Relationship between cytotoxicity,drug accumulation,DNA damage and repair of human ovarian cancer cells treated with doxorubicin: modulation by the tiapamil analog RO11-2933

Summary The effect ofN-(3,4-dimethoxyphenyl)N-methyl-2-(naphthyl)-m-dithiane-2-propylamine hydrochloride (RO11-2933), an analog of the calcium channel blocker tiapamil, on doxorubicin (DOX)-induced cytotoxicity and DNA damage in human ovarian cancer cells sensitive and resistant to DOX was investigated. A2780-DX2, A2780-DX3, and A2780-DX6 cell sublines were characterized by 7-, 26-, and 48-fold resistance after 2 h DOX exposure and 30-, 50-, and 500-fold resistance after 72 h DOX exposure, respectively. Increased drug efflux resulting in a lower intracellular drug accumulation, decreased DOX-induced DNA single-strand breaks (DNA SSBs), and rapid DNA repair correlated with the degree of resistance. In addition, DNA SSBs were rapidly repaired within 8 h in A2780-DX3 cells, whereas no significant repair of DNA SSBs was observed in sensitive cells. In comparison with verapamil, RO11-2933 was found to reverse DOX resistance at lower and nontoxic concentrations (2 M as compared with 10 M verapamil). This reversion was complete in cells with a low degree of resistance (A2780-DX1 and A2780-DX2) but partial in highly resistant cells (A2780-DX3 and A2780-DX6), and continuous exposure to RO11-2933 was essential for optimal reversal of drug resistance. Interestingly, RO11-2933 was found to inhibit the repair of DNA SSBs induced by DOX but not those induced by X-ray. These results suggest that the potentiation of DNA SSBs and the specific inhibition of DNA repair by RO11-2933 in multidrug-resistant cells could be of particular value in overcoming MDR in the clinic.Abbreviations RO11-2933 N-(3,4-dimethoxyphenethyl)-N-methyl-2-(2-naphthyl)-m-dithiane-2-propylamine hydrochloride - DOX doxorubicin-HCl - SSBs single-strand breaks - MDR multidrug resistance This work was supported in part by CA 18420 and CA 21071     

胆石形成基本因素和条件研究

通过扫描电镜和能谱仪同步检测胆囊粘膜、胆石和鲕石的超微结构、金属元素及其氧化物,观察胆石核心的细菌及胆囊收缩素对异形胆囊的收缩效应,探索肝胆功能、肝胆疾病和胆石症的关系。综合研究结果提出:胆石形成的启动因素是肝胆系统的感染与炎症;胆石形成的基本条件是肝胆系统整合和自稳态生理调节的紊乱;胆石结构形成是胆道内胆汁理化力学作用的结果:"肝胆同治"是胆石症的防治原则。     

Region-specific growth properties and trophic requirements of brain- and spinal cord-derived rat embryonic neural precursor cells

To determine whether neural precursor cells have region-specific growth properties, we compared the proliferation, mitogenicity, and differentiation of these cells isolated from the embryonic day 16 rat forebrain and spinal cord. Neural precursor cells isolated from both regions were cultured in growth medium supplemented with epidermal growth factor, basic fibroblast growth factor, or epidermal growth factor+basic fibroblast growth factor. Under all three conditions, both neural precursor cell populations proliferated for multiple passages. While spinal cord-derived neural precursor cells proliferated moderately faster in epidermal growth factor-enriched growth medium, brain-derived cells proliferated much faster in basic fibroblast growth factor-enriched growth medium. When exposed to both epidermal growth factor and basic fibroblast growth factor, the two neural precursor cell populations expanded and proliferated more rapidly than when exposed to a single factor, with brain-derived neural precursor cells expanding significantly faster than spinal cord-derived ones (P<0.0001). Differentiation studies showed that both neural precursor cell populations were multi-potent giving rise to neurons, astrocytes, and oligodendrocytes. However, neuronal differentiation from brain-derived neural precursor cells was greater than spinal cord-derived ones (11.95+/-5.00% vs 1.92+/-1.13%; passage 2). Further, the two neural precursor cell populations differentiated into a similar percentage of oligodendrocytes (brain: 8.66+/-5.85%; spinal cord: 7.69+/-3.91%; passage 2). Immunofluorescence and Western blot studies showed that neural precursor cells derived from both regions expressed receptors for basic fibroblast growth factor and epidermal growth factor. However, brain-derived neural precursor cells expressed higher levels of the two receptors than spinal cord-derived ones in growth medium containing epidermal growth factor+basic fibroblast growth factor. Thus, our results showed that neural precursor cells isolated from the two regions of the CNS have distinct properties and growth requirements. Identifying phenotypic differences between these neural precursor cell populations and their growth requirements should provide new insights into the development of cell therapies for region-specific neurological degenerative diseases.     

