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Biomedical subjects

A Costa

Publications and source records attributed to A Costa.

At least 91 records · Page 5Linked to original sources
PubMed2001

The Veronesi quadrantectomy: an established procedure for the conservative treatment of early breast cancer.

A little more than 100 years ago Halsted pioneered a surgical approach that led, for the first time, to the cure of breast cancer in some patients. Veronesi's contribution was to offer the same possibility while considerably reducing the mutilation that went with cure. This article reviews the development of the conservative surgical approach in breast cancer and synoptically presents the results of large-scale clinical trials conducted by Veronesi's group in Milan in the 1970s and 1980s to demonstrate the efficacy of quadrantectomy, radiotherapy and axillary dissection (QUART) as conservative treatment for small size breast cancer. These studies set in motion the world-wide trend to conservative surgery in all forms of cancer. The article goes on to describe the surgical procedures of quadrantectomy and complete axillary dissection as developed by Veronesi, and outlines new indications for, and developments of this established conservative technique.

Axilla↗
PubMed2000

Apoptosis induced by gp120 in the neocortex of rat involves enhanced expression of cyclooxygenase type 2 and is prevented by NMDA receptor antagonists and by the 21-aminosteroid U-74389G.

The effects of a single dose of the HIV-1 coat protein gp120 given into one lateral cerebral ventricle (i.c.v.) on the expression of cyclooxygenase type 2 (COX-2) and PGE(2) levels have been studied using Western blotting and ELISA techniques applied to brain tissue extracts obtained from the neocortex of individual rats, one of the regions of the central nervous system where the viral protein causes apoptosis. The results demonstrate that COX-2 expression is almost doubled 6 h after a single dose (100 ng) of gp120 and this is paralleled by a statistically significant elevation of PGE(2). Enhanced COX-2 expression is implicated in the mechanisms of apoptosis evoked by gp120 because the latter is prevented by NS398 (10 mg/kg i.p.), a selective inhibitor of COX-2 activity. Protection is also afforded by NMDA receptor antagonists, such as MK801 (0.3 mg/kg i.p.) and CGP040116 (10 mg/kg i.p.), and by the free radical scavenger, U-74389G (10 mg/kg i.p.), supporting a glutamate-mediated, excitotoxic, mechanism of apoptotic death induced by gp120. These data together with the observation that MK801 failed to prevent gp120-enhanced COX-2 expression indicate that products of the arachidonic cascade may be responsible for elevation of synaptic glutamate leading neocortical cells to oxidative stress and excitotoxic apoptosis.

Animals↗
PubMed2000

The FtsJ/RrmJ heat shock protein of Escherichia coli is a 23 S ribosomal RNA methyltransferase.

Ribosomal RNAs undergo several nucleotide modifications including methylation. We identify FtsJ, the first encoded protein of the ftsJ-hflB heat shock operon, as an Escherichia coli methyltransferase of the 23 S rRNA. The methylation reaction requires S-adenosylmethionine as donor of methyl groups, purified FtsJ or a S(150) supernatant from an FtsJ-producing strain, and ribosomes from an FtsJ-deficient strain. In vitro, FtsJ does not efficiently methylate ribosomes purified from a strain producing FtsJ, suggesting that these ribosomes are already methylated in vivo by FtsJ. FtsJ is active on ribosomes and on the 50 S ribosomal subunit, but is inactive on free rRNA, suggesting that its natural substrate is ribosomes or a pre-ribosomal ribonucleoprotein particle. We identified the methylated nucleotide as 2'-O-methyluridine 2552, by reverse phase high performance liquid chromatography analysis, boronate affinity chromatography, and hybridization-protection experiments. In view of its newly established function, FtsJ is renamed RrmJ and its encoding gene, rrmJ.

Amino Acid Sequence↗
PubMed2000

The semantic interference effect in the picture-word interference paradigm: does the response set matter?

In three picture-word interference experiments we explore some properties of the semantic interference (SI) effect in the picture-word interference paradigm. In Experiments 1 and 2, we test whether SI may be obtained when the distractor words are not part of the response set and when only one picture per semantic category is included in the experiment. In Experiment 3, we explore if the magnitude of the SI effect depends on whether or not the distractor words are part of the response set. Reliable SI effects were obtained in all three experiments and the magnitude of the effect did not vary as a function of whether or not distractor words are part of the response set. These results are problematic for the selection mechanism in the WEAVER++ lexical access model (Levelt, W. J. M., Roelofs, A., & Meyer, A. S. (1999). A theory of lexical access in speech production. Behavioral and Brain Sciences. 22, 1-75; Roelofs, A. (1992). A spreading-activation theory of lemma retrieval in speaking. Cognition, 42, 107-142).

