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At least 937 records · Page 52Linked to original sources
PubMed2000

Usefulness of continuous oxygen insufflation into trachea for management of upper airway obstruction during anesthesia.

BACKGROUND: Severe complications associated with upper airway obstruction often occur during the perioperative period. Development of a simple and reliable technique for reversing the impaired airway patency may improve airway management. The purpose of the current study is to evaluate the usefulness of transtracheal oxygen insufflation (TTI) for management of upper airway obstruction during anesthesia and to explore the mechanisms of TTI in detail. METHODS: During propofol anesthesia in eight spontaneously breathing patients, the upper airway cross-sectional area and pressure-flow measurements during neck flexion with TTI were compared with those during triple airway maneuvers (TAM) without TTI. Blood gas analyses assessed efficacy of CO2 elimination during TTI in an additional nine patients. RESULTS: TTI achieved adequate PaCO2 and PaO2 levels equivalent to those during TAM. In addition to a significantly smaller cross-sectional area during TTI, the location and slope of the pressure-flow relation during TTI completely differed from those during TAM, indicating that upper airway resistance was much higher during TTI. Notably, minute ventilation during TTI was significantly smaller than that during TAM, suggesting reduced dead space or other mechanisms for CO2 elimination. CONCLUSIONS: TTI is capable of maintaining adequate blood gases through mechanisms different from those of conventional airway support in anesthetized subjects with upper airway obstruction.

Adult↗
PubMed1995

Possible mechanisms in the emergence of tamoxifen-resistant breast cancer.

Tamoxifen (TAM), a non-steroidal antiestrogen, is the endocrine treatment of choice for all stages of breast cancer. However, despite a favorable initial response to therapy, most tumors will eventually exhibit TAM resistance resulting in disease recurrence. Several mechanisms of TAM resistance have been proposed, yet a single distinct mechanism has not been identified. We will systematically consider the following steps of the estrogen receptor (ER)-mediated signal transduction pathway to identify possible sites of alteration leading to tamoxifen-resistance: (1) ligand metabolism and availability, (2) loss or mutation of the ER, (3) defects in ER post-translational modification, and (4) alteration of the estrogen response element (ERE). In particular, the ERE will be discussed as a position in the signal transduction pathway with considerable potential, if altered, to confer TAM resistance.

Antineoplastic Agents, Hormonal↗
PubMed2004

Rate of thymidine analogue resistance mutation accumulation with zidovudine- or stavudine-based regimens.

Zidovudine (ZDV) and stavudine (d4T) select for the same set of thymidine analogue resistance mutations (TAMs). To compare the rate at which TAMs emerge, genotypic analysis of HIV-1 was performed on serial plasma samples from treatment-naive subjects randomly assigned to receive ZDV or d4T in combination with lamivudine. After 72 weeks of follow-up, TAMs were detected in samples from 50% of ZDV-treated subjects and 45% of d4T-treated subjects (P = 0.79). The frequency of K70R and T215Y or F mutations was similar in both groups, although M41L was observed more frequently in samples from ZDV-treated subjects. This randomized study shows that TAMs accumulate at similar rates during treatment with ZDV or d4T, but the specific pattern of mutations may differ somewhat in patients treated with these thymidine analogues.

Drug Resistance, Multiple, Viral↗
PubMed2004

Patterns of resistance emerging in HIV-1 from antiretroviral-experienced patients undergoing intensification therapy with tenofovir disoproxil fumarate.

