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2.
J Urol ; 206(6): 1361-1372, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34288714

RESUMO

PURPOSE: Ejaculatory dysfunction (EjD) and erectile dysfunction after cancer treatment are clinically important complications, but their exact prevalence by various kinds of cancer site and type of treatment is unknown. The aim of this systematic review and meta-analysis was to examine the available evidence and provide pooled estimates for prevalence of EjD and erectile dysfunction in relation to all cancer sites and identify characteristics associated with EjD in cancer patients. MATERIALS AND METHODS: We performed a systematic review and meta-analysis of cross-sectional and case-control studies. We searched 4 electronic databases (Medline®, CINAHL, PsychInfo and Embase®) until July 22, 2020. All retrospective or prospective studies reporting the prevalence of EjD in male patients with cancer were included in this review. A random effects meta-analysis was conducted calculating prevalence proportions with 95% confidence intervals. Prevalence proportions were calculated for the incidences of EjD by cancer site and type of treatment. RESULTS: A total of 64 studies (a total of 10,057 participants) were included for analysis. The most common cancer sites were bladder, colon, testis and rectum. The prevalence rates of EjD after surgical intervention ranged from 14.5% (95% CI 2.2-56.3) in colon cancer to 53.0% (95% CI 23.3-80.7) in bladder cancer. The prevalence rates of erectile dysfunction ranged from 6.8% (95% CI 0.8-39.1) in bladder cancer to 68.7% (95% CI 55.2-79.6) in cancer of the rectum. CONCLUSIONS: In a large study-level meta-analysis, we looked at a high prevalence of EjD and erectile dysfunction at various cancer sites and across different treatment types. Prospective studies of EjD and erectile dysfunction after various kinds of cancer treatments are warranted.

3.
Br J Gen Pract ; 71(706): e372-e380, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33926885

RESUMO

BACKGROUND: Prevalence of erectile dysfunction (ED) in male survivors of cancer across cancer types has not been systematically analysed. AIM: To estimate the prevalence of ED in all types of cancer and identify characteristics associated with ED in survivors of cancer. DESIGN AND SETTING: Systematic review and meta-analysis (MA) of cross-sectional studies. METHOD: MEDLINE, CINAHL, PsycINFO, and EMBASE were searched, targeting reports published from inception to 1 February 2020. All retrospective or prospective studies reporting prevalence of ED in male patients with cancer and using a validated tool for detection of ED were included. A random-effects MA model was used to pool prevalence of ED as absolute estimates at three different stages, that is, 'healthy', 'at diagnosis', and 'after treatment'. A univariate MA regression including the three-level group variable as the only independent variable was used to assess the difference in ED prevalence across the three groups. Further MAs were conducted for studies involving patients at diagnosis and after treatment, and statistical inferences were made with setting for multiple testing controlling for a false discovery rate (FDR) <0.05. RESULTS: In total, 1301 studies were assessed for inclusion. Of these, 141 were potentially eligible and subsequently scrutinised in full text. Finally, 43 studies were included with a total of 13 148 participants. Overall, pooled data of the included studies showed an ED prevalence of 40.72% (95% confidence interval [CI] = 31.80 to 50.29) in patients with cancer, with prevalences of 28.60% (95% CI = 12.10 to 53.83) at time of diagnosis and 42.70% (95% CI = 32.97 to 53.03) after treatment, with significant difference between these two stages and across cancer locations, controlling for an FDR <0.05. CONCLUSION: Erectile dysfunction was particularly high in male survivors of cancer and was associated with cancer treatment, cancer site, and age.


