亮氨酸脑啡肽的电子结构及构效关系研究

对亮氨酸脑啡肽进行了量子化学(INDO)计算,研究其电子结构特征,讨论其活性部位、作用机理及构效关系。同吗啡和R31833进行了活性部位的电子结构与空间结构比较,推断它们的活性药效结构具有共同特点,与阿片受体相互作用时作用方式相同,作用部位有对应关系,因而具有相同的药理性质。     

Immunochemical evaluation of S-antigen of rabbit pineal gland

Purified S-antigen of photoreceptor cells induces experimental autoimmune uveoretinitis (EAU) and experimental autoimmune pinealitis (EAP) in laboratory animals. However, in rabbits, S-antigen induces only EAU without EAP. To evaluate this difference, the authors studied immunochemical reactivity of rabbit pineal gland with a panel of anti-S-antigen monoclonal antibodies (MAb). Rabbit pineal gland reacted with the MAbs by ELISA and immunoblot but not by immunohistochemistry. In contrast, rabbit retina like guinea pig retina, guinea pig pineal gland and bovine retina reacted with these MAbs by immunohistochemistry as well as by ELISA and immunoblot. Also, S-antigen purified from rabbit retina reacted as did bovine and guinea pig S-antigen. Therefore, S-antigen in situ in rabbit pineal gland is different from S-antigen of rabbit retina and different from S-antigen of pineal gland and retina of other species. Just as the MAbs did not react with S-antigen in rabbit pineal gland, it is possible that S-antigen activated lymphocytes may not recognize S-antigen in rabbit pineal gland and thereby not induce EAP.     

Upregulation of the ATR‐CHEK1 pathway in oral squamous cell carcinomas

The ATR‐CHEK1 pathway is upregulated and overactivated in Ataxia Telangiectasia (AT) cells, which lack functional ATM protein. Loss of ATM in AT confers radiosensitivity, although ATR‐CHEK1 pathway overactivation compensates, leads to prolonged G₂ arrest after treatment with ionizing radiation (IR), and partially reverses the radiosensitivity. We observed similar upregulation of the ATR–CHEK1 pathway in a subset of oral squamous cell carcinoma (OSCC) cell lines with ATM loss. In the present study, we report copy number gain, amplification, or translocation of the ATR gene in 8 of 20 OSCC cell lines by FISH; whereas the CHEK1 gene showed copy number loss in 12 of 20 cell lines by FISH. Quantitative PCR showed overexpression of both ATR and CHEK1 in 7 of 11 representative OSCC cell lines. Inhibition of ATR or CHEK1 with their respective siRNAs resulted in increased sensitivity of OSCC cell lines to IR by the colony survival assay. siRNA‐mediated ATR or CHEK1 knockdown led to loss of G₂ cell cycle accumulation and an increased sub‐G₀ apoptotic cell population by flow cytometric analysis. In conclusion, the ATR‐CHEK1 pathway is upregulated in a subset of OSCC with distal 11q loss and loss of the G₁ phase cell cycle checkpoint. The upregulated ATR‐CHEK1 pathway appears to protect OSCC cells from mitotic catastrophe by enhancing the G₂ checkpoint. Knockdown of ATR and/or CHEK1 increases the sensitivity of OSCC cells to IR. These findings suggest that inhibition of the upregulated ATR–CHEK1 pathway may enhance the efficacy of ionizing radiation treatment of OSCC. © 2013 Wiley Periodicals, Inc.     

部分脱乙酰甲壳质生物套管小间隙桥接修复周围神经损伤:免疫组织化学观察

目的:神经断端保留小间隙的静脉桥接模拟神经外膜形成神经再生室,为周围神经再生创造了良好的生理环境,从而保证神经束的良好对合。实验采用部分脱乙酰甲壳质作为套管材料,用小间隙桥接方法修复坐骨神经损伤,观察套管内的神经再生情况,并与传统外膜缝合法进行比较。方法:实验于2001-01/2002-10在北京大学人民医院创伤骨科实验室完成。①主要材料:实验所用中空圆柱形套管为北京大学人民医院与中国纺织科学院共同发明的一种部分脱乙酰甲壳质生物套管(专利号:01136314.2)。实验中所用套管尺寸为:管长4 mm,壁厚0.1 mm,内径1.5 mm。②实验动物:健康成年雄性SD大鼠20只,随机分成2大组,每组10只,每一大组全部10只动物的左腿坐骨神经为一组,右腿坐骨神经为另一组,每组10根坐骨神经。另取5只同样大鼠双侧坐骨神经未做处理作为正常对照组。③实验方法:外膜原位缝合组:切断坐骨神经,显微镜下神经外膜原位缝合;生物套管小间隙原位桥接组:切断坐骨神经,显微镜下小间隙套管桥接;断端旋转180°外膜缝合组:切断坐骨神经,显微镜下远端旋转180°后,神经外膜缝合;断端旋转180°生物套管小间隙桥接组:切断坐骨神经,显微镜下远端旋转180°后,小间隙套管桥接。④实验评估:术后第7,14,21,28,42天取坐骨神经,进行免疫组织化学染色及观察。结果:再生神经延套管中央走行,7 d时已有部分纤维通过2 mm间隙,14 d时有髓纤维数量明显多于近端。21 d后,套管组与原位外膜组新生有髓神经纤维数相近。再生纤维胞核数量较多,髓鞘纤细。套管结构完整。结论:此种部分脱乙酰甲壳质生物套管内的再生神经连续、整齐,髓鞘完整,其神经再生情况好于传统外膜缝合法。     

Cytogenetics of cranial base tumors

Summary Many different tumor types can arise in or invade the skull base. The more common tumors include, but are not limited to, angiofibromas, chondrosarcomas, chordomas, hemangiopericytomas, meningiomas, carcinomas, olfactory neuroblastomas, paragangliomas, pituitary adenomas, and rhabdomyosarcomas. Several of these tumors, including meningiomas, hemangiopericytomas, and rhabdomyosarcomas are characterized by nonrandom cytogenetic abnormalities. In this paper, we review the recognized chromosomal aberrations in cranial base tumors and illustrate the insights that can be gained into the genetic basis of tumor formation using karyotypes from skull base tumors that we have examined. As in tumors in other locations, chromosomal findings may be of diagnostic and prognostic value in cranial base tumors.     

Microsatellite instability in oral cancer

Generalized genomic instability, detected as somatic changes in allele sizes at microsatellite loci in tumors compared to peripheral lymphocyte DNA, is a recently recognized mechanism of mutation in cancer. Such instability results from the Somatic loss of DNA mismatch repair capability. Germ-line mutations at DNA mismatch repair loci confer susceptibility to colon cancer in hereditary non-polyposis colorectal cancer. Somatic loss of DNA mismatch repair has been reported in a large variety of other tumor types. Our goal was to determine the frequency of microsatellite instability in a large series of oral tumors. Out of 91 tumors analyzed for microsatellite instability, 6 (7%) showed microsatellite instability. Instability was observed at multiple loci with a range of 50-74% of loci affected. Alterations include both increase (74%) and decrease (26%) in allele sizes. The proportion of alleles affected ranged from 30-58% of all alleles. Our data suggest that somatic genomic instability plays a role in the pathogenesis of a small subset of oral tumors. © 1995 Wiley-Liss, Inc.     

Oral antibiotics in the management of perforated appendicitis in children

After appendectomy for perforated appendicitis children have traditionally been managed with intravenous broad-spectrum antibiotics for 5 to 10 days and then until fever and leukocytosis have resolved. We prospectively evaluated a protocol of hospital discharge on oral antibiotics when oral intake is tolerated-regardless of fever or leukocytosis-in a consecutive series of 80 children between one and 15 years of age who underwent appendectomy (38 open and 42 laparoscopic) for perforated appendicitis. At discharge subjects began a 7-day course of oral trimethoprim/sulfamethoxazole and metronidazole. Patients were discharged between 2 and 18 days postoperatively (mean 5.3 days). Sixty-six were discharged on oral antibiotics, and 28 of these had persistent fever or leukocytosis. Two patients (2.5%) developed postoperative intra-abdominal abscesses while inpatients. Wound infections developed in seven patients (8.8%) four of whom were on intravenous antibiotics. Among the 66 children who were discharged on oral antibiotics without having had an inpatient infectious complication there were three wound infections (4.4%). None of these patients had a fever or leukocytosis at discharge. We conclude that after appendectomy for perforated appendicitis children may be safely discharged home on oral antibiotics when enteral intake is tolerated regardless of fever or leukocytosis.     

Mechanisms leading to chromosomal instability

Chromosomal instability is a common feature of cancer cells. Several cellular mechanisms lead to numerical and structural chromosomal instability in cancer cells, including defects in chromosomal segregation, cellular checkpoints that guard against reproduction of abnormal cells, telomere stability, and the DNA damage response. Human papillomavirus interferes with these processes, causing chromosomal instability and tumor formation in some of the epithelial cells which it infects. The rate of discoveries about the mechanisms leading to chromosomal instability in cancer cells is increasing rapidly. Although these mechanisms were thought to be unrelated, they are intimately intertwined, connecting the complex network of cellular pathways. Since chromosomal instability is undoubtedly a major cause of tumor evasion of therapy, understanding the mechanisms leading to chromosomal instability has major translational significance.     

Chromosomal instability and marker chromosome evolution in oral squamous cell carcinoma

Squamous cell carcinoma of the head and neck and its subset, oral squamous cell carcinoma (OSCC), arise through a multistep process of genetic alterations as a result of exposure to environmental agents, such as tobacco smoke, alcoholic beverages, and viruses, including human papillomavirus. We and others have shown that the karyotypes of OSCC are near-triploid and contain multiple structural and numerical abnormalities. However, despite a background of clonal chromosomal aberrations, individual cells within a culture express many nonclonal numerical and structural abnormalities, termed chromosomal instability (CIN). To evaluate CIN in oral cancer cells, we isolated clones from two OSCC cell lines and carried out classical cytogenetic analysis, fluorescence in situ hybridization using centromere-specific probes, and spectral karyotyping. We observed variation in chromosome number within clones and between clones of the same cell line. Although similar numbers of centromeric signals for a particular chromosome were present, "homologs" of a chromosome varied structurally from cell to cell (marker chromosome evolution) as documented by classical and spectral karyotyping. In addition to the numerical chromosome variations within a clone, we observed marker chromosome evolution by structural chromosome alterations. It appears that both intrinsic structural alterations and extrinsic cytoskeletal factors influence chromosome segregation, resulting in individual tumor cells that express unique karyotypes. We show that CIN and marker chromosome evolution are essential acquired features of neoplastic cells. Proliferation of this heterogeneous cell population may provide some cells with the ability to evade standard therapies.