Study GS-99-907 was a 48-week, phase 3, double-blind, placebo-controlled intensification trial of tenofovir disoproxil fumarate (tenofovir DF). Antiretroviral-experienced patients added tenofovir DF 300 mg once daily to their existing regimen. The patterns of HIV-1 resistance development and the corresponding virologic responses were evaluated in a virology substudy at week 48. Although 94% of these treatment-experienced patients had nucleoside-associated resistance mutations (NAMs) at baseline, addition of tenofovir DF resulted in a mean reduction in viral load of -0.59 log10 copies/mL after 24 weeks that was durable through 48 weeks. Relative to the placebo-controlled arm, patients in the tenofovir DF arm had a reduced frequency of development of resistance mutations to all classes of HIV-1 inhibitors, with reduction in new protease inhibitor (PI)-associated mutations achieving statistical significance. The K65R mutation, which occurred in 8 patients (3%), was the only emergent mutation directly associated with tenofovir DF therapy. New thymidine analogue-associated mutations (TAMs) emerged in 19% of patients by week 48. Other than K65R, the patterns of mutations that developed were not significantly different between the tenofovir DF and placebo control arms, suggesting that the background therapies caused their development. The K65R mutation emerged only in patients with no detectable TAMs at baseline, whereas new TAMs developed similarly between patients with or without TAMs at baseline. Development of K65R was associated with mostly low-level changes in phenotypic susceptibility to tenofovir DF and other nucleoside reverse transcriptase inhibitors and was not associated with viral load rebound. No novel patterns of genotypic or phenotypic resistance to tenofovir were identified. Therefore, intensification with once-daily tenofovir DF therapy resulted in a sustained reduction in HIV-1 viral load and a low risk for development of the K65R mutation in this treatment-experienced patient population.

Acquired Immunodeficiency Syndrome↗
PubMed2004

Diminished representation of HIV-1 variants containing select drug resistance-conferring mutations in primary HIV-1 infection.

This study compared the incidence of HIV-1 variants harboring mutations conferring resistance to thymidine analogues, ie, thymidine analogue mutations (TAMs), nonnucleoside reverse transcriptase (RT) inhibitors (NNMs), lamivudine (3TC) (ie, M184V), and protease inhibitors (PIs) acquired in primary HIV infection (PHI) (n = 59) to their observed prevalence in a corresponding potential transmitter (PT) population of persons harboring resistant infections (n = 380). Both of these populations in the context of this cohort analysis possessed similar demographics. Whereas the frequencies of observed TAMs, NNMs, M184V, and protease-associated mutations (PRAMs) were similar in the PT groups, the prevalence of M184V and major PI mutations were significantly lower in the PHI group (PHI/PT ratios of 0.14 and 0.39, respectively). There was a decreased prevalence in the PHI population of resistant viruses co-expressing NNMs or TAMs with M184V compared with viruses that harbored NNMs or TAMs in the absence of M184V (P < 0.0001). It was also observed that individuals in the PT subgroups who harbored RT mutations or PRAMs with M184V had lower levels of plasma viremia than individuals who lacked M184V (P < 0.05). These findings suggest that both decreased viremia and viral fitness in the case of M184V-containing HIV-1 variants may impact on viral transmissibility.

Acute Disease↗
PubMed2006

Diminished selection for thymidine-analog mutations associated with the presence of M184V in Ethiopian children infected with HIV subtype C receiving lamivudine-containing therapy.

BACKGROUND: We retrospectively studied the effect of the lamivudine-induced reverse transcription mutation M184V on selection of thymidine analog mutations (TAMs) in HIV subtype C-infected children and on clinical outcome. METHODS: We genotyped 135 blood samples from 55 children. TAMs accumulation, viral load and clinical outcome were compared in children maintained on zidovudine/stavudine + lamivudine + protease inhibitor/nonnucleoside reverse transcriptase inhibitor (PI/NNRTI) despite loss of viral suppression and in children treated with, or switched to, other nucleoside reverse transcriptase inhibitors (NRTIs). Drug susceptibility and replication capacity of selected samples were measured. RESULTS: M184V developed in 18 of 22 of children who had received only zidovudine/stavudine + lamivudine + PI/NNRTI during a mean of 23.2 +/- 3.2 months versus in 3 of 14 children treated with other drugs and/or having multiple regimen changes (P = 0.001). TAMs appeared, respectively, in 2 of 22 versus 12 of 14 (P < 0.0001). The 2 groups did not differ significantly in baseline HIV-RNA or CD4 count, sampling time, and follow-up period. In M184V-containing samples, we found large reductions in susceptibility to lamivudine and emtricitabine but not to other NRTIs. When T215Y was present without M184V, susceptibility to zidovudine was reduced 8-fold. When both M184V + T215Y occurred, susceptibility to zidovudine was substantially increased. Average inhibition concentration 50 values were similar to those documented in the Stanford database for subtype B HIV with these mutation patterns. CONCLUSIONS: Maintaining a thymidine analog + lamivudine-based regimen reduced accumulation of TAMs and increased zidovudine susceptibility. This is likely the result of an increased susceptibility to thymidine analog (zidovudine) in the context of M184V documented here for the first time in subtype C-infected children. This retrospective study supports the strategy of maintaining lamivudine-containing therapy in subtype C-infected children. This strategy may be beneficially applied in the treatment of children in Africa, where thymidine analog + lamivudine-based regimen became available recently but further options are limited.

