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31.
P Eiselt BS Kim B Chacko B Isenberg MC Peters KG Greene WD Roland AB Loebsack KJ Burg C Culberson CR Halberstadt WD Holder DJ Mooney 《Canadian Metallurgical Quarterly》1998,14(1):134-140
Apoptosis associated oligonucleosomal fragmentation of DNA can result from the activation of endonucleases that exhibit different pH optima and are either sensitive or insensitive to divalent cations. DNA fragmentation due to activation of cation sensitive endonucleases occurs in the absence of a change in intracellular pH whereas intracellular acidification is a feature of apoptosis characterized by activation of cation insensitive acidic endonuclease. We have reported earlier that somatostatin (SST) induced DNA fragmentation and apoptosis is signaled in a receptor subtype selective manner uniquely via human somatostatin receptor subtype 3 (hSSTR3). In the present study we investigated the pH dependence and cation sensitivity of endonuclease induced in hSSTR3 expressing CHO-K1 cells by the SST agonist octreotide (OCT) and its effect on intracellular pH. We show that OCT induced apoptosis is associated with selective stimulation of a divalent cation insensitive acidic endonuclease. The intracellular pH of of cells undergoing OCT induced apoptosis was 0.9 pH units lower than that of control cells. The effect of OCT on endonuclease and pH was inhibited by orthovanadate as well as by pretreatment with pertussis toxin, suggesting that hSSTR3 initiated cytotoxic signaling is protein tyrosine phosphatase mediated and is G protein dependent. These findings suggest that intracellular acidification and activation of acidic endonuclease mediate wild type p53 associated apoptosis signaled by hormones acting via G protein coupled receptors. 相似文献
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AI Robles ML Rodriguez-Puebla AB Glick C Trempus L Hansen P Sicinski RW Tennant RA Weinberg SH Yuspa CJ Conti 《Canadian Metallurgical Quarterly》1998,12(16):2469-2474
Cyclin D1 is part of a cell cycle control node consistently deregulated in most human cancers. However, studies with cyclin D1-null mice indicate that it is dispensable for normal mouse development as well as cell growth in culture. Here, we provide evidence that ras-mediated tumorigenesis depends on signaling pathways that act preferentially through cyclin D1. Cyclin D1 expression and the activity of its associated kinase are up-regulated in keratinocytes in response to oncogenic ras. Furthermore, cyclin D1 deficiency results in up to an 80% decrease in the development of squamous tumors generated through either grafting of retroviral ras-transduced keratinocytes, phorbol ester treatment of ras transgenic mice, or two-stage carcinogenesis. 相似文献
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QY Yao DS Croom-Carter RJ Tierney G Habeshaw JT Wilde FG Hill C Conlon AB Rickinson 《Canadian Metallurgical Quarterly》1998,72(5):4352-4363
In apparent contrast to earlier work on Epstein-Barr virus (EBV) carriage in the general Caucasian population, in vitro virus isolations from human immunodeficiency virus (HIV)-positive male homosexual cohorts have shown frequent examples of multiple EBV infection and an overall prevalence of type 2 EBV strains exceeding 30%. Here we ask to what extent these findings might hold true in another T-cell-immunocompromised cohort, HIV-positive hemophilic patients. Resident EBV strains were rescued within lymphoblastoid cell lines derived from the blood and throat washings of 39 such individuals, using the same in vitro protocols of virus isolation as for the homosexual cohort. A mean of 19 independent cell lines was made per patient, and in each case the resident virus was characterized by PCR-based viral genomic analysis and by immunoblotting to reveal the viral "EBNAprint." By these criteria a significant proportion (14 of 39) of the hemophilic cohort carried more than one EBV strain, suggesting that T-cell impairment does indeed sensitize virus carriers to reinfection with new strains of exogenously transmitted virus. However, the overall incidence of type 2 EBV infection was 10%, which is close to that observed in the earlier work with healthy carriers and substantially lower than that seen in HIV-positive homosexuals. We infer that type 2 EBV is relatively rare in the general Caucasian population but has become endemic in the homosexual community. 相似文献
36.
AM Jackson AV Ivshina O Senko A Kuznetsova A Sundan MA O'Donnell S Clinton AB Alexandroff PJ Selby K James VA Kuznetsov 《Canadian Metallurgical Quarterly》1998,159(3):1054-1063
PURPOSE: The goal of this research was to discover new biological indicators in urine which could be used for short-term prognosis of local Bacillus Calmette-Guerin (BCG) therapy outcome in patients with superficial bladder cancer. PATIENTS AND METHODS: We measured and statistically evaluated soluble immunological molecules in urine from bladder cancer patients (n = 34) receiving BCG intravesically. Urine was collected following each of 6 weekly treatments, processed and assayed. The data base included measurements of interleukin-1 (IL-2, IL-4, IL-6, IL-10, IL-12, soluble intercellular adhesion molecule-1 (sICAM-1), tumour necrosis factor-alpha (TNF alpha), soluble CD14 (sCD14), interferon-gamma (IFN gamma), GM-CSF, volume of urine and its pH. The clinical response was evaluated by urine histology and random quadrant biopsy 3 months after the start of therapy. Patients were divided into 2 groups, with good and poor therapeutic effect. The initial complete response rate was 62% (21/34). The data base was analyzed using traditional multivariate statistical methods and a pattern recognition method which deals with combinatorial-statistical analysis (statistically weighted syndromes (SWS) method) of the gradated features. The SWS method is capable of identifying robust patterns in small "fuzzy" sets with high dimensional objects and some missing values. RESULTS: Only one parameter gave significant differences at p < 0.05, GM-CSF at instillation 6. Repeated measurement analysis of variance, backward stepwise multiple logistic regression and linear discriminant analysis failed to show any significance. However, significant differences in the structure of correlation between features in the groups with and without therapeutic effect were observed and four highly informative variables (the masses of sICAM-1, TNF alpha, sCD14 and pH) relating to 5th-6th installations were selected by SWS. These features provided accurate individual prediction of therapeutic outcome for all our patients. Cross-validation analysis and computer simulation showed the statistically significant stability of the prediction. CONCLUSION: We have selected a set of urinary variables that could be considered as a perspective combination of indicators (syndromes) of outcome of pre-operation BCG therapy of patients with superficial bladder cancer. A larger patient database will provide testing and evaluation of the biological and clinical significance of selected features. The computational syndrome-disease approach should be applicable for the solution of decision-making problems for management of cancer. 相似文献
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The smoking habits of 56 families who lost babies to the sudden infant death syndrome (SIDS) were compared to those of 86 control families. A higher proportion of SIDS mothers smoked both during pregnancy (61% vs. 42%) and after their babies were born (59% vs. 37%). SIDS mother also smoked a significantly greater number of cigarettes than controls. Exposure to cigarette smoke ("passive smoking") appears to enhance the risk of SIDS for reasons not known. 相似文献
39.