Humans↗
PubMed2000

Autophosphorylation of Tyr397 and its phosphorylation by Src-family kinases are altered in focal-adhesion-kinase neuronal isoforms.

In brain, focal adhesion kinase (FAK) is regulated by neurotransmitters and has a higher molecular mass than in other tissues, due to alternative splicing. Two exons code for additional peptides of six and seven residues ('boxes' 6 and 7), located on either side of Tyr(397), which increase its autophosphorylation. Using in situ hybridization and a monoclonal antibody (Mab77) which does not recognize FAK containing box 7, we show that, although mRNAs coding for boxes 6 and 7 have different patterns of expression in brain, FAK+6,7 is the main isoform in forebrain neurons. The various FAK isoforms fused to green fluorescent protein were all targeted to focal adhesions in non-neuronal cells. Phosphorylation-state-specific antibodies were used to study in detail the phosphorylation of Tyr(397), a critical residue for the activation and function of FAK. The presence of boxes 6 and 7 increased autophosphorylation of Tyr(397) independently and additively, whereas they had a weak effect on FAK kinase activity towards poly(Glu,Tyr). Src-family kinases were also able to phosphorylate Tyr(397) in cells, but this phosphorylation was decreased in the presence of box 6 or 7, and abolished in the presence of both. Thus the additional exons characteristic of neuronal isoforms of FAK do not alter its targeting, but change dramatically the phosphorylation of Tyr(397). They increase its autophosphorylation in vitro and in transfected COS-7 cells, whereas they prevent its phosphorylation when co-transfected with Src-family kinases.

Alternative Splicing↗
PubMed2000

Chemoprevention of breast cancer: the Italian experience.

The activity of our group is focused on the conduction of chemoprevention clinical trials of breast cancer in at-risk subjects, among which we include women on hormone replacement therapy (HRT). The role of the insulin-like growth factor (IGF) system and of mammographic breast density as surrogate biomarkers for breast cancer prevention is also being investigated. The IGF system is involved in human carcinogenesis of several solid tumors. IGF-I is a potent mitogen for breast cancer cells; elevated circulating IGF-I levels have been associated with a higher risk of premenopausal breast cancer, prostate and colorectal cancer in prospective studies. Both tamoxifen and the synthetic retinoid fenretinide (4-HPR) have been shown to decrease plasma IGF-I levels. A trial of their combination is ongoing in premenopausal women with increased risk for breast cancer. Mammographic breast density has also been associated with an increased risk of breast cancer in several prospective studies. In this article, we discuss the rationale for selection of appropriate cohorts, candidate agents, and putative surrogate biomarkers in our breast cancer prevention trials. Moreover, updated results of the secondary prevention trial of 4-H PR and of the primary prevention trial of tamoxifen are presented. Finally, the rationale for a reduction of tamoxifen dose in future prevention trials is provided.

Anticarcinogenic Agents↗
PubMed2000

Stimulating effect of HIV-1 coat protein gp120 on corticotropin-releasing hormone and arginine vasopressin in the rat hypothalamus: involvement of nitric oxide.