Anti-HIV Agents↗
PubMed2004

Progression through meiosis I and meiosis II in Arabidopsis anthers is regulated by an A-type cyclin predominately expressed in prophase I.

Meiosis is often described as a special case of cell division since it differs from mitosis in having two nuclear divisions without an intervening S-phase. It will be of great interest to uncover what molecular mechanisms underlie these special features of meiosis. We previously reported that the tardy asynchronous meiosis (tam) mutant of Arabidopsis (Arabidopsis thaliana) is slower in cell cycle progression in male meiosis. Here we report that TAM encodes the A-type cyclin, CYCA1;2. The point mutation in tam replaced a conserved threonine with an isoleucine in the linker region between the alpha4 and alpha5 helices of the first cyclin fold. By studying the dynamics of a CYCA1;2-green fluorescent protein fusion protein under the control of the CYCA1;2 promoter, we found that the fusion protein was most abundant at pachytene, but was undetectable from late prophase I until telophase II. Nonetheless, cell cycle progression in tam was delayed in both pachytene and meiosis II. We conclude either that the CYCA1;2 produced in prophase I indirectly regulates meiosis II progression, or that a very low level of CYCA1;2 directly regulates meiosis II progression. Either of these scenarios is a deviation from the typical mode of action of mitotic cyclins in mitosis and meiosis I, in which each nuclear division is coupled with a peak of expression of mitotic cyclins.

Arabidopsis↗
PubMed1991

Piroxicam, indomethacin and aspirin action on a murine fibrosarcoma. Effects on tumour-associated and peritoneal macrophages.

Growth of a methylcholanthrene-induced fibrosarcoma in BALB/c mice was accompanied by an increase in the activation state of tumour-associated macrophages (TAM), as measured by their FcIgG receptor expression, phagocytic index and beta-glucuronidase levels. All of these parameters were markedly higher in TAM than in peritoneal macrophages (PM) derived from the same animal. On the other hand, PM from tumour-bearing mice showed lower activation parameters than PM from normal animals. We also studied the effect on tumour development of three inhibitors of prostaglandin synthesis: indomethacin, piroxicam and aspirin. Intraperitoneal administration of these drugs during 8 d was followed by the regression of palpable tumours. Indomethacin (90 mg/d) induced 45% regression, while with piroxicam (two 400 mg/d doses and six 200 mg/d doses) and aspirin (1 mg/d) 32% and 30% regressions, respectively, were observed. The growth rate of nonregressing tumours, which had reached different volumes by the end of the treatment, was delayed to a similar extent by the three anti-inflammatory non-steroidal drugs (NSAID). With respect to TAM, the treatment did not induce any significant change in their activation state, though both piroxicam and indomethacin increased slightly the TAM number. In contrast, NSAID administration was followed by a remarkable increase in the activation parameters of PM when compared with PM from tumour-bearing mice receiving no treatment. Indeed, these parameters were in some cases higher than those of PM from normal mice. The leukocytosis (60,000/microliters) with neutrophilia (80%) induced by tumour growth on peripheral blood leukocytes (PBL) was reversed by the treatment to values close to normal, in parallel with the reduction of tumour size. A drop in haematocrit was also noted which was most probably a consequence of tumour growth rather than of the treatment. This study reveals that the three NSAID tested have a remarkable antitumour activity, which correlates with the restoration of PM activity and PBL values.

Animals↗
PubMedDate not supplied

Function of estrogen receptor isoforms alpha and beta in endometrial carcinoma cells.

