Amifostine (WR-2721) shortens the engraftment period of 4- hydroperoxycyclophosphamide-purged bone marrow in breast cancer patients receiving high-dose chemotherapy with autologous bone marrow support

4-Hydroperoxycyclophosphamide (4-HC), a commonly used marrow-purging agent, is active against many tumors, but is also toxic to normal marrow progenitors. Amifostine (WR-2721) is a sulfhydryl compound with chemoprotectant activity. Preclinical studies using suspensions of bone marrow and breast cancer cells demonstrated that ex vivo treatment with amifostine followed by 4-HC resulted in protection of marrow progenitors, with no compromise in the antitumor effect of 4-HC. This fact stimulated the development of a clinical trial. Bone marrow was harvested from 15 poor-prognosis breast cancer patients and randomly assigned to ex vivo treatment with amifostine followed by 4-HC (amifostine + 4-HC), or treatment with 4-HC alone. High-dose chemotherapy was then administered followed by infusion of the purged autologous bone marrow support (ABMS). Leukocyte engraftment, defined as a white blood cell count > or = 1 x 10(9)/L, was achieved in an average of 26 days for patients whose marrow was purged with amifostine + 4-HC versus 36 days for patients whose marrow was purged with 4-HC alone (P = .032). The average number of platelet transfusions (12 v 29; P = .017) and days of antibiotic therapy (28 v 40; P = .012) were significantly less for patients whose marrow was exposed to amifostine + 4-HC, compared with 4-HC alone. Unpurged backup marrow fractions were infused into three patients whose marrow was purged with 4-HC alone, because of inadequate marrow recovery. None of the patients who received amifostine + 4-HC-purged marrow required a backup marrow fraction. Complete remissions were achieved in 83% of patients with measurable disease, with no difference between the two cohorts. Forty- three percent of patients remained alive and progression-free at a mean of 13 months posttransplant. There was no significant difference in the rate or pattern of relapse for patients whose marrow was purged with amifostine + 4-HC compared with those whose marrow was purged with 4-HC alone. Ex vivo treatment of marrow with amifostine significantly shortens the time to marrow recovery, thereby reducing the risk of myelosuppressive complications in breast cancer patients receiving high- dose chemotherapy and 4-HC-purged ABMS. Since supportive care requirements are also significantly decreased, amifostine may reduce the cost of such therapy.     

Colorectal neoplasms: accuracy of US in demonstrating the depth of invasion

Six normal and 16 neoplastic colorectal specimens were examined with 8.5-MHz ultrasound (US). An articulated system facilitated precise spatial correlation between US and histologic sections. Images were blindly interpreted and then compared with histologic results. All six normal specimen showed five distinct echo layers and were distinguished from neoplastic specimens by all the observers. The central echogenic layer, corresponding to the submucosa, is useful in determining the depth of origin of a neoplasm and the presence of submucosal invasion. US had an accuracy of 92.5% in demonstrating invasion of the submucosa and 77% for invasion of the muscularis externa. For mucosal neoplasms with invasion through the muscularis externa and extension into the subserosal tissues, nearly 90% of US interpretations were correct. High-frequency US may be useful in determining the depth of invasion of mucosal tumors with respect to the submucosa and in differentiating mucosal from extramural masses.     

Risk factors for HIV infection among women in Dodoma region,Tanzania

Ｉｎｔｈｉｓｐａｐｅｒ ,ｗｅｒｅｐｏｒｔｅｄｒｉｓｋｆａｃｔｏｒｓａｓｓｏｃｉａｔｅｄｗｉｔｈＨＩＶｉｎｆｅｃｔｉｏｎａｍｏｎｇｗｏｍｅｎａｎｄｔｈｅｉｒｉｍｐｌｉｃａｔｉｏｎｓｆｏｒＡＩＤＳｐｒｅｖｅｎｔｉｏｎｅｆｆｏｒｔｓｉｎｔｈｅＤｏｄｏｍａｒｅｇｉｏｎ ,Ｔａｎｚａｎｉａ .1　ＳＵＢＪＥＣＴＳＡＮＤＭＥＴＨＯＤＳ1.1　Ｔｈｅｐｏｐｕｌａｔｉｏｎａｎｄｓａｍｐｌｅｓｅｌｅｃｔｉｏｎ　ＴｈｅｓｔｕｄｙｗａｓｃｏｎｄｕｃｔｅｄｉｎｔｈｅＤｏｄｏｍａｒｅｇｉｏｎ ,ｗｈｉｃｈｈａｓａｎｅｓｔｉｍａｔｅ…     

Pixel overflow artifacts in SPECT evaluation of the skeleton

The successful application of single photon emission computed tomography (SPECT) techniques to radionuclide evaluation of the skeleton depends on strict quality control measures, recognition of potential artifacts, and the selection of appropriate cases for specific reprocessing techniques. The application of simple image-processing routines to problems of "hot spot" and bladder pixel overflows facilitated a reduction in the technical inadequacy rate from 19% to 2% for SPECT evaluation of 100 hips, as well as improvement in diagnostic image quality in a variety of additional cases.     

