Imaging of hypoxia in human tumors with [F-18]fluoromisonidazole.

Fluoromisonidazole (FMISO) has been shown to bind selectively to hypoxic cells in vitro and in vivo at radiobiologically significant oxygen levels. When labeled with the positron emitter fluorine-18 (F-18), its uptake in tissue can be detected quantitatively with high precision by positron emission transaxial tomography (PETT). This paper presents the first experiences with PETT imaging of [F-18]FMISO uptake in human malignancies, and describes the development of this technique as a tool for the non-invasive assessment of tumor hypoxia. Eight patients with selected cancers were imaged prior to primary radiotherapy, and 3 returned for follow-up scans, for a total of 11 imaging studies. Six of eight pre-radiotherapy studies revealed retention of [F-18]FMISO in tumors that significantly exceeded plasma concentrations by 2 hr after drug injection; all five patients with head and neck primaries had such "positive" scans. An analytic method for the interpretation of [F-18] FMISO PETT images is presented, defining hypoxic elements within a tumor volume as regions with a threshold regional tumor:plasma [F-18]FMISO ratio of greater than or equal to 1.4 by 2 or more hours after injection. Toward the end of a course of fractionated radiotherapy, three repeat studies in patients with initially positive scans showed no tumor accumulation of drug above the threshold ratio of 1.4, suggesting reoxygenation had occurred. Pharmacokinetic and dosimetry data support continued use of [F-18]FMISO as a safe hypoxia probe. Two imaging protocols have been developed for human studies; a long protocol allows for more complete biodistribution and dosimetry information, and a shorter protocol facilitates increased patient accrual by applying a simple, clinically expedient imaging procedure. When correlated with tumor outcome, [F-18]FMISO PETT imaging may be developed as a predictor of tumor response to conventional radiotherapy. The implications of this technique in addressing persistent questions of tumor hypoxia in human oncology is discussed.     

Characterization of clones of tumorigenic feline cells transformed by a chemical carcinogen

Tumorigenic clonal lines derived from soft agar colonies induced by DMBA-transformed feline embryo cells were isolated and characterized. The morphologically altered clonal cells formed large aggregates, growing in this aggregate form when suspended in liquid growth medium above an agar base and forming colonies in soft agar with high efficiency. When inoculated into athymic nude mice, chemically altered clonal cells produced progressively growing sarcomas. Cells established from the tumors morphologically resembled the DMBA-transformed feline embryo cells and were characterized as cat cells by karyological analysis. The tumorigenic lines were negative for feline oncornavirus-associated cell membrane antigen (FOCMA), and for "gag-X" the transformation-related polyprotein which is encoded by the replication defective feline sarcoma virus.     

Tumor colony formation by Friend virus-infected cells in immunosuppressed mice.

We have investigated the role of host immunological factors in the formation of "tumor colonies" in the spleens of unirradiated C57BL/6 X C3Hf/Bi FI mice 9 days after i.v. injection of spleen cells from Friend virus (FV)-infected C3Hf/Bi donors. Pretreatment of hosts with antilymphocyte serum (ATS) increased the number of tumor colonies. Pretreatment with formalinized FV-infected cells had the opposite effect, and ATS diminished the inhibitory effect of preimmunization. Cell suspensions from 11 individual FV-infected donors were examined. The suspensions differed with respect to their behavior on transplantation into untreated and ATS-pretreated F1 hybrid hosts. With several suspensions, the number of tumor colonies produced was approximately proportional to the number of cells injected; in all of these, ATS increased the slope of the line relating colony number to cell number. With most of the suspensions, tumor colony-forming efficiencies in untreated hosts strikingly decreased with increasing number of cells injected; ATS induced an increase in the number of tumor colonies and rendered the colony-forming response more nearly proportional to cell number. With two suspensions, few or no colonies developed; pretreatment with ATS had no significant effect. When the 11 cell suspensions were considered together, a proportional relation was found between the magnitude of the ATS effect (i.e., colony number in the presence of ATS minus colony number in the absence of ATS) and the colony-forming efficiency in ATS-treated mice. The ATS effect on the average was equivalent to a 2-fold increase in tumor colony-forming efficiency. We interpret these findings to indicate that two factors interact to determine the number of tumor colonies produced by spleen cells from FV-infected C3H donors in untreated F1 hybrid hosts. One is a property of the FV-infected cell population and includes its frequency of tumor colony-forming units; this factor varies widely among different cell suspensions. The other is a property of the tumor colony-forming units-host interrelationship and includes the vulnerability of tumor colony-forming units to the host immune response elicited by the injected cells; this factor appears to be constant with different cell suspensions. The present results show that the two factors can be dissociated in immunosuppressed hosts.     

