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C Giorgi

Publications and source records attributed to C Giorgi.

At least 19 recordsLinked to original sources
PubMed2006

Up-regulation of proliferating cell nuclear antigen (PCNA) is closely associated with high-risk human papillomavirus (HPV) and progression of cervical intraepithelial neoplasia (CIN), but does not predict disease outcome in cervical cancer.

OBJECTIVE: Proliferating cell nuclear antigen (PCNA) is essential for DNA replication of mammalian cells and their small DNA tumour viruses. The E7 oncoprotein of high-risk human papillomavirus (HPV) is known to activate PCNA, shown to be up-regulated in CIN and cervical cancer (CC), but still incompletely studied as an intermediate endpoint marker in this disease. MATERIAL AND METHODS: As part of our HPV-PathogenISS study, a series of 150 CCs and 152 CIN lesions were examined using immunohistochemical (IHC) staining for PCNA, and tested for HPV using PCR with three primer sets (MY09/11, GP5+/GP6+, SPF). Follow-up data were available from all SCC patients, and 67 of the CIN lesions had been monitored with serial PCR for HPV after cone treatment. RESULTS: Expression of PCNA increased in parallel with the grade of CIN, with major up-regulation upon transition to CIN3 (OR 21.77; 95%CI 6.59-71.94) (p = 0.0001). Intense PCNA expression was 100% specific indicator of CIN, with 100% PPV, but suffers from low sensitivity (34.8%) and NPV (10.8%). PCNA expression was also significantly associated to HR-HPV with OR 3.02 (95%CI 1.71-5.34) (p = 0.0001), and this association was not confounded by the histological grade (Mantel-Haenszel common OR = 2.03; 95%CI 1.06-3.89) (p = 0.033). Expression of PCNA did not predict clearance/persistence of HR-HPV after treatment of CIN, and it was not a prognostic predictor in CC in univariate or in multivariate analysis. CONCLUSIONS: Up-regulation of PCNA was closely associated with HR-HPV and progressive CIN, most feasibly explained by the abrogation of normal cell cycle control by the E7 ongogene, reverting the p21(Cip1)-mediated inhibition of PCNA. However, the fact that PCNA is also expressed in normal squamous epithelium precludes the use of this marker as a potential screening tool for CC.

Adolescent↗
PubMed2006

Down-regulated nucleoside diphosphate kinase nm23-H1 expression is unrelated to high-risk human papillomavirus but associated with progression of cervical intraepithelial neoplasia and unfavourable prognosis in cervical cancer.

OBJECTIVE: One of the factors leading to an invasive phenotype is the nm23 family of metastases-associated genes. Of the six known members, nm23-H1 is the most frequently studied potential anti-metastatic gene in cervical cancer. However, the possible molecular links to oncogenic human papillomavirus (HPV) are completely unexplored as yet. MATERIALS AND METHODS: As a part of the HPV-Pathogen Istituto Superiore di Sanità study, a series of 150 squamous cell carcinomas (SCCs) and 152 cervical intraepithelial neoplasia (CIN) lesions were examined by immunohistochemical staining for nm23-H1, and tested for HPV by polymerase chain reaction (PCR) with three sets of primers (MY09/11, GP5(+)/GP6(+) and short PCR fragment). Follow-up data were available on all patients with SCC, and 67 CIN lesions were monitored by serial PCR for clearance or persistence of HPV after cone treatment. RESULTS: A linear decrease (p = 0.001) was observed in nm23-H1 expression, starting from CIN1 (85% with normal expression), with the most dramatic down regulation on transition from CIN2 (70% normal) to CIN3 (39%) and further to SCC (25%). Reduced expression was associated with CIN3 or cancer at an odds ratio 8.72 (95% confidence interval 4.13 to 18.41). Nm23-H1 was of no use as a marker of the high-risk human papillomavirus (HR-HPV) type, and it did not predict clearance or persistence of HR-HPV after treatment of CIN. Importantly, nm23-H1 expression was a significant prognostic factor in cervical cancer, reduced expression being associated with lower survival (p = 0.022) in univariate analysis. In the multivariate (Cox) regression model, however, only the International Federation of Gynecology and Obstetrics stage (p = 0.001) and age (p = 0.011) remained independent prognostic predictors. CONCLUSIONS: Down-regulated nm23-H1 expression is markedly associated with progression from CIN2 to CIN3, and predicts poor prognosis in cervical cancer. Nm23-H1 down regulation is probably orchestrated by mechanisms independent of HR-HPV oncoproteins and is possibly related to the emergence of a proteolytic phenotype.