The aim of this study was to explore how to modulate the expression of estrogen receptors (ER) alpha and beta and to verify the role of ERalpha and beta in relationship to estrogen and tamoxifen (TAM). A series of oligodeoxyribonucleotides (ODN) corresponding to regions of the ERalpha or beta was tested in human endometrial cancer cell lines (HEC-1B). The change in HEC-1B proliferation in response to 17beta-estradiol (E(2)) and TAM under the impact of antisense ODN was studied. The results of the study are as follows: 1) transfection with antisense ODN significantly inhibited ERalpha and ERbeta protein production, 2) the cells lost the ability to proliferate in response to E(2) after transfection with ERalpha antisense ODN especially at 24, 48, and 72 h. There was no obvious change in response to E(2) in HEC-1B cell lines that were transfected with ERbeta antisense ODN, and 3) after transfection with ERalpha antisense ODN, HEC-1B cells lost the ability to proliferate in response to TAM at 48 h. This inhibition was also observed after transfection with ERbeta antisense ODN at 24 h. ERalpha may be the primary receptor in the proliferation of HEC-1B cells in response to E(2). Both ERalpha and ERbeta are involved in the agonist impact of TAM on endometrial cancer cells.

Cell Proliferation↗
PubMed1998

Association of dehydroepiandrosterone sulfate, body composition, and physical fitness in independent community-dwelling older men and women.

OBJECTIVES: To determine the association of dehydroepiandrosterone sulfate (DHEAS), body composition, and physical fitness in independent community-dwelling men and women aged 60 to 80 years. DESIGN: Cross sectional analysis. PARTICIPANTS: Independent men and women, 60 years of age and older, living in urban and suburban communities of Southeastern Wisconsin. MEASUREMENTS: History, physical examination, physical activity level, and anthropometrics were measured for every subject. Total adipose mass (TAM) and lean body mass were measured using dual energy X-ray absorptiometry. Dehydroepiandrosterone sulfate, insulin-like growth factor-1 (IGF-1), total testosterone (TT), and free testosterone (FT) were measured using radioimmunoassay. Physical fitness was measured as VO2max using exercise stress tests. Blood for lipids was analyzed using standard assays. RESULTS: In men, the DHEAS was significantly correlated to age (r = -.32), TAM (r = -.27), percent fat (r = -.30), HDL cholesterol (r = .34), TT (r = .30), VO2max (r = .23), and percent lean body mass (% LBM) (r = .33). In women, the DHEAS was not significantly correlated to any of the variables examined except body mass index (BMI) (r = .23). In men, after partialling out age, DHEAS was significantly correlated to HDL, % fat, TAM, % LBM, and TT. Multivariate analysis for men revealed that high density lipoprotein cholesterol (HDL) was the strongest predictor of serum DHEAS level, followed by % LBM, BMI, and age. The men in the highest quartile of serum DHEAS levels were different from those in the lowest quartile in terms of age, TT, FT, % fat, TAM, % LBM, HDL, and low density lipoprotein (LDL) cholesterol level. No such differences were found in the two groups of women. CONCLUSION: In this group of independent community-dwelling older men, several factors were found to be associated with the serum DHEAS concentration, whereas in a group of older women, no such associations were identified with the exception of BMI. Men in the highest quartile of serum DHEAS level, compared with those with a serum DHEAS level in the lowest quartile, were younger, leaner, more fit, had higher TT and FT levels, and had a favorable lipid profile. No such differences were identified between the women in the highest and the lowest quartiles of serum DHEAS level.

Absorptiometry, Photon↗
PubMed1987

Effect of macrophage depletion on growth and neovascularization of hamster buccal pouch carcinomas.