Assuntos
Disfunção Erétil , Neoplasias , Estudos Transversais , Disfunção Erétil/epidemiologia , Disfunção Erétil/etiologia , Humanos , Masculino , Prevalência , Estudos Prospectivos , Estudos Retrospectivos , Sobreviventes
4.
Clin Exp Med ; 20(3): 409-416, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32219665

RESUMO

The objective of the present study was to investigate the association between angiotensin-converting enzyme (ACE) inhibitor use and cancer incidence (overall, and breast, prostate, and colorectal cancers specifically) in a large representative sample of US adults. Cross-sectional data on cancer diagnosis, timing of cancer diagnosis, ACE inhibitor use, and other characteristics were extracted from 49 512 adults aged ≥ 20 years participating in the National Health and Nutrition Examination Survey (1999-2016). Multivariable-logistic and propensity score matching (PSM) regressions examined the relationship between pre-diagnosis use of ACE inhibitors and diagnosis of all cancers, and breast, prostate, and colorectal cancers specifically. Overall, we observed an increased likelihood of cancer diagnosis [odds ratio (OR) 1.269, 95% confidence interval (CI) 1.088-1.480] among those who used ACE inhibitors compared to non-ACE inhibitor use, and for prostate cancer diagnosis (OR 1.438, 95% CI 1.090-1.897), after adjusting for age, sex, body mass index, race/ethnicity, educational attainment, physical activity, alcohol drinking status, smoking status, and high blood pressure. PSM regression retrieved more conservative estimates such that the increased likelihood of cancer diagnosis was only observed when comparing ACE inhibitor users with non-drug users (OR 1.022, 95% CI 1.016-1.027). Compared with non-ACE inhibitor use, ACE inhibitor use was associated with an increased risk of prostate cancer. In conclusion, in this large representative sample of US adults, it was found that ACE inhibitor use may have a marginal influence on some cancers.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Neoplasias da Mama/epidemiologia , Neoplasias Colorretais/epidemiologia , Neoplasias da Próstata/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/induzido quimicamente , Neoplasias Colorretais/induzido quimicamente , Estudos Transversais , Feminino , Humanos , Incidência , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Neoplasias da Próstata/induzido quimicamente , Fatores de Risco , Inquéritos e Questionários , Estados Unidos/epidemiologia
5.
Cancers (Basel) ; 11(8)2019 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-31405192

RESUMO

Liquid biopsy (LB) is a non-invasive approach representing a promising tool for new precision medicine strategies for cancer treatment. However, a comprehensive analysis of its reliability for pancreatic cancer (PC) is lacking. To this aim, we performed the first meta-analysis on this topic. We calculated the pooled sensitivity, specificity, positive (LR+) and negative (LR-) likelihood ratio, and diagnostic odds ratio (DOR). A summary receiver operating characteristic curve (SROC) and area under curve (AUC) were used to evaluate the overall accuracy. We finally assessed the concordance rate of all mutations detected by multi-genes panels. Fourteen eligible studies involving 369 patients were included. The overall pooled sensitivity and specificity were 0.70 and 0.86, respectively. The LR+ was 3.85, the LR- was 0.34 and DOR was 15.84. The SROC curve with an AUC of 0.88 indicated a relatively high accuracy of LB for molecular characterization of PC. The concordance rate of all mutations detected by multi-genes panels was 31.9%. LB can serve as surrogate for tissue in the molecular profiling of PC, because of its relatively high sensitivity, specificity and accuracy. It represents a unique opportunity to be further explored towards its introduction in clinical practice and for developing new precision medicine approaches against PC.

