clinical results

In animals, perfluorochemicals (PFCs) are effective ultrasound (US) contrast agents that produce hepatic, splenic, and tumor enhancement. The use of Fluosol-DA 20%, an emulsion of perfluorodecalin and perfluorotripropylamine, was studied in nine non-critically ill patients with cancer who had liver lesions. US studies without Fluosol were compared with studies obtained 24, 48, and 72 hours after Fluosol infusion. Vital signs and extensive laboratory analyses are performed before and after Fluosol infusion. Liver metastases from colonic, pancreatic, and gastric carcinoma exhibited rim or diffuse enhancement after a Fluosol dose of 1.6 g/kg or greater. Fluosol produced echogenic enhancement of the liver and spleen relative to kidney at a dose of 2.4 g/kg, allowing the detection of nonenhancing lesions. In addition, Fluosol at a dose of 1.6 g/kg or greater allowed detection of lesions not seen before contrast medium was administered in three of the seven patients studied. There was a mild increase in the level of serum glutamic oxaloacetic transaminase in two patients, one given 2.4 and the other 3.2 g/kg of Fluosol. Mild and transient allergic reactions without change in vital signs were experienced by two patients.     

Classical and anaplastic seminoma: difference in survival

Classical and anaplastic seminoma are traditionally treated with radiation therapy and are said to have the same prognosis. A retrospective study was undertaken of 90 seminoma patients treated with radiation therapy between 1961 and 1985. The classical group consisted of 71 patients of whom 50 had stage I and 21 had stage II disease. The anaplastic group consisted of 19 patients of whom ten had stage I and nine had stage II disease. The median follow-up time was 64 months for the entire group. The 10-year relapse-free survival rate for the classical group was 94% and for the anaplastic group was 70% (P less than .05). For patients with classical stage I disease, the relapse-free actuarial survival rate was 98%; for patients with anaplastic stage I disease, it was 64% (P less than .02). For the classical stage II disease group, the relapse-free actuarial survival rate was 84% and for the anaplastic stage II disease group, 75% (P less than .70). Four patients in the classical group (6%) had relapses; of these, one patient had local recurrence of tumor, and three had distant metastases. In the anaplastic group, four patients (21%) had relapses; two patients had local recurrence of tumor, and two had distant metastases. Therefore the data suggest a difference in survival and relapse rates between classical and anaplastic seminoma.     

Elastin point mutations cause an obstructive vascular disease, supravalvular aortic stenosis

Supravalvular aortic stenosis (SVAS) is an inherited obstructive vascular disease that affects the aorta, carotid, coronary and pulmonary arteries. Previous molecular genetic data have led to the hypothesis that SVAS results from mutations in the elastin gene, ELN. In these studies, the disease phenotype was linked to gross DNA rearrangements (35 and 85 kb deletions and a translocation) in three SVAS families. However, gross rearrangements of ELN have not been identified in most cases of autosomal dominant SVAS. To define the spectrum of ELN mutations responsible for this disorder, we refined the genomic structure of human ELN and used this information in mutational analyses. ELN point mutations co-segregate with the disease in four familial cases and are associated with SVAS in three sporadic cases. Two of the mutations are nonsense, one is a single base pair deletion and four are splice site mutations. In one sporadic case, the mutation arose de novo. These data demonstrate that point mutations of ELN cause autosomal dominant SVAS.      

DNA cross-link-dependent RAD50/MRE11/NBS1 subnuclear assembly requires the Fanconi anemia C protein