The effect of macrophage depletion on growth and neovascularization of 7,12-dimethylbenz(a)anthracene (DMBA)-induced hamster buccal pouch carcinomas (HBPC) was evaluated by quantitating tritiated thymidine (3[H]TdR) incorporation by tumor cells and microvascular endothelium in light microscopic autoradiographs. Tumors that were depleted of macrophages with systemic hydrocortisone acetate (HA) and intratumor injections of antimacrophage serum (AMS) were examined 7 days after treatment. In control animals 30% of infiltrating host cells were esterase-positive tumor-associated macrophages (TAM) and 28.14% of tumor cells and 14.45% of endothelial cells were 3[H]TdR labelled. Hamsters treated with HA or HA and control serum showed no significant reduction in either the number of TAM or proportion of [3H]TdR labelled tumor of endothelial cells. AMS administered alone had no effect on either the content of TAM or 3[H]TdR labelling. In contrast hamsters treated with HA and AMS showed a 54% decrease in TAM and a 50% and 63% reduction in tumor and endothelial cell labelling respectively. These results suggest that growth and neovascularization of these tumors is mediated in part by macrophages.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1993

Cell cycle kinetic effects of tamoxifen on human breast cancer cells. Flow cytometric analyses of DNA content, BrdU labeling, Ki-67, PCNA, and statin expression.

Tamoxifen is known to inhibit the growth of some human mammary carcinoma cells; this effect is accompanied by a decrease in the proportion of cells synthesizing DNA. In this work, flow cytometry of DNA and of bromodeoxyuridine labeling and the evaluation of the cell cycle-related antigens Ki-67, PCNA, and statin were used to investigate the changes in the proliferation kinetics of MCF-7 cells before and after treatment with 10(-7) M TAM. The treatment with TAM induced a significant decrease in the fraction of S-phase cells and an increase in those with a DNA content typical of G0/1 phase. The TAM-induced block in G0/1 is paralleled by a decrease in the frequency of cells expressing Ki-67 and PCNA, and by an increase in statin-positive (G0) cells. These results confirmed that the TAM-induced inhibition of cell growth is associated with major changes in the cell cycle parameters of MCF-7 cells, and provide the first experimental evidence that two main mechanisms are operating: the accumulation of cells in G1, before the onset of S-phase, and the exit of some cells from the cycling compartment.

Biomarkers, Tumor↗
PubMed2004

Transmitted human immunodeficiency virus type 1 carrying the D67N or K219Q/E mutation evolves rapidly to zidovudine resistance in vitro and shows a high replicative fitness in the presence of zidovudine.

Drug-naive patients infected with drug-resistant human immunodeficiency virus type 1 (HIV-1) who initiate antiretroviral therapy show a shorter time to virologic failure than patients infected with wild-type (WT) viruses. Resistance-related HIV genotypes not commonly seen in treated patients, which likely result from reversion or loss of primary resistance mutations, have also been recognized in drug-naive persons. Little work has been done to characterize the patterns of mutations in these viruses and the frequency of occurrence, their association with phenotypic resistance, and their effect on fitness and evolution of resistance. Through the analysis of resistance mutations in 1082 newly diagnosed antiretroviral-naive persons from the United States, we found that 35 of 48 (72.9%) persons infected with HIV-1 containing thymidine analog mutations (TAMs) had viruses that lacked a primary mutation (T215Y/F, K70R, or Q151M). Of these viruses, 9 (25.7%) had only secondary TAMs (D67N, K219Q, M41L, or F77L), and all were found to be sensitive to zidovudine (AZT) and other drugs. To assess the impact of secondary TAMs on the evolution of AZT resistance, we generated recombinant viruses from cloned plasma-derived reverse transcriptase sequences. Two viruses had D67N, three had D67N and K219Q/E, and three were WT. Four site-directed mutants with D67N, K219Q, K219E, and D67N/K219Q were also made in HIV-1(HXB2). In vitro selection of AZT resistance showed that viruses with D67N and/or K219Q/E acquired AZT resistance mutations more rapidly than WT viruses (36 days compared to 54 days; P = 0.003). To investigate the factors associated with the rapid selection of AZT mutations in these viruses, we evaluated fitness differences among HXB2(WT) and HXB2(D67N) or HXB2(D67N/K219Q) in the presence of AZT. Both HXB2(D67N/K219Q) and HXB2(D67N) were more fit than HXB2(WT) in the presence of either low or high AZT concentrations, likely reflecting low-level resistance to AZT that is not detectable by phenotypic testing. In the absence of AZT, the fitness cost conferred by D67N or K219Q was modest. Our results demonstrate that viruses with unique patterns of TAMs, including D67N and/or K219Q/E, are commonly found among newly diagnosed persons and illustrate the expanding diversity of revertant viruses in this population. The modest fitness cost conferred by D67N and K219Q supports persistence of these mutants in the untreated population and highlights the potential for secondary transmission. The faster evolution of these mutants toward AZT resistance is consistent with the higher viral fitness in the presence of AZT and shows that these viruses are phenotypically different from WT HIV-1. Our study emphasizes the need for clinical studies to better define the impact of these mutants on treatment responses and evolution of resistance.