6.
J Cancer ; 8(19): 4048-4056, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29187880

RESUMO

The use of polyADPribose polymerase inhibitors in cancer treatment provides a unique opportunity to target DNA repair processes in cancer cells while leaving normal tissue intact. The PARP-1 enzyme repairs DNA single strand breaks (SSB). Therefore PARP-1 inhibition in BRCA1 negative cancers results in the formation of cytotoxic DNA double strand breaks (DSB) causing synthetic lethality. The use of PARP1 inhibitors is gaining momentum in the treatment of a variety of tumours with BRCA1 involvement including breast, ovarian, pancreatic and prostate cancer. Our previous work showed that the PARP-1 inhibitor Olaparib causes both hypersensitivity of BRCA1+/- cells following exposure to gamma radiation due to the persistence of DNA strand breaks in cells, measured by the DNA damage biomarker γ-H2AX. Therefore dual treatment of cancers with radiotherapy and PARP1 inhibition may lead to cases of increased normal tissue toxicity in cancer patients. In this study we exposed two normal lymphoblastoid cell lines and three heterozygous BRCA1 lymphoblastoid cell lines to the PARP-1 inhibitor Olaparib and gamma radiation and after measured BRCA1 protein expression and apoptosis levels following treatment. BRCA1 protein foci analysis was performed on cells exposed to 2 Gy radiation in the presence or absence of 5 µM Olaparib. Using immunofluorescence and imaging flow cytometry, foci were measured in untreated cells and at 0.5, 3, 5 and 24 hours post-irradiation. Exposing normal and BRCA1+/- cells to Olaparib followed by gamma radiation results in a dramatic change in BRCA1 protein foci expression, with a significant reduction in BRCA1 protein expression observed in the heterozygote cells, together with an increase in apoptosis levels in these cells. In conclusion, combining PARP1 inhibitors with radiotherapy in treating of BRCA1-related cancers has clinical relevance, however this study and our previous publications serve to highlight the potential problems of increased side effects in these scenarios.

7.
Am J Physiol Heart Circ Physiol ; 311(5): H1297-H1310, 2016 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-27638881

RESUMO

The effect of endurance exercise on circulating microvesicle dynamics and their impact on surrounding endothelial cells is unclear. Here we tested the hypothesis that exercise intensity modulates the time course of platelet (PMV) and endothelial-derived (EMV) microvesicle appearance in the circulation through hemodynamic and biochemical-related mechanisms, and that microvesicles formed during exercise would stimulate endothelial angiogenesis in vitro. Nine healthy young men had venous blood samples taken before, during, and throughout the recovery period after 1 h of moderate [46 ± 2% maximal oxygen uptake (V̇o2max)] or heavy (67 ± 2% V̇o2max) intensity semirecumbent cycling and a time-matched resting control trial. In vitro experiments were performed by incubating endothelial cells with rest and exercise-derived microvesicles to examine their effects on cell angiogenic capacities. PMVs (CD41+) increased from baseline only during heavy exercise (from 21 ± 1 × 103 to 55 ± 8 × 103 and 48 ± 6 × 103 PMV/µl at 30 and 60 min, respectively; P < 0.05), returning to baseline early in postexercise recovery (P > 0.05), whereas EMVs (CD62E+) were unchanged (P > 0.05). PMVs were related to brachial artery shear rate (r2 = 0.43) and plasma norepinephrine concentrations (r2 = 0.21) during exercise (P < 0.05). Exercise-derived microvesicles enhanced endothelial proliferation, migration, and tubule formation compared with rest microvesicles (P < 0.05). These results demonstrate substantial increases in circulating PMVs during heavy exercise and that exercise-derived microvesicles stimulate human endothelial cells by enhancing angiogenesis and proliferation. This involvement of microvesicles may be considered a novel mechanism through which exercise mediates vascular healing and adaptation.


Assuntos
Plaquetas/fisiologia , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Micropartículas Derivadas de Células/fisiologia , Células Endoteliais/fisiologia , Exercício Físico/fisiologia , Neovascularização Fisiológica/fisiologia , Adulto , Artéria Braquial , Voluntários Saudáveis , Humanos , Técnicas In Vitro , Masculino , Norepinefrina/sangue , Consumo de Oxigênio , Resistência Física , Descanso/fisiologia , Adulto Jovem
8.
Cytometry A ; 87(8): 717-23, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26087127