Adolescent↗
PubMed2006

Upregulation of nuclear factor-kappaB (NF-kappaB) is related to the grade of cervical intraepithelial neoplasia, but is not an independent predictor of high-risk human papillomavirus or disease outcome in cervical cancer.

Nuclear factor-kappaB (NF-kappaB) has a pivotal function in controlling a wide variety of gene functions, and has shown to be constitutively activated in many human cancers. The molecular links of NF-kappaB to oncogenic human papillomavirus (HPV) in cervical intraepithelial neoplasia (CIN) lesions and its prognostic value in cervical cancer (CC) are incompletely understood. As part of our HPV-PathogenISS study, a series of 150 squamous-cell carcinomas (SCCs) and 152 CIN lesions were examined using immunohistochemical staining for NF-kappaB, and tested for HPV using PCR with three primer sets (MY09/11, GP5+/GP6+, and SPF). Follow-up data were available from all SCC patients, and 67 CIN lesions had been monitored with serial PCR for HPV clearance/persistence after cone treatment. Cytoplasmic NF-kappaB expression was associated with CIN3/cancer at OR 3.55 (95% CI, 1.79-7.05), while nuclear NF-kappaB expression had an OR of 21.90 (95% CI, 2.96-161.74) (P = 0.0001). Strong nuclear expression was a rare event (8.8%) also in CC, but it was related to high-risk human papillomavirus (HR-HPV) detection, with OR 2.15 (95% CI, 1.08-4.30) (P = 0.022). This association was confounded, however, by the histological grade (Mantel-Haenszel common OR = 1.46; 95% CI, 0.70-3.03) (P = 0.308). Cytoplasmic or nuclear NF-kappaB expression did not predict clearance/persistence of HR-HPV after treatment of CIN, and neither one proved to be a prognostic predictor in CC. Overexpression of cytoplasmic NF-kappaB is significantly associated with progression to CIN3 and cancer. This is paralleled by only a slight increase in nuclear expression of NF-kappaB, which could be explained by the mechanisms whereby HR-HPVs escape from the transcriptional control of NF-kappaB, i.e., E7-mediated impaired nuclear translocation of cytoplasmic NF-kappaB, and E6-conditioned attenuated NF-kappaB (p65)-dependent transcriptional activity.

Adolescent↗
PubMed2006

Upregulation of telomerase (hTERT) is related to the grade of cervical intraepithelial neoplasia, but is not an independent predictor of high-risk human papillomavirus, virus persistence, or disease outcome in cervical cancer.

Telomerase activation and telomere maintenance are essential for cell immortalization and represent a rate-limiting step in cancer progression. The E6 oncoprotein of high-risk human papillomavirus (HPV) is known to activate telomerase, but its expression in CIN lesions and its prognostic value in cervical cancer (CC) are still incompletely understood. As part of our HPV-PathogenISS study, a series of 150 CCs and 152 CIN lesions were examined using immunohistochemical (IHC) staining for hTERT (telomerase reverse transcriptase), and tested for HPV using PCR with three primer sets (MY09/11, GP5(+)/GP6(+), SPF). Follow-up data were available from all SCC patients, and 67 CIN lesions had been monitored with serial PCR for HPV after cone treatment. Expression of hTERT was increased in parallel with the grade of CIN, with major up-regulation upon transition to CIN3 (OR 18.81; 95% CI 8.48-41.69; P = 0.0001). Positive hTERT expression was 90% specific indicator of CIN, with 98.7% PPV, but suffers from low sensitivity (57.5%) and NPV (14.3%). hTERT expression was also significantly associated to HR-HPV with OR 3.38 (95% CI 1.90-6.02; P = 0.0001), but this association was confounded by the histological grade (Mantel-Haenszel common OR = 1.83; 95% CI 0.92-3.79; P = 0.086). Expression of hTERT did not predict clearance/persistence of HR-HPV after treatment of CIN, and it was not a prognostic predictor in cervical cancer in univariate or multivariate survival analysis. It was concluded that up-regulation of hTERT was closely associated with HR-HPV, due to activation by the E6 oncoprotein. hTERT is a late marker of cervical carcinogenesis, significantly associated with progression to CIN3. Theoretically, a combination of hTERT assay (showing high SP and PPV) with another test showing high SE and high NPV (e.g. Hybrid Capture 2 for HPV), should provide an ideal screening tool capable of high-performance detection of CIN lesions.