Epigenetic silencing of microRNA-199b-5p is associated with acquired chemoresistance via activation of JAG1-Notch1 signaling in ovarian cancer

Epithelial ovarian cancer is a highly lethal and aggressive gynecological malignancy. The high mortality rate is due in part to the fact that many advanced cancer patients become refractory to current chemotherapeutic agents, leading to tumor recurrence and death. However, the underlying mechanisms leading to chemoresistance remain obscure. Here, we report that the loss of miR-199b-5p due to progressive epigenetic silencing leads to the activation of the JAG1-mediated Notch1 signaling cascade, thereby leading to the development of acquired chemoresistance in ovarian cancer. Using miRCURY LNA™ microRNA array and Q-PCR analyses of two pairs of cisplatin-sensitive and –resistant ovarian cancer cell lines, we identified miR-199b-5p as significantly down-regulated in cisplatin-resistant ovarian cancer cells and confirmed that miR-199b-5p is clinically associated with advanced and poor survival ovarian cancers. Interestingly, the loss of miR-199b-5p could be restored by 5-Aza-dC-mediated demethylation, and methylated specific PCR (MS-PCR), bisulfite-sequencing and pyrosequencing revealed that the promoter region of miR-199b-5p was hypermethylated. Computational and mechanistic analyses identified JAG1 as a primary target of miR-199b-5p. Notably, the reduced expression of miR-199b-5p was found to be inversely correlated with the increased expression of JAG1 using an ovarian cancer tissue array. Enforced expression of miR-199b-5p sensitized ovarian cancer cells to cisplatin-induced cytotoxicity both in vitro and in vivo. Conversely, re-expression of miR-199b-5p and siRNA-mediated JAG1 knockdown or treatment with Notch specific inhibitor γ-secretase (GSI) attenuated JAG1-Notch1 signaling activity, thereby enhancing cisplatin-mediated cell cytotoxicity. Taken together, our study suggests that the epigenetic silencing of miR-199b-5p during tumor progression is significantly associated with acquired chemoresistance in ovarian cancer through the activation of JAG1-Notch1 signaling.     

新吩嗪化合物K3-Ye的分离和结构鉴定

自一株基因工程链霉菌K₃的发酵液中分离得到一吩嗪类新化合物,经光谱数据(UL,IR,¹HNMR,¹³CNMR,DEPT)分析,确定其结构为1-吩嗪氧基乙酸甲酯,代号K₃-Ye。经初步测定它有较强的抗核苷转运活性。     

AMG-1对突触体内游离钙水平及大鼠尾动脉收缩力的影响

观察了AMG-1对高钾所致大鼠脑突触体内游离钙浓度[Ca²⁺]i升高,及去甲肾上腺素引起的离体大鼠尾动脉环收缩力的影响。结果表明,AMG-110和100μmol·L^-1可对抗高钾(30mmol·L^-1)引起的[Ca²⁺]i升高,使分别降低19±11%及57±12%;在无钙Krebs-Hensleleit液中,AMG-1能抑制去甲肾上腺素引起大鼠尾动脉收缩力的作用。     

Serum, plasma and paraffin-embedded tissues as sources of DNA for studying cancer susceptibility genes

The ability to isolate DNA from archived human serum, plasma and paraffin-embedded human tissues enhances opportunities to study breast, lung and other cancer risk factors. We report herein a simple and fast protocol for the extraction of genomic DNA from these sources. Using a phenol-based extraction method, the recovery for DNA is quantitative and reproducible. DNA yields in serum (250 microl) were between 162 and 1060 ng (n = 18 subjects), in plasma (250 microl) were between 165 and 375 ng (n = 5 subjects) and in embedded tissues (5-microm thick sections for ethanol fixed, and between 5- and 20-microm sections for formaldehyde fixation) were between 1 microg and 11.7 microg (n = 32 subjects). The extraction method was combined with newly designed PCR- based assays for cancer susceptibility marker genes such as CYP1A1 (exon 7), CYP2E1 (Dra1, Rsa1), GSTM1 and NAT2 [NAT2*5A (C481T), NAT2*6A (G590A), NAT2*7A (G857A)]. Genotyping results from the serum and paraffin-embedded tissues compared favorably to results from archived freshly frozen tissues, where concordance was 98% for serum, 100% for ethanol-fixed embedded tissues, and 97% for formaldehyde-fixed and paraffin-embedded tissues. This facile method will allow for the use of archived tissue samples of prospective cohort and other studies where intact DNA was not previously available.      

速激肽NK-1受体拮抗剂SR-140333对抗原引起致敏大鼠气道高反应性的影响

为观察速激肽ＮＫ１受体拮抗剂ＳＲ１４０３３３对抗原攻击引起的致敏大鼠气道高反应性的影响，测定了致敏大鼠在抗原攻击前后的基础呼吸频率，对ＭＣｈ的反应性及支气管肺泡灌洗液中的白细胞数量。实验结果显示，致敏大鼠吸入ＯＡ后６ｈ基础呼吸频率增加，并显著增加乙酰甲胆碱（ＭＣｈ）的反应性、ＭＣｈ的－ｌｏｇＰＣ３０值和支气管肺泡灌洗液中的白细胞数量。ｉｐ速激肽ＮＫ１受体拮抗剂ＳＲ１４０３３３（０１ｍｇ·ｋｇ－１）或地塞米松（０５ｍｇ·ｋｇ－１），可明显抑制上述反应，小剂量ＳＲ１４０３３３（００１ｍｇ·ｋｇ－１）仅有部分抑制作用。结果提示抗原攻击可引起致敏大鼠气道高反应性和气道炎症，速激肽ＮＫ１受体拮抗剂可抑制这些反应