Anti-HIV Agents↗
PubMed1998

Tumor necrosis factor alpha gene regulation: enhancement of C/EBPbeta-induced activation by c-Jun.

Tumor necrosis factor alpha (TNF alpha) is a key regulatory cytokine whose expression is controlled by a complex set of stimuli in a variety of cell types. Previously, we found that the monocyte/macrophage-enriched nuclear transcription factor C/EBPbeta played an important role in the regulation of the TNF alpha gene in myelomonocytic cells. Abundant evidence suggests that other transcription factors participate as well. Here we have analyzed interactions between C/EBPbeta and c-Jun, a component of the ubiquitously expressed AP-1 complex. In phorbol myristate acetate (PMA)-treated Jurkat T cells, which did not possess endogenous C/EBPbeta, expression of c-Jun by itself had relatively little effect on TNF alpha promoter activity. However, the combination of C/EBPbeta and c-Jun was synergistic, resulting in greater than 130-fold activation. This effect required both the leucine zipper and DNA binding domains, but not the transactivation domain, of c-Jun, plus the AP-1 binding site centered 102/103 bp upstream of the transcription start site in the TNF alpha promoter. To determine if C/EBPbeta and c-Jun might cooperate to regulate the cellular TNF alpha gene in myelomonocytic cells, U937 cells that possess endogenous C/EBPbeta and were stably transfected with either wild-type c-Jun or the transactivation domain deletion mutant (TAM-67) were examined. U937 cells expressing ectopic wild-type c-Jun or TAM-67 secreted over threefold more TNF alpha than the control line in response to PMA plus lipopolysaccharide. Transient transfection of the U937 cells expressing TAM-67 suggested that TAM-67 binding to the -106/-99-bp AP-1 binding site cooperated with endogenous C/EBPbeta in the activation of the -120 TNF alpha promoter-reporter. DNA binding assays using oligonucleotides derived from the TNF alpha promoter suggested that C/EBPbeta and c-Jun interact in vitro and that the interaction may be DNA dependent. Our data demonstrate that the TNF alpha gene is regulated by the interaction of the ubiquitous AP-1 complex protein c-Jun and the monocyte/macrophage-enriched transcription factor C/EBPbeta and that this interaction contributes to the expression of the cellular TNF alpha gene in myelomonocytic cells. This interaction was unique in that it did not require the c-Jun transactivation domain, providing new insight into the cell-type-specific regulation of the TNF alpha gene.

CCAAT-Enhancer-Binding Proteins↗
PubMedDate not supplied

Induction of apoptosis in breast cancer cells in response to vitamin D and antiestrogens.

1,25-Dihydroxycholecalciferol D3 (1,25(OH)2D3), the active metabolite of vitamin D, is a potent inhibitor of breast cancer cell growth both in vivo and in vitro. We have shown that MCF-7 cells treated with 100 nM 1,25(OH)2D3 exhibit characteristic apoptotic morphology (pyknotic nuclei, chromatin and cytoplasmic condensation, nuclear matrix protein reorganization) within 48 h. In the experiments reported here, we examined the interactions between 1,25(OH)2D3 and the antiestrogen 4-hydroxytamoxifen (TAM), which also induces apoptosis in MCF-7 cells. Our data suggest that TAM significantly potentiates the reduction in cell number induced by 1,25(OH)2D3 alone. Combined treatment with 1,25(OH)2D3 and TAM enhances the degree of apoptosis assessed using morphological markers that identify chromatin and nuclear matrix protein condensation. We have selected a subclone of MCF-7 cells resistant to 1,25(OH)2D3 (MCF-7D3Res). These cells express the vitamin D receptor and exhibit doubling times comparable to the parental MCF-7 cells, even when grown in 100 mM 1,25(OH)2D3. Treatment of both parental and resistant MCF-7 cells with TAM induces apoptosis and clusterin. These data emphasize that apoptosis can be induced in MCF-7 cells either by activation of vitamin-D-mediated signalling or disruption of estrogen-dependent signalling.