Adolescent↗
PubMed2006

Aberrant expression of VEGF-C is related to grade of cervical intraepithelial neoplasia (CIN) and high risk HPV, but does not predict virus clearance after treatment of CIN or prognosis of cervical cancer.

AIMS: Increased angiogenesis leads to invasion in cervical cancer. Vascular endothelial growth factors (VEGFs) are involved in angiogenesis, but molecular links to the most important aetiological agent, human papillomavirus (HPV), need clarifying. MATERIAL/METHODS: Archival samples-150 squamous cell carcinomas (SCCs) and 152 cervical intraepithelial neoplasia (CIN) lesions-were examined immunohistochemically for anti-VEGF-C antibody and for HPV by polymerase chain reaction (PCR). Follow up data were available for all SCC cases, and 67 CIN lesions were monitored with serial PCR to assess HPV clearance/persistence after treatment. RESULTS: High risk (HR) HPV types were closely associated with CIN (odds ratio, 19.12; 95% confidence interval, 2.31 to 157.81) and SCC (27.25; 3.28 to 226.09). There was a linear increase of VEGF-C expression-weak in CIN1 and intense in CIN3 and SCC (20.49; 8.69 to 48.26). VEGF-C upregulation was a sensitive (93.5%; 95% CI, 90.1% to 96.9%) marker of HR-HPV type (4.70; 2.17 to 10.21), but lost its significance in multivariate regression-p16(INK4a) and survivin were equally strong independent predictors of HR-HPV. Aberrant expression of VEGF-C did not predict clearance/persistence of HR-HPV after treatment of CIN. In cervical cancer, VEGF-C had no prognostic value in univariate or multivariate survival analysis. After adjustment for HR-HPV, FIGO stage, age, and tumour grade, only FIGO stage and age remained independent prognostic predictors. CONCLUSIONS: VEGF-C is an early marker of cervical carcinogenesis, with linearly increasing expression starting from low grade CIN. VEGF-C expression is closely related to HR-HPV in cervical lesions, probably because of its p53 independent upregulation by the E6 oncoprotein of HR-HPV.

Adolescent↗
PubMed2006

Down-regulation of E-cadherin is closely associated with progression of cervical intraepithelial neoplasia (CIN), but not with high-risk human papillomavirus (HPV) or disease outcome in cervical cancer.

OBJECTIVE: E-cadherin plays a pivotal role in maintenance of normal adhesion in epithelial cells but has also been shown to suppress tumour invasion and participate in cell signalling. Known to be capable of reversing the invasive phenotype of high-risk human papillomavirus (HPV)-transformed keratinocytes, E-cadherin is down-regulated in CIN and cervical cancer (CC), but still incompletely studied as an intermediate endpoint marker in this disease. MATERIAL AND METHODS: As part of our HPV-PathogenISS study, a series of 150 CCs and 152 CIN lesions were examined using immunohistochemical (IHC) staining for E-cadherin, and tested for HPV using PCR with three primer sets (MY09/11, GP5+/GP6, SPF). Follow-up data were available from all squamous cell carcinoma (SCC) patients, and 67 CIN lesions were monitored with serial PCR for HPV after cone treatment. RESULTS: Expression of E-cadherin was reduced in parallel with the increasing grade of CIN, with major down-regulation upon transition to CIN3 and further to invasive cancer (OR 6.95; 95% CI 2.67-18.09) (p = 0.0001). Negative markedly reduced E-cadherin expression was a 90.9% specific indicator of CIN, with 97.4% PPV, but suffered from low sensitivity (27.0%) and NPV (9.1%). E-cadherin expression was completely unrelated to HR-HPV (p = 0.982), and did not predict clearance/persistence of HR-HPV after treatment of CIN. Similarly, E-cadherin expression was not a prognostic predictor of CC in univariate or multivariate analysis. CONCLUSIONS: Down-regulation of E-cadherin was closely associated with progressive CIN and cell proliferation. It is tempting to speculate that part of this cell proliferation is mediated through the canonic Wnt signalling pathway, after liberation of transcriptionally competent beta-catenin from the E-cadherin/catenin complex, most notably orchestrated by E6 and E7 oncoproteins of HR-HPV. Such a liberation of beta-catenin would abrogate the negative transcriptional control of E-cadherin on the Lef/TCF/beta-catenin responsive genes. The exact role of HR-HPV oncoproteins E6 and E7 in this process remains to be seen in future studies.