RESUMO

Accurate and rapid methods for the detection of DNA damage foci in eukaryotic cells are central to DNA repair studies, which identify differences in DNA repair capacity in cell lines. Such assays have been important in delineating mechanisms of DNA repair in human cells. Previously we were the first to demonstrate the use of imaging flow cytometry for the detection of γ-H2AX foci in cells exposed to ionizing radiation causing the induction of DNA strand breaks. In this report we extend these studies and show an enhancement of foci quantitation and image resolution using next generation imaging flow cytometry with the Amnis Imagestream(X) Mark II. We demonstrate using cell lines derived from normal individuals, and DNA double strand break repair defective cells that the number of foci observed is significantly increased when using 60× as compared to 40× magnification. Also, foci numbers and resolution is further increased with the application of the focus stacking (Extended Depth of Field-EDF) capacity activated. This report represents the first such demonstration of multimagnification and EDF for the enhanced quantitation of DNA damage in cells and provides a level of resolution, which near matches in situ microscopy methods for the detection of γ-H2AX foci.


Assuntos
Dano ao DNA/genética , Histonas/genética , Linhagem Celular , Quebras de DNA de Cadeia Dupla/efeitos da radiação , Reparo do DNA/genética , Citometria de Fluxo/métodos , Humanos , Citometria por Imagem/métodos , Radiação Ionizante
9.
Chemotherapy ; 60(5-6): 310-20, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-26138778

RESUMO

Chemotherapeutic anticancer drugs mediate cytotoxicity by a number of mechanisms. However, alkylating agents which induce DNA interstrand crosslinks (ICL) are amongst the most effective anticancer agents and often form the mainstay of many anticancer therapies. The effectiveness of these drugs can be limited by the development of drug resistance in cancer cells and many studies have demonstrated that alterations in DNA repair kinetics are responsible for drug resistance. In this study we developed two cell lines resistant to the alkylating agents nitrogen mustard (HN2) and cisplatin (Pt). To determine if drug resistance was associated with enhanced ICL DNA repair we used immunocytochemistry and imaging flow cytometry to quantitate the number of γ-H2AX and Rad51 foci in the nuclei of cells after drug exposure. γ-H2AX was used to evaluate DNA strand breaks caused by repair incision nucleases and Rad51 was used to measure the activity of homologous recombination in the repair of ICL. In the drug-resistant derivative cell lines there was overall a significant increase in the number and persistence of both γ-H2AX and Rad51 foci in the nuclei of cells over a 72-hour period, when compared to the non-resistant parental cell lines (ANOVA p < 0.0001). In a Pt-resistant ovarian cancer cell line (A2780cis(R)) a similar enhancement of DNA repair was observed when compared to the non-drug-resistant wild-type ovarian cancer cells (A2780) following exposure to HN2. Our data suggest that using DNA repair biomarkers to evaluate mechanisms of resistance in cancer cell lines and human tumours may be of experimental and clinical benefit. We concede, however, that examination of a larger population of cell lines and tumours is required to fully evaluate the validity of this approach.


Assuntos
Cisplatino/farmacologia , Reparo do DNA/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Histonas/biossíntese , Mecloretamina/farmacologia , Rad51 Recombinase/biossíntese , Antineoplásicos/farmacologia , Biomarcadores Tumorais/biossíntese , Biomarcadores Tumorais/genética , Linhagem Celular Transformada , Linhagem Celular Tumoral , Reparo do DNA/fisiologia , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos/fisiologia , Regulação Neoplásica da Expressão Gênica , Histonas/genética , Humanos , Rad51 Recombinase/genética
10.
Cytometry A ; 81(2): 130-7, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22170789