Apoptosis↗
PubMed1997

Ventilatory and metabolic responses to ambient hypoxia or hypercapnia in rats exposed to CO hypoxia.

We have investigated at ambient temperatures (Tam) of 25 and 5 degrees C the effects of ambient hypoxia (Hxam; fractional inspired O2 = 0.14) and hypercapnia (fractional inspired CO2 = 0.04) on ventilation (V), O2 uptake (VO2), and colonic temperature (Tc) in 12 conscious rats before and after carotid body denervation (CBD). The rats were concomitantly exposed to CO hypoxia (HxCO; fractional inspired CO = 0.03-0.05%), which decreases arterial O2 saturation by approximately 25-40%. The results demonstrate the following. 1) At Tam of 5 degrees C, in both intact and CBD rats, V/VO2 is larger when Hxam or CO2 is associated with HxCO than with normoxia. At Tam of 25 degrees C, this is also the case except for CO2 in CBD rats. 2) At Tam of 5 degrees C, the changes in VO2 and Tc seem to result from additive effects of the separate changes induced by Hxam, CO2, and HxCO. It is concluded that, in conscious rats, central hypoxia does not depress respiratory activity. On the contrary, particularly when VO2 is augmented during a cold stress, both V/VO2 during HxCO and the ventilatory responses to Hxam and CO2 are increased. The mechanisms involved in this relative hyperventilation are likely to involve diencephalic integrative structures.

Animals↗
PubMed2000

Morphological evidence for a subpopulation selection effect by estrogen and antiestrogen treatments in the heterogeneous MCF-7 cell line.

Recently, we developed a method to quantitatively study tumour cell heterogeneity in terms of both nuclear size and estrogen receptor (ER) content by image cytometry. The method, previously used to analyse the proliferation of the breast cancer cell line MCF-7, was applied here to analyse the growth of this cell line under estradiol (E2), hydroxytamoxifen (OH-TAM), and both E2 and OH-TAM treatments. The method extracts characteristic parameters of single nuclei and features that measure the global and local organisation of the cells in their growing phase. Modifications of the heterogeneity of the cell line are emphasised through phenotypic changes and modifications of the spatial organisation of the cells. The hormone (E2) generates a very fast growth of cells with small nuclei that became ER negative in the long term. The antihormone (OH-TAM) produces a gradual selection of ER negative or poorly positive cells with large nuclei. These modifications are reversed when E2 and OH-TAM are simultaneously used. Moreover, estradiol induces a permissive context of proliferation, whereas hydroxytamoxifen acts only on some subpopulations. The combination of cell count, cytomorphology, and cell organisation revealed the magnitude of the potential of structuration of hormones or antihormones on in vitro growing cells.

Breast Neoplasms↗
PubMed2004

Extensive chromosomal breaks are induced by tamoxifen and estrogen in DNA repair-deficient cells.

Tamoxifen (TAM) possesses antiestrogen activity and is widely used for the treatment or prevention of breast cancer. However, it is also carcinogenic in human uterus and rat liver, highlighting the profound complexity of its actions. To explore the molecular mechanisms of TAM-induced mutagenesis, we analyzed the effects of this drug on gene-disrupted chicken B lymphocyte (DT40) clones deficient in various DNA repair pathways. Rad18, Rev3, and Polkappa are involved in translesion DNA synthesis (TLS), which facilitates recovery from replication blocks on damaged template strands. DT40 cells deficient in TLS were found to be hypersensitive to TAM, exhibiting an increase in chromosomal breaks. Furthermore, these mutants were also hypersensitive to 4-hydroxyestradiol, a physiological metabolite of estrogen. These data suggest a contribution of TLS to the prevention of chromosomal breaks by TAM and estrogen, and they therefore indicate that such error-prone DNA synthesis underlies mutagenesis induced by these agents.

Animals↗