Adolescent↗
PubMed2004

p16(INK4A) expression is related to grade of cin and high-risk human papillomavirus but does not predict virus clearance after conization or disease outcome.

The role of p16(INK4A) as a marker of HR-HPV and in the diagnosis of CIN has been well established, but its predictive value in the clearance of the virus after CIN treatment and its use as a prognostic marker of cervical cancer has not been studied. A series of 302 archival samples, including 150 squamous cell carcinomas (SCCs) and 152 CIN lesions, were subjected to immunohistochemical staining for p16(INK4A) and HPV testing using PCR with three primer sets (MY09/11, GP5/GP6, SPF). Follow-up data were available of 88 SCC patients, and 67 of the CIN lesions had been followed-up with serial PCR after conization. HR-HPV types were closely associated with CIN (OR 19.12; 95%CI 2.31-157.81) and SCC (OR 27.25; 95%CI 3.28-226.09). There was a significant linear relationship between the lesion grade and intensity of p16(INK4A) staining (p = 0.0001). The expression of p16(INK4A) was also closely related to HR-HPV (p = 0.0001). p16(INK4A) staining was a 100% specific indicator of CIN, with 100% PPV, and showed 83.5% sensitivity and 80.1% PPV in detecting HR-HPV. However, p16(INK4A) staining did not predict clearance/persistence of HR-HPV after treatment of CIN. Similarly, despite a slightly more favorable survival in women with strong/intense p16(INK4A) staining in univariate analysis, p16(INK4A) expression was not an independent prognostic predictor in multivariate survival (Cox) analysis. After adjustment for p16(INK4A) staining, HR-HPV, histological grade, International Federation of Gynecology and Obstetrics (FIGO) stage, and age, only the last two were significant prognostic predictors (p = 0.0001 and p = 0.003, respectively). The present data confirm the role of p16(INK4A) as a highly specific marker of CIN and HR-HPV type, but expression of this protein does not seem to be of any prognostic value in cervical cancer or in predicting the clearance of HR-HPV after treatment of CIN. We speculate that different subgroups of cervical cancer are characterized by aberrant p16(INK4A)/cyclin D/Rb pathways that are due to different mechanisms that can be mutually exclusive.

Adolescent↗
PubMed2004

Assessment of risk factors and human papillomavirus (HPV) related pathogenetic mechanisms of CIN in HIV-positive and HIV-negative women. Study design and baseline data of the HPV-PathogenISS study.

OBJECTIVES: In women with HIV-associated immunosuppression, HPV infections have an increased risk of progression to high-grade cervical intraepithelial neoplasia (CIN). With the HAART-induced prolonged survival and more protracted clinical course of AIDS, progression of CIN to cervical cancer (CC) has become a clinically relevant issue, and the mechanisms responsible for HIV-HPV interactions need further elucidation. The study design and analysis of the baseline data of our new project are presented. MATERIAL AND METHODS: This project is a combination of a prospective cohort study of HIV- and HIV+ women, and a retrospective analysis of CIN lesions and cervical cancer. Up to the present, 244 women have been enrolled (17 HIV+) and subjected to epidemiological interview, colposcopic examination, sampling for HPV testing and typing (PCR, InnoLiPA), and HPV serology. The retrospective series of biopsies were analysed for 13 biomarkers (monitoring key molecular events) using immunohistochemistry and tested for HPV by PCR and TaqMan. RESULTS: HIV- and HIV+ women differ in their exposure status to many of the key epidemiological risk factors of cervical cancer, the most significant ones being number of sexual partners (p = 0.0001), age at onset of sexual activity (p = 0.002), and contraception (yes-no) (p = 0.009). The differences in the baseline clinical observations are less dramatic; HIV-positive women had more frequent HSIL PAP tests (p = 0.040), CIN2 or higher in cervical biopsy (p = 0.049), and external genital warts (p = 0.019). The factors predicting intermediate endpoint markers of cervical cancer, i.e., HSIL PAP smear, ATZ2 in colposcopy, and high-grade CIN in biopsy were analysed in univariate and multivariate regression models. All factors significant in univariate analysis were entered in the multivariate model; HIV-status and Pap smear history maintained their independent predictive power of the HSIL Pap test. The most powerful predictor of ATZ2 colposcopy was HSIL in Pap test. Only the HSIL Pap test and ATZ2 colposcopy remained significant independent predictors of high-grade CIN (p = 0.0001 and p = 0.008, respectively) in the multivariate model. CONCLUSIONS: The three intermediate endpoint markers are closely interrelated, but predicted in part by different covariantes in the causal pathway to cervical cancer. To elucidate whether the increased risk of HIV-positive women to high-grade CIN is due a) to their different exposure status to the risk factors, b) to the direct effects of HIV, or c) to molecular interactions between HIV and HPV, we need to complete these analyses separately in HIV+ and HIV- women.