Subjects with human immunodeficiency virus type 1 (HIV-1) infection display increased activity of the hypothalamo-pituitary-adrenal (HPA) axis, which may play a role in both HIV-related neurodegenerative processes and disease progression. It has been speculated that the HIV coat protein gp120 may be responsible for these changes, and previous experimental evidence in both transgenic and nontransgenic mice supports this view. We speculated that one of the effects of gp120 in the CNS is to act within the hypothalamus to affect both corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP), the principal regulators of HPA axis. We therefore administered i.p. gp120 (100 ng/rat) or vehicle to male Wistar rats and then detected Fos protein (an index of neuronal activation), CRH, and AVP immunoreactivity in the cellular compartments of the hypothalamic paraventricular nucleus (PVN). In addition, we tested the direct effect of various concentrations of gp120 on the release of CRH and AVP from rat hypothalamic explants maintained in vitro. Any modulation of gp120 effects by nitric oxide (NO) pathways was also sought by coadministering i.p. to rats or adding to the hypothalamic preparations the NO synthase inhibitor N(G)-methyl-l-arginine (l-NMMA). Gp120 induced the expression of Fos protein in both the parvo- and the magnocellular PVN, which was significantly attenuated by l-NMMA 10(-6) nM/L (P < 0.001 vs gp120 alone). Double immunochemistry showed costaining for Fos protein and CRH or AVP in the PVN following gp120; the number of double-labeled CRH and AVP cells for Fos protein was markedly reduced (P < 0.001) by coadministration of l-NMMA 10(-6) nM/L. In the in vitro studies, addition of gp120 to the hypothalamic explants in the dose range of 10 pM-1 nM resulted in a clear stimulation of both CRH and AVP release (P < 0.05-0.001 compared to control); in the presence of l-NMMA at 10-fold higher concentrations the stimulatory effect of gp120 on the release of both peptides was completely lost. It would therefore appear that gp120 activates CRH and AVP-producing neurons in the hypothalamic PVN and stimulates the release of both peptides in vitro via NO-dependent mechanisms. These findings, in line with previous evidence, further suggest that the increased activity of the HPA axis associated with HIV infection may be of central origin, due to the effects of gp120 on hypothalamic CRH and AVP release.

Animals↗
PubMed2000

Immortalized hypothalamic luteinizing hormone-releasing hormone (LHRH) neurons induce a functional switch in the growth factor responsiveness of astroglia: involvement of basic fibroblast growth factor.

Recent evidence indicates that astroglial-derived growth factors (GFs) participate in the development of luteinizing hormone-releasing hormone (LHRH) neurons, but it is still unknown whether LHRH neurons may exert a reciprocal modulation of glial cell function. Using immortalized hypothalamic LHRH (GT1-1) neurons in co-culture with glial cells, we have recently shown that basic fibroblast growth factor (bFGF) plays a prominent role in the glial-induced acquisition of the mature LHRH phenotype by GT1-1 cells. We have resorted to this model and combined biochemical and morphological approaches to study whether the response of glial cells to a number of GFs (including bFGF, insulin-like growth factor I, IGF-I, epidermal growth factor, EGF and insulin) expressed during LHRH neuron differentiation, is modulated by co-culture with pure LHRH neurons. Pre-treatment of hypothalamic astrocytes with an inactive ('priming') dose of bFGF for 12 h powerfully increased astroglia proliferative response to IGF-I (10 ng/ml), EGF (10 g/ml) and insulin (10 microg/ml), inducing a 65-100% increase in the [3H]thymidine incorporation compared to untreated cultures. When astroglial cells and developing GT1-1 neurons were co-cultured for 5 days in vitro (DIV), the [3H]thymidine incorporation was significantly higher than in astroglial cells cultured without neurons. Application of the different GFs to the co-culture for either 12 or 24 h further stimulated DNA synthesis to various extent according to the GF applied and the time of application. Localization of the proliferating cells by dual immunohistochemical staining, followed by cell counting and bromodeoxiuridine (BrdU) labeling index calculation, revealed that the incorporation of BrdU was restricted to the nuclei of LHRH-immunopositive neurons. Such changes were accompanied by extensive morphological alterations of astroglial and LHRH fiber networks, whereas neutralization of bFGF activity in GT1-1 neuron-glial co-cultures by a bFGF-antibody, dramatically counteracted the observed effects. The functional switch of astroglia proliferative response to GFs coupled to the potent morphological and functional modifications of developing glia and pure LHRH neurons observed in vitro, support a bidirectional interaction between immortalized LHRH neurons and astroglial cells and identify bFGF as a key player in this crosstalk.

Animals↗
PubMed2000

Recent advances in cancer chemoprevention, with emphasis on breast and colorectal cancer.