Role of new population of peripheral CD11c(+)CD8(+) T cells and CD4(+)CD25(+) regulatory T cells during acute and remission stages in rheumatoid arthritis patients.

BACKGROUND AND PURPOSE: Rheumatoid arthritis (RA) is a CD4(+)-dependent chronic systemic inflammatory disease with autoimmune features. Autoreactive CD4(+) T-cell activation can result in autoimmune diseases. One of the key regulators is the CD4(+)CD25(high) regulatory T (Treg) cell. In an animal arthritis model, CD11c(+)CD8(+) T cells were found to be elevated, and could suppress pathogenic CD4(+) T cells after cross-linking with CD137. The purpose of this study was to compare the expression of CD137, CD4(+)CD25(high) Treg cells, and CD11c(+)CD8(+) in the peripheral blood T lymphocytes of RA patients during active and remissive states, and evaluate the correlation with disease activity. METHODS: Thirty nine RA patients treated at the rheumatology outpatient clinic at the Changhua Christian Hospital were assessed clinically for disease activity and classified as either highly active or remissive by the Disease Activity Score 28. Peripheral blood mononuclear cells were isolated from these patients and compared against normal controls. RESULTS: The presence of CD11c(+)CD8(+) T cells or the expression of CD137 molecules in peripheral blood cells was not related to disease activity. In contrast, CD4(+)CD25(high) Treg cell levels were increased significantly in patients with active RA compared with patients with remissive RA or controls (p<0.05). These lymphocytes were intact, without evidence of apoptosis. CONCLUSIONS: Our results indicate that CD4(+)CD25(high) Treg cells play an important role in modulating RA disease activity and can serve as a parameter of disease activity.     

Effects of x-ray and CT image enhancements on the robustness and accuracy of a rigid 3D/2D image registration

A rigid body three-dimensional/two-dimensional (3D/2D) registration method has been implemented using mutual information, gradient ascent, and 3D texturemap-based digitally reconstructed radiographs. Nine combinations of commonly used x-ray and computed tomography (CT) image enhancement methods, including window leveling, histogram equalization, and adaptive histogram equalization, were examined to assess their effects on accuracy and robustness of the registration method. From a set of experiments using an anthropomorphic chest phantom, we were able to draw several conclusions. First, the CT and x-ray preprocessing combination with the widest attraction range was the one that linearly stretched the histograms onto the entire display range on both CT and x-ray images. The average attraction ranges of this combination were 71.3 mm and 61.3 deg in the translation and rotation dimensions, respectively, and the average errors were 0.12 deg and 0.47 mm. Second, the combination of the CT image with tissue and bone information and the x-ray images with adaptive histogram equalization also showed subvoxel accuracy, especially the best in the translation dimensions. However, its attraction ranges were the smallest among the examined combinations (on average 36 mm and 19 deg). Last the bone-only information on the CT image did not show convergency property to the correct registration.     

Genetic imbalances in pleomorphic xanthoastrocytoma detected by comparative genomic hybridization and literature review.