透明质酸在宫颈上皮及宫颈癌组织中的表达

目的 :探讨透明质酸 (HA)在正常宫颈上皮及宫颈癌中的表达及其与肿瘤发生发展的关系。方法 :用免疫组化法检测 5 9例宫颈浸润癌、35例宫颈上皮内瘤样病变 (CIN)及11例正常宫颈组织中HA和CD4 4v6的表达。结果 :正常宫颈上皮不表达HA。慢性炎症者上皮底层细胞以及细胞间质表达HA ,随病变加重及CIN发生 ,HA表达增强。癌旁组织的上皮细胞HA呈强阳性表达 ,伴有基质HA强阳性染色。癌细胞HA阳性率为 6 7.2 7% ,与病理类型有关 ,角化癌高表达 ,而腺癌不表达 ,在低分化鳞癌中多见不规则灶性HA阴性区。宫颈鳞癌的肿瘤基质HA表达普遍增强。肿瘤基质的HA表达与CD4 4v6呈正相关。结论 :正常宫颈上皮不表达HA ,但炎症与致瘤因素可促使HA表达 ,HA的代谢失衡可能与宫颈癌的发生及浸润行为有关     

科学技术对中药发展的巨大推动作用

概述了近代科学技术对中药发展的巨大推动作用,列举了正反两方面的影响;指出中药的发展只有紧紧依靠科技进步,才能解决目前存在的问题,实现中药现代化。     

Changes in expression of sodium cotransporters and aquaporin-2 during ischemia-reperfusion injury in rabbit kidney

Ischemic renal injury is associated with defects in transport functions of the proximal tubules and urinary concentration ability. To determine whether alterations in expression of various transporter genes contribute to an impairment in renal functions, the expression of various solute transport genes was analyzed in renal cortex and medulla of rabbits with ischemic acute renal failure. Rabbits were subjected to 60 min of renal pedicle clamping followed by 24, 48, or 72 h of reperfusion. Urine volume and glomerular filtration rate were markedly decreased, which were accompanied by an increase in serum creatinine level and fraction Na+ excretion. Glucosuria and phosphaturia were evident during reperfusion periods. These alterations in renal functions were persisted to 72 h after reperfusion. The Na+-dependent uptakes of glucose and phosphate by brush border membrane vesicles were inhibited by 24 h of reperfusion. mRNA levels for Na+-glucose, Na+-phosphate, and Na+-succinate cotransporter analyzed by RT-PCR were not changed by 60 min of ischemia alone, but were significantly reduced by 24 h of reperfusion. mRNA levels for apical Na+-K+-2Cl- cotransporter, NaCl cotransporter, and turea transporter in the medulla were not changed during reperfusion. Protein levels for AQP2 in the medulla, but not AQP1 in the cortex, analyzed by Western blot were significantly reduced at 24 h after reperfusion. These results suggest that reductions in expression of Na+-cotransporter genes in the proximal tubules may be important factors in the impairment in Na+-dependent reabsorption of solutes and that decrease in AQP2 protein may be involved in defect in urinary concentration ability in rabbits with ischemic acute renal failure.     

Peroxiredoxins in breast carcinoma.

PURPOSE: Peroxiredoxins (Prxs) are a novel group of peroxidases containing high antioxidant efficiency and some of them having also effects on cell differentiation and apoptosis. The mammalian Prx family has six distinct members located in various subcellular locations, including peroxisomes and mitochondria, places where oxidative stress is most evident. EXPERIMENTAL DESIGN: We examined immunohistochemically a large set of samples from patients with breast carcinoma and investigated associations with parameters such as tumor-node-metastasis classification, hormone receptor status, and patient survival. Three biopsies of healthy breast tissue were used as controls. RESULTS: Expression of peroxiredoxins I, III, IV, and V was found in >or=80% of cases, whereas the expression of Prx II and VI was less frequent. Increased expression of Prx III was found to associate with the presence of progesterone (P = 0.02) and estrogen (P = 0.03) receptors, and Prxs IV (P = 0.009) and VI (P = 0.04) were overexpressed in progesterone receptor positive cases. Prx V was the only isoform that associated with items of tumor-node-metastasis classification, it was connected to a larger tumor size (P = 0.05) and positive lymph node status (P = 0.04). Prx V positivity was also connected with shorter survival (P = 0.04), whereas Prxs III (P = 0.002) and IV (P = 0.02) were related to better prognosis, probably resulting from their connection with a positive hormone receptor status. CONCLUSIONS: In conclusion, we found that expression of peroxiredoxins, especially III, IV and V, is increased in breast malignancy, suggesting the induction of Prxs as response to increased production of reactive oxygen species in carcinomatous tissue.