Fanconi anemia (FA) is a cancer-predisposition syndrome characterized by hypersensitivity to interstrand-cross-link (ICL) inducers. FA hypersensitivity to ICL has been correlated with alterations in homologous recombination, non-homologous end-joining, telomere maintenance, DNA-damage assessment and checkpoint regulation, processes in which the components of the RAD50/MRE11/NBS1 (RMN) complex are involved. To better characterize the mechanisms by which ICL are processed in human cells and to gain insight into their toxicity in FA, we examined (i). the RMN complex assembling in response to the ICL inducers mitomycin C (MMC) and photoactivated 8-methoxypsoralen and (ii). the proficiency of FA cells to perform RMN activation in response to ICL inducers. We show here that ICL activates the assembly of the RMN proteins into subnuclear foci, and that their formation proceeds independently of ICL incision, a step mainly dependent on XP-F/ERCC1 heterodimer activity. Interestingly, FA cells were unable to form RMN foci in response to either ICL inducer. Analysis by pulsed-field gel electrophoresis and single-cell gel electrophoresis of MMC-treated cells showed that FA cells from complementation group C (FA-C cells, defective in the FANCC gene) form double-strand breaks and unhook MMC-induced ICL similarly to FANCC wild-type cells. These observations imply that the absence of RMN assembly in FA-C cells is not simply due to the absence of DNA ends produced as intermediates of ICL processing, and indicates a direct role for FANCC in RMN focus assembly in response to ICL inducers. Moreover, we show that the formation of foci, including BRCA1 and/or RAD51 proteins, is significantly delayed in FA cells. These alterations in the assembly of DNA-repair proteins in FA provide an interpretation for the DNA-damage processing anomalies observed in FA cells and for the genetic instability and the cancer predisposition of the syndrome.     

Evidence for preferential repair of 3-carbethoxypsoralen plus UVA induced DNA lesions in the active MAT{alpha} locus in Saccharomyces cerevisiae using the UvrABC assay

The occurrence of preferential repair in Saccharomyces cerevisiaeof the active MAT locus compared with the inactive HML locuswas confirmed after 254 nm UV irradiation. Experiments carriedout using the UvrABC excinuclease assay with the monofunctionalfurocoumarin 3-carbethoxypsoralen (3-CPs) plus UVA radiationwhich induce mainly monoadducts in DNA demonstrated preferentialrepair of the active MAT locus compared with the inactive HMLlocus in a SIR⁺ strain. However, as after 254 nm UV irradiation,no difference in the rate of removal of 3-CPs plus UVA inducedlesions was observed between the two loci in the sir-3 mutantin which both loci are active. Thus, it appears that 3-CPs plusUVA induced monoadducts as well as pyrimidine dinners a e subjectto preferential repair. ³To whom correspondence should be addressed     

Radiation-induced arrest of cells in G2 phase elicits hypersensitivity to DNA double-strand break inducers and an altered pattern of DNA cleavage upon re-irradiation

PURPOSE: To determine how radiation-induced arrest in G2 affects the response of mammalian cells to a challenging dose of radiation or to antitumour drugs producing DNA double-strand breaks. MATERIALS AND METHODS: V79 fibroblast survival to 5 Gy gamma-rays followed at intervals by 3 Gy irradiation or by contact with an equitoxic dose of neocarzinostatin or etoposide, was measured by clonogenic assays. The pattern of radiation-induced DNA double-strand breaks was determined by filter elution and CFGE (continuous field gel electrophoresis) or PFGE (pulsed-field gel electrophoresis) in G2-arrested cells as well as in nonpre-irradiated asynchronous or synchronized cells. The cell-cycle phase specificity of drug susceptibility was determined in synchronized HeLa cells. RESULTS: Cell kill by radiation-drug combined treatment varied markedly with the time elapsed after priming irradiation. Pre-irradiated, G2-arrested V79 fibroblasts demonstrated excess double-stranded DNA cleavage upon re-irradiation and hypersensitivity to drugs and radiation, although maximum resistance to both neocarzinostatin and etoposide in synchronized HeLa cells was in G2. This effect occurred in the megabase range only, with a peak around 4 Mbp; no change in the electrophoretic migration profile of DNA was observed below 1 Mbp. Moreover, the DNA migration profile and the yield of DNA cleavage in G2-arrested cells were close to those expected from S-phase cells. CONCLUSION: The available data suggest that mechanisms operating within the radiation-induced G2 block promote susceptibility to DNA double-strand break inducers at this stage. It is also proposed that the conformation of DNA in cells accumulated in G2 following irradiation bears resemblance to that for cells in S phase, due either to active repair mechanisms or to inhibition of chromosome disentanglement at the S-G2 transition.     

激素治疗增加绝经后健康妇女尿失禁的发病率和严重程度

问题：在绝经后健康妇女中，激素治疗（hormone therapy，HT）对尿失禁（urinary incontinence，UI）的效果如何？