RESUMO

The measurement of γ-H2AX foci induction in cells provides a sensitive and reliable method for the quantitation of DNA damage responses in a variety of cell types. Accurate and rapid methods to conduct such observations are desirable. In this study, we have employed the novel technique of multispectral imaging flow cytometry to compare the induction and repair of γ-H2AX foci in three human cell types with different capacities for the repair of DNA double strand breaks (DSB). A repair normal fibroblast cell line MRC5-SV1, a DSB repair defective ataxia telangiectasia (AT5BIVA) cell line, and a DNA-PKcs deficient cell line XP14BRneo17 were exposed to 2 Gy gamma radiation from a (60)Cobalt source. Thirty minutes following exposure, we observed a dramatic induction of foci in the nuclei of these cells. After 24 hrs, there was a predictable reduction on the number of foci in the MRC5-SV1 cells, consistent with the repair of DNA DSB. In the AT5BIVA cells, persistence of the foci over a 24-hr period was due to the failure in the repair of DNA DSB. However, in the DNA-PKcs defective cells (XP14BRneo17), we observed an intermediate retention of foci in the nuclei indicative of partial repair of DNA DSB. In summary, the application of imaging flow cytometry has permitted an evaluation of foci in a large number of cells (20,000) for each cell line at each time point. This provides a novel method to determine differences in repair kinetics between different cell types. We propose that imaging flow cytometry provides an alternative platform for accurate automated high through-put analysis of foci induction in a variety of cell types.


Assuntos
Quebras de DNA de Cadeia Dupla , Reparo do DNA , Citometria de Fluxo/métodos , Histonas/metabolismo , Citometria por Imagem/métodos , Linhagem Celular , Núcleo Celular/metabolismo , Núcleo Celular/efeitos da radiação , Quebras de DNA de Cadeia Dupla/efeitos da radiação , Reparo do DNA/efeitos da radiação , Relação Dose-Resposta à Radiação , Fluorescência , Raios gama , Humanos
11.
Int J Cancer ; 129(12): 2928-34, 2011 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-21491423

RESUMO

The normal tissue tolerance levels to fractionated radiotherapy have been appreciated by a century of careful clinical observations and radiobiological studies in animals. During clinical fractionated radiotherapy, these normal tissue tolerance levels are respected, and severe sequelae of radiotherapy are avoided in the majority of patients. Notwithstanding, a minority of patients experience unexpectedly severe normal tissue reactions. The ability to predict which patients might form this minority would be important. We have conducted a study to develop a rapid and reliable diagnostic test to predict excessive normal tissue toxicity (NTT) in radiotherapy patients. A flow cytometric immunocytochemical assay was used to measure DNA damage in peripheral blood lymphocytes (PBL) from cancer patients exposed to 2-Gy gamma radiation. DNA damage and repair was measured by induction of cellular γ-H2AX in unirradiated and exposed cells at specific time points following exposure. In 12 cancer patients that experienced severe atypical NTT following radiotherapy, there was a failure to repair DNA double-strand breaks (DSB) as measured by γ-H2AX induction and persistence. In ten cancer patients that experienced little or no NTT and in seven normal (noncancer controls), efficient repair of DNA DSB was observed in the γ-H2AX assay. We conclude that a flow cytometric assay based on γ-H2AX induction in PBL of radiotherapy patients may represent a robust, rapid and reliable biomarker to predict NTT during radiotherapy. Further research is required with a larger patient cohort to validate this important study.


Assuntos
Histonas/metabolismo , Radioterapia/efeitos adversos , Adulto , Biomarcadores/metabolismo , Quebras de DNA de Cadeia Dupla , Dano ao DNA , Reparo do DNA , Relação Dose-Resposta à Radiação , Feminino , Raios gama , Humanos , Linfócitos/efeitos da radiação , Masculino , Pessoa de Meia-Idade
12.
J Med Genet ; 47(3): 176-81, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19797196

RESUMO

BACKGROUND: Radiotherapy-induced DNA double-strand breaks (DSBs) are critical cytotoxic lesions. Inherited defects in DNA DSB repair pathways lead to hypersensitivity to ionising radiation, immunodeficiency and increased cancer incidence. A patient with xeroderma pigmentosum complementation group C, with a scalp angiosarcoma, exhibited dramatic clinical radiosensitivity following radiotherapy, resulting in death. A fibroblast cell line from non-affected skin (XP14BRneo17) was hypersensitive to ionising radiation