Adult↗
PubMed2002

Intrathecal methotrexate affects cognitive function in children with medulloblastoma.

BACKGROUND: Cognitive impairment occurs after malignant brain tumor treatment in children, following brain radiotherapy and systemic and intrathecal chemotherapy. OBJECTIVES: 1) To compare two groups of children who underwent surgery for cerebellar medulloblastoma with their cousins and siblings, assessing intelligence, executive function, attention, visual perception, and short-term memory. Both groups were treated with the same combined radiotherapy-chemotherapy, but differed in that only one group received intrathecal methotrexate (MTX+). 2) To relate these measures to MRI findings (leukomalacia). RESULTS: The two groups performed worse than their control subjects in all tests. The MTX+ group younger than 10 years performed significantly worse in all tests, particularly executive ones. The group older than 10 years performed significantly worse only in short-term memory. Younger patients without MTX performed significantly worse than controls only in some neuropsychological measures; there were no differences between older patients and control subjects. Only in the MTX+ group was there a direct correlation between extent of leukomalacia and performance in some tests. CONCLUSIONS: The administration of intrathecal methotrexate to children with medulloblastoma worsens the cognitive deficits induced by chemotherapy and radiotherapy. The use of intrathecal methotrexate in the treatment of medulloblastoma and other malignancies should be reassessed.

Adolescent↗
PubMed2001

Exploring the photocatalytic properties and the long-lifetime chemosensor ability of Cl(2)[Ru(Bpy)(2)L] (L = 2,5,8,11,14-pentaaza[15])-2,2'-bipyridilophane).

In this work a new water-soluble long-lifetime chemosensor, containing a polyamine unit connected to a complexed Ru(II) metal center, is described. Its crystal structure has been characterized by X-ray analysis. The polyamine macrocyclic unit is capable of anchoring cationic or anionic substrates, according to its protonation state. Examples of electron transfer involving the ruthenium complex core and the bound substrate are presented. The photocatalytic ability of such a system is illustrated by the oxidation of iodide to iodine promoted by light absorption at 436 nm.

Journal Article↗
PubMed2001

Cd(II) and Pb(II) complexation by dipyridine-containing macrocycles with different molecular architecture. Effect of complex protonation on metal coordination environment.

The coordination features of the three dipyridine-containing polyamine macrocycles 2,5,8,11,14-pentaaza[15]-[15](2,2')[1,15]-bipyridylophane (L1), 5,8,11-trimethyl-2,5,8,11,14-pentaaza[15]-[15](2,2')[1,15]-bipyridylophane (L2), and 4,4'-(2,5,8,11,14-pentaaza[15]-[15](2,2')-bipyridylophane) (L3) toward Cd(II) and Pb(II) have been studied by means of potentiometric, microcalorimetric, and spectrophotometric UV-vis titrations in aqueous solutions. All ligands form 1:1 metal complexes. In the L1 and L2 complexes the metals are lodged inside the macrocyclic cavity, coordinated to the heteroaromatic nitrogens. On the other hand, the insertion of a rather rigid dipyridine moiety within a macrocyclic structure does not allow all the aliphatic amine groups to coordinate to the metals and several protonated complexes are found in solution. The particular molecular architecture of L3, which displays two well-separated binding moieties, strongly affects its coordination behavior. In the [PbL3](2+) complex and in its protonated species, the metal is lodged inside the macrocyclic cavity, not bound to the heteroaromatic nitrogens. A similar coordination environment is found in [CdL3](2+). In this case, however, protonation of the complex takes place on the aliphatic amine groups and gives rise to translocation of the metal outside the cavity, coordinated by the dipyridine moiety.