Thyroid cancer after exposure to external radiation: a pooled analysis of seven studies 总被引:1,自引:0,他引:1
E Ron JH Lubin RE Shore K Mabuchi B Modan LM Pottern AB Schneider MA Tucker JD Boice 《Canadian Metallurgical Quarterly》1995,141(3):259-277
The thyroid gland of children is especially vulnerable to the carcinogenic action of ionizing radiation. To provide insights into various modifying influences on risk, seven major studies with organ doses to individual subjects were evaluated. Five cohort studies (atomic bomb survivors, children treated for tinea capitis, two studies of children irradiated for enlarged tonsils, and infants irradiated for an enlarged thymus gland) and two case-control studies (patients with cervical cancer and childhood cancer) were studied. The combined studies include almost 120,000 people (approximately 58,000 exposed to a wide range of doses and 61,000 nonexposed subjects), nearly 700 thyroid cancers and 3,000,000 person years of follow-up. For persons exposed to radiation before age 15 years, linearity best described the dose response, even down to 0.10 Gy. At the highest doses (> 10 Gy), associated with cancer therapy, there appeared to be a decrease or leveling of risk. For childhood exposures, the pooled excess relative risk per Gy (ERR/Gy) was 7.7 (95% CI = 2.1, 28.7) and the excess absolute risk per 10(4) PY Gy (EAR/10(4) PY Gy) was 4.4 (95% CI = 1.9, 10.1). The attributable risk percent (AR%) at 1 Gy was 88%. However, these summary estimates were affected strongly by age at exposure even within this limited age range. The ERR was greater (P = 0.07) for females than males, but the findings from the individual studies were not consistent. The EAR was higher among women, reflecting their higher rate of naturally occurring thyroid cancer. The distribution of ERR over time followed neither a simple multiplicative nor an additive pattern in relation to background occurrence. Only two cases were seen within 5 years of exposure. The ERR began to decline about 30 years after exposure but was still elevated at 40 years. Risk also decreased significantly with increasing age at exposure, with little risk apparent after age 20 years. Based on limited data, there was a suggestion that spreading dose over time (from a few days to > 1 year) may lower risk, possibly due to the opportunity for cellular repair mechanisms to operate. The thyroid gland in children has one of the highest risk coefficients of any organ and is the only tissue with convincing evidence for risk about 1.10 Gy. 相似文献
40.
GA Kaltsas JJ Mukherjee PN Plowman JP Monson AB Grossman GM Besser 《Canadian Metallurgical Quarterly》1998,83(12):4233-4238
Pituitary tumors are mostly benign lesions, although 5-35% are locally invasive. A small number exhibit a more aggressive course, infiltrating dura, bone and sinuses, and are designated highly aggressive. However, the presence of metastases separate from the pituitary in the central nervous system or at a distance is necessary to designate pituitary tumors as carcinomas, i.e. truly malignant. When conventional therapeutic modalities fail, systemic chemotherapy remains the last option. We report seven such patients, three with highly aggressive and four with malignant pituitary tumors (n=4) four women; median age, 32 yr; range, 23-48 yr), who received one or more courses of chemotherapy with lomustine and 5-fluorouracil (median, two courses; range, one to six courses). Three patients with systemic metastatic disease had a shorter survival (median, 5 months; range, 1-14 months) than the one patient with central nervous system metastases alone (10 yr). A patient with an aggressive nonmetastatic prolactinoma who initially responded to chemotherapy died from another nondisease-associated cause. Two patients, one with an aggressive and one with a metastatic tumor, achieved symptomatic improvement with a median duration of 6 months. A hormonal reduction greater than 50% was observed in two of seven patients; only one patient who had an aggressive tumor obtained an objective tumor response. The median survival from the time of initiation of chemotherapy in patients with malignant tumors ranged from 3-65 months. Two patients with malignant tumors developed disease progression while receiving chemotherapy; no patient with extracranial metastases showed a response. Treatment was well tolerated, with minimal individual side-effects. Three patients with no response to initial treatment received different chemotherapeutic regimens with no additional response. All patients with metastatic malignant tumors eventually died. Treatment with cytotoxic chemotherapy is noncurative, and current experience is limited. Until another more specific form of treatment is available, chemotherapy may still be of some value in patients with highly aggressive and malignant pituitary tumors, at least in achieving a temporary remission or delay in progression. The combination of lomustine/5-fluorouracil proved easy to administer with minimal toxicity, although the response rate was only 14%. Until a more specific treatment is found, an optimal chemotherapeutic regimen needs to be established. 相似文献