Chemoprevention is a recently introduced and rapidly growing area of oncology that is identifying agents with a potentially preventive role in cancer. Several clinical trials have recently shown the feasibility of this approach in reducing the risk of major human cancers. In the USA, a large trial that demonstrated a reduction of approximately 50% in the risk of developing breast cancer led to Food and Drug Administration (FDA) approval of tamoxifen as a preventive agent in women at increased risk. Although the results could not be reproduced in two smaller European trials, further investigations into this agent are clearly warranted. Raloxifene, another selective oestrogen receptor modulator which has reduced the risk of breast cancer in a trial in women with osteoporosis, is being compared with tamoxifen in a large primary prevention trial in at-risk women. Retinoids are a group of compounds that have proved especially effective in reducing the occurrence of second primary tumours in subjects with skin, head and neck or liver cancer. Fenretinide, a synthetic retinoic acid derivative, has recently been shown to decrease the occurrence of a second breast malignancy in premenopausal women. Results with non-steroidal anti-inflammatory drugs (NSAIDs) have proved consistently encouraging in epidemiological studies in lowering the incidence of colorectal cancer. Clinical trials with selective cyclo-oxygenase inhibitors potentially devoid of gastrointestinal (GI) toxicity are currently underway in at-risk subjects. Calcium and selenium have also received much attention as chemopreventive agents. Originally investigated against skin cancer, selenium showed efficacy in reducing prostate, lung and colon cancer incidence. Similarly, vitamin E was effective in reducing prostate cancer incidence and mortality in a lung cancer prevention trial in heavy smokers. The challenges of conducting well-designed and unequivocal chemoprevention trials are considerable, but advances in techniques of identification of at-risk subjects and establishing surrogate endpoint biomarkers should contribute greatly to future studies. Current knowledge suggests that a pharmacological approach to preventing cancer, using natural or synthetic agents, could become an important way forward.

Antineoplastic Agents↗
PubMed2000

[The experience of menstruation and its disorders in 603 women using contraception in 1999].

AIM: An epidemiological survey completed during the first quarter of 1999 assesses the frequency of menstrual disorders as well as their effects on the lives of women using contraception. MATERIALS AND METHODS: The results presented involve a sample of 603 women, with 405 using the pill and 198 fitted with an IUD. The average age of onset of menstruation in the sampled population was 12.8 years. Although most women declared that they felt no anxiety at the time, over one-third of the women surveyed explained that they felt a certain hesitancy in discussing the topic. Even today, certain feelings, such as shame or pride, are still evoked in the interviews. Although over half believe that it is normal to menstruate, the process is nevertheless considered "somewhat bothersome" by certain women who also refer to "purification." Traditional cultural perspectives remain a strong influence. Menstrual disorders predating the initial use of contraception were reported in 150 women (occasional intermenstrual bleeding, 130 cases; other anomalies excluding metrorrhagia, 27 cases). Even if most of the women believe these problems to be inevitable, they also claim to be relatively troubled by these disorders, which often involve a considerable degree of discomfort. Such disorders are significantly more frequent in the "IUD" group, as well as in women who claim a very early onset of menstruation and those who consider explanations provided by the physician as "insufficient." CONCLUSION: The difference creates a certain fear with respect to any social or individual norm that may have been internalized. Thus the information presented in this study may provide ways and means to better understand women in general and our women patients in particular.

Adolescent↗
PubMed2000

Correlation of genotypes and route of transmission with histologic activity and disease stage in chronic hepatitis C.

Our objective was to evaluate the histopathological features of chronic hepatitis C of 64 liver biopsies and to correlate this with the route of transmission of hepatitis C virus, the genotype of HCV, and the patient's age. Moderate chronic hepatitis was the most frequently observed (62.5%). Cirrhosis was observed in 14 patients (21.9%) and was more frequently found among patients over 40 years of age (34.3% vs. 6.9%, P = 0.025). The mean histopathological activity index (HAI) was significantly higher in the sporadic (10+/-3.1) than the posttransfusional (7.5+/-3.7) and the intravenous drug use (IVDU) groups (6.3+/-2.8) (P<0.02). Moreover the sporadic group showed more fibrosis (P<0.04) than the posttransfusional group. No liver cirrhosis was found in the IVDU group. The overall prevalence of HCV variants was: 54.7% type 1b, 4.6% type 1a, 37.5% type 2c, 1.6% type 2b, 1.6% type 2. The genotype distribution showed no relation to the HAI, hepatitis activity (grade), and fibrosis (stage) of the liver disease. In conclusion, the sporadic route of transmission of HCV was related to a more severe chronic hepatic disease, a finding that could influence future antiviral therapies. The predominance of HCV type 1b in this study reflects the higher frequency of this variant in our area. Our data suggests that the ultimate consequence of HCV chronic infection depends on patient age rather than on HCV genotype.

Adult↗