Journal Article↗
PubMed2001

Release of U18 snoRNA from its host intron requires interaction of Nop1p with the Rnt1p endonuclease.

An external stem, essential for the release of small nucleolar RNAs (snoRNAs) from their pre-mRNAs, flanks the majority of yeast intron-encoded snoRNAs. Even if this stem is not a canonical Rnt1p substrate, several experiments have indicated that the Rnt1p endonuclease is required for snoRNA processing. To identify the factors necessary for processing of intron-encoded snoRNAs, we have raised in vitro extracts able to reproduce such activity. We found that snoRNP factors are associated with the snoRNA- coding region throughout all the processing steps, and that mutants unable to assemble snoRNPs have a processing-deficient phenotype. Specific depletion of Nop1p completely prevents U18 snoRNA synthesis, but does not affect processing of a dicistronic snoRNA-coding unit that has a canonical Rnt1p site. Correct cleavage of intron-encoded U18 and snR38 snoRNAs can be reproduced in vitro by incubating together purified Nop1p and Rnt1p. Pull-down experiments showed that the two proteins interact physically. These data indicate that cleavage of U18, snR38 and possibly other intron-encoded snoRNAs is a regulated process, since the stem is cleaved by the Rnt1p endonuclease only when snoRNP assembly has occurred.

DNA Primers↗
PubMed2001

Coordination properties of a polyamine cryptand with two different binding moieties. A case of a pH-modulated antenna device based on a new Eu(III) cryptate complex.

Protonation and alkali- and alkaline-earth-metal coordination by the dipyridine-containing cryptand L have been studied by means of potentiometric and spectroscopic (UV-vis, (1)H NMR) measurements in aqueous solutions. This ligand is constituted by an aliphatic polyamine chain and a coordinating cleft, delimited by two dipyridine units, where the metal ion is lodged. The resulting complexes are characterized by an unusually high stability. The polyamine chain is not involved, or weakly involved, in metal coordination, and facile protonation can occur on the nitrogen atoms of this moiety. Similar coordination features are found in the Eu(III) complex. A fluorescence emission study reveals that the Eu(III) cryptate shows the characteristic visible emission of the metal, due to the intramolecular energy transfer to the metal ion mainly from the lower energy triplet state of the cryptand. On the other hand, the emission intensity is modulated by pH, giving a maximum at neutral pH and decreasing at both acidic and alkaline pH values.

Journal Article↗
PubMed2001

Protonation and Zn(II) coordination by dipyridine-containing macrocycles with different molecular architecture. A case of pH-controlled metal jumping outside-inside the macrocyclic cavity.

The synthesis of the macrocyclic ligand 4,4'-(2,5,8,11,14-pentaaza[15])-2,2'-bipyridylophane (L3), which contains a pentaamine chain linking the 4,4'-positions of a 2,2'-dipyridine moiety, is reported. Protonation and Zn(II) complexation by L3 and by macrocycle L2, containing the same pentaamine chain connecting the 6,6'-positions of 2,2'-dipyridine, were studied by means of potentiometric, UV-vis, and fluorescent emission measurements. While in L2 all the nitrogen donor atoms are convergent inside the macrocyclic cavity, in L3 the heteroaromatic nitrogen atoms are located outside. Both ligands form mono- and dinuclear Zn(II) complexes in aqueous solution. In the mononuclear Zn(II) complexes with L2, the metal is coordinated inside the macrocyclic cavity, bound to the heteroaromatic nitrogen donors and three amine groups of the aliphatic chain. As shown by the crystal structure of the [ZnL2](2+) complex, the two benzylic nitrogens are not coordinated and facile protonation of the complex takes place at slightly acidic pH values. Considering the mononuclear [ZnL3](2+) complex, the metal is encapsulated inside the cavity, not coordinated by the dipyridine unit. Protonation of the complex occurs on the aliphatic polyamine chain and gives rise to translocation of the metal outside the cavity, bound to the heteroaromatic nitrogens.