Pleomorphic xanthoastrocytoma (PXA) is a rare, low-grade astrocytic tumor found in the central nervous system. Histologically, the tumor is characterized by markedly pleomorphic and lipidized cells. Although most of the patients have a favorable prognosis, a small number of cases undergoing recurrence or progression to anaplastic astrocytoma were reported. Very few genetic studies have been performed on PXA because of its rarity and the pathogenesis of this neoplasm is largely unknown. In order to provide an overview of genetic alterations in PXA, we performed comparative genomic hybridization to identify chromosomal imbalances (DNA gains and losses) in three cases of PXA. Genetic imbalance was detected on at least one chromosome for each case. One case, which revealed multiple genetic alterations, showed a poor prognosis. DNA gain on chromosome 7 and loss on 8p were demonstrated in two of three cases, suggesting that the candidate gene(s) located on these regions may play a role in the development of PXA. Further studies are needed to identify the residing candidate genes that are involved in the tumorigenesis of PXA. In addition, the histopathological features and previous genetic studies on PXA are reviewed.     

Radiation-induced lung injury in vivo: Expression of transforming growth factor—Beta precedes fibrosis

Cytokine release from irradiated cells has been postulated to start soon after irradiation preceding detectable clinical and pathological manifestation of lung injury. The expression of transforming growth factor beta (TGF), a fibrogenic and radiation-inducible cytokine, was studied from 1–16 weeks after the 15 and 30 Gray (Gy) of thoracic irradiation to rats. Thoracic irradiation caused an increase in TGF protein in bronchoalveolar lavage (BAL) fluid peaking at 3–6 weeks as compared to sham-irradiated control rats. Steady state TGF mRNA expression as shown by whole lung northern blot assay paralleled the TGF protein expression in BAL fluid. The peak of TGF protein increase in BAL fluid between 3 and 6 weeks coincided with the initial influx of inflammatory cells in BAL fluid, but preceded histologically discernable pulmonary fibrosis that was not apparent until 8–10 weeks after irradiation. In conclusion, TGF and mRNA and protein upregulation preceded the radiation-induced pulmonary fibrosis, suggesting a pathogenetic role in the development of radiation fibrosis.     

多脏器恶性肿瘤术后肝黏膜相关淋巴组织淋巴瘤

目的 探讨肝黏膜相关淋巴组织淋巴瘤的临床病理特征。方法 对1例罕见多脏器恶性肿瘤术后肝黏膜相关淋巴瘤病例结合文献进行临床、病理和免疫组化分析。结果 患者于8年和3年前先后发生胃恶性间质瘤、阴囊阴茎皮肤湿疹样癌，有长期化疗史。肿瘤组织学以单核样B细胞为主，并有淋巴滤泡和淋巴上皮病变形成。免疫表型示瘤细胞CD45、CD79α、CD20阳性，CD5、CD10、ALK、TdT阴性，bcl—2、Ki—67少数肿瘤细胞阳性。结论 肝黏膜相关淋巴瘤可以发生于多脏器恶性肿瘤术后，其发病可能与长期使用免疫抑制剂有关，诊断本病时需与肝继发性淋巴瘤及肝的炎性假瘤鉴别。     

Training in clinical genetics and genetic counseling in Asia

The status of training in clinical genetics and genetic counseling in Asia is at diverse stages of development and maturity. Most of the training programs are in academic training centers where exposure to patients in the clinics or in the hospital is a major component. This setting provides trainees with knowledge and skills to be competent geneticists and genetic counselors in a variety of patient care interactions. Majority of the training programs combine clinical and research training which provide trainees a broad and integrated approach in the diagnosis and management of patients while providing opportunities for research discoveries that can be translated to better patient care. The background on how the training programs in clinical genetics and genetic counseling in Asia evolved to their current status are described. Each of these countries can learn from each other through sharing of best practices and resources.     

尺神经深支,骨间前神经旋前方肌支的应用解剖

尺神经深支向近侧无损伤分离后,可超越旋前方肌上缘以上26.58mm,此时宽1.80mm、厚1.00mm,可与宽1.35mm、厚0.89mm的旋前方肌支缝合。