To understand the biological role of BRCA1 in sporadic breast cancers, the relationship between DNA methylation of the BRCA1 promoter region and BRCA1 expression was studied using molecular biological and immunohistochemical methods. Furthermore, BRCA1 expression was compared with the expression of various cell cycle regulatory proteins and the morphological nuclear grade of cancer cells. Of 32 sporadic breast cancers investigated in this study, 10 (31%) revealed DNA methylation of the BRCA1 promoter region. The expression of BRCA1 was observed in the nuclei of cancer cells and 18 (56%) of 32 cancers were positive for BRCA1 immunoreactivity. Breast cancers with BRCA1 methylation lacked BRCA1 expression, except for only three cancers, and there was a significant inverse relationship between BRCA1 methylation and its expression in sporadic breast cancers (P = = = =0.043). Compared with the expression of various cell cycle regulatory proteins, breast cancers with BRCA1 methylation showed decreased expression of estrogen receptor (P = = = =0.016) and p27 (P = = = =0.018) and increased expression of p21 (P = = = =0.011). Furthermore, breast cancers without BRCA1 expression or with BRCA1 methylation had a tendency to contain nuclei with higher grade. These findings indicate that BRCA1 methylation might greatly influence its expression and BRCA1 expression might play an important role in cell cycle regulation and influence the grade of malignancy of sporadic breast cancers.Key words: BRCA1 -Expression -Immunohistochemistry -DNA methylation -Sporadic breast cancers BRCA1 has been identified by positioning cloning methods as a strong candidate for the 17q-linked gene for familial breast cancers and has been linked to more than 45% of familial breast cancers and 80% of families with breast and ovarian cancer.1) BRCA1 is a putative tumor suppressor gene located on chromosome 17q21 and spans 100 kb of genomic DNA, which encodes a protein of 220 kD consisting of 1863 amino acids.1) The BRCA1 protein is mainly localized in cell nuclei and is phosphorylated in a cell cycle-dependent manner.2) As regards subcellular nuclear localization, the BRCA1 protein has been reported to colocalize with Rad51, a homologue of bacterial RecA, in S phase cells, 3) which suggests a role for BRCA1 in the control of recombination and of genome integrity. However, the exact biological function of BRCA1 still remains unclear.More than 300 germline mutations have been identified so far in patients with familial breast and/or ovarian cancer.1, 4) These mutations are distributed across the entire coding region of the BRCA1 gene, and the majority is predicted to result in truncated proteins or loss of a BRCA1 transcript. Therefore, mutations in the BRCA1 gene may play a significant role in the tumorigenesis of familial breast cancer. 5,6) Though it has been shown that BRCA1 mRNA levels are reduced or absent in both sporadic and familial breast cancer, 7, 8) a few somatic mutations in the BRCA1 gene have been identified in sporadic breast cancers.9) Fr...
Feasibility of chromosomal manipulation in mammalian cells was first reported 15 years ago. Although this technique is useful for precise understanding of gene regulation in the chromosomal context, a limited number of laboratories have used it in actual practice because of associated technical difficulties. To overcome the practical hurdles, we developed a Cre-mediated chromosomal recombination system using fluorescent proteins and various site-specific recombinases. These techniques enabled quick construction of targeting vectors, easy identification of chromosome-rearranged cells, and rearrangement leaving minimum artificial elements at junctions. Applying this system to a human cell line, we successfully recapitulated two types of pathogenic chromosomal translocations in human diseases: MYC/IgH and BCR/ABL1. By inducing recombination between two loxP sites targeted into the same chromosome, we could mark cells harboring deletion or duplication of the inter-loxP segments with different colors of fluorescence. In addition, we demonstrated that the intrachromosomal recombination frequency is inversely proportional to the distance between two recombination sites, implicating a future application of this frequency as a proximity sensor. Our method of chromosomal manipulation can be employed for particular cell types in which gene targeting is possible (e.g. embryonic stem cells). Experimental use of this system would open up new horizons in genome biology, including the establishment of cellular and animal models of diseases caused by translocations and copy-number variations.
Whole-blood aggregometry is useful for monitoring the efficacy of anti-platelet therapy for KD.
Introduction: We have suggested that inhibition of P2X4 purinoceptor, which is involved in the endothelial flow sensing mechanism, prevents cerebral aneurysm development and growth in an animal model. Therefore, we retrospectively investigated whether a P2X4 inhibitor, paroxetine used as an antidepressant, has an inhibitory effect on the growth of unruptured cerebral aneurysms and the rate of recanalization after coil embolization. Methods: Among the cases registered in the J-ASPECT Study, the Japanese stroke inpatient reimbursement database, from 2010 to 2019, we searched for cases who were taking paroxetine and with registered unruptured cerebral aneurysm or had undergone cerebral aneurysm coil embolization. We then invited medical centers with these cases to participate in the study and enrolled cases that met the selection criteria by referring to the imaging data and patient background of the cases. The inhibitory effect in the paroxetine-treated group was compared with that of the control group in a multivariate analysis after adjustment for age, gender, and known risk factors. Results: There were 708 cases at 226 facilities nationwide that were potentially matched in the criteria. Seventy-four facilities participated, of which 74 cases at 45 facilities met the selection criteria. A total of 700 control cases were enrolled from 14 core participating centers. The rate of growth incidence of aneurysms was 0.0318 for paroxetine-treated cases (n=36) and 0.0960 for control cases (397). The significant factors (regression coefficients) were paroxetine (-2.26), specific sites of occurrence (-1.28), shape irregularity (1.63), age (0.11), female (1.54), hypertension (-0.55), statin (0.87), and family history of stroke (0.71). The significant factors (odds ratios) in recanalization after 1 year of coil embolization were paroxetine (0.21), complete embolization (0.26), ruptured aneurysm (3.95), and size (1.14). Conclusions: This retrospective study suggests that P2X4 inhibitors including paroxetine may be clinically applicable as agents to inhibit the growth of unruptured cerebral aneurysms and recanalization after 1 year of aneurysm coil embolization. The use of reimbursement information may be useful when collecting very rare cases.
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