Journal Article↗
PubMed2000

Affinity and nuclease activity of macrocyclic polyamines and their CuII complexes.

The stability constants of Cu(II) complexes that consist of either an oxaaza macrocycle with two triamine moieties linked by dioxa chains, or two macrocyclic ligands with a polyamine chain which are connecting the 2 and 9 positions of phenanthroline, have been determined by means of potentiometric measurements. The results are compared to those reported for other ligands with a similar molecular architecture. Of the complexes that contain phenanthroline in their macrocycle, the Cu(II) ion of the complex with the smallest and most rigid macrocycle (L3) has an unsaturated coordination sphere, while in the complex with the largest macrocycle (L5) the Cu(II) ion is coordinatively almost saturated. These results are corroborated by the crystal structure of the [CuL5](ClO4)2 complex. The affinity of the ligands and the complexes towards nucleic acids was studied by measuring the changes in the melting temperature, which showed that the affinity of the macrocyclic ligands towards double-stranded DNA or RNA is generally smaller than that of their linear analogues that bear a similar charge, with a strong preference for polyA-polyU, a model for RNA. However, the complexes of two of the changed macrocyclic ligands which contain a phenanthroline unit (L4, L5) showed a distinctly larger increase in their melting temperature deltaTm with DNA (polydA-polydT), which is reversed again in favor of RNA upon metallation to the dinuclear copper complex with L5. Experiments with supercoiled plasmid DNA showed a particularly effective cleavage with a mononuclear Cu(II) complex that contains a phenanthroline unit (L6). Related ligands showed less activity towards DNA, but not so towards the biocidic bis(p-nitrophenyl)phosphate (BNPP). In both cases (with DNA and BNPP) the activity seemed to increase with decrease of coordinative saturation of the Cu(II) ion, with the exception of one particular ligand (L6). Experiments with radical scavengers in the DNA experiments showed some decrease in cleavage, which indicates the participation of redox processes.

Binding Sites↗
PubMed2000

The neurodevelopmental price of survival in children with malignant brain tumours.

Increasing survival rates in malignant brain tumors treatment have directed attention to the side effects of long-term disease control. Nevertheless, although the treatment protocols are continuously remodelled, the quality of life of children surviving for a long time is still poor. The most severe sequelae are neurocognitive disorders, which are associated with neurobehavioural alterations. The last are partly derived directly from the lesion localisation and treatments, but are often reinforced by academic and social failure. The deleterious effect of radiotherapy (CRT) is very well documented and confirmed in all the studies. The radiation dose delivered according to the age has reduced, but not fully eliminated, the negative influence on mental functioning. Also the CRT hyperfractionation has reduced, but not cancelled, this cognitive negative impact. Intrathecal methotrexate per se is responsible for a severe cognitive impairment, which can be even more severe in association to CRT. Some surgical approaches have been responsible for postoperative behavioural disturbances. Serial neuropsychological and behavioural evaluations, which should also include the survivors' own perception of their quality of life, are badly needed. The results of these evaluations should be covariate with several factors (age, type of surgery, lesion site, hydrocephalus, complementary therapies) in an attempt to define interdisciplinary treatment protocols to maximise survival while minimising cognitive/behavioural deficits.

Brain Damage, Chronic↗
PubMed2000

Robotics in child neurosurgery.

We felt there was a need for a new device with "minimal invasive" tracking hardware, to be used in image-guided neurosurgery, and the system we designed to fill this need is now presented. It combines precision of movement, stability and self-positioning capabilities together with optically tracked registration and procedural control within the structure of a surgical microscope. The results are reduced setup time and minimal "distraction" from the procedure itself, factors of special relevance in child neurosurgery. The system is composed of a six-axis industrial robot suitable for use in the operating room, carrying a surgical microscope. Three progressive scan-synchronized infrared cameras mounted around the lenses of the scope are used to register the patient's position and track surgical instruments with reference to the registered space. Orientation of the microscope during surgery is obtained with a six-axis joystick used as a microscope handle. The system has been clinically used in 14 cases, and it has proven itself to be reliable, providing the expected performance advantages. The implementation of a tracked ultrasound or endoscope intraoperative imaging source is also described.

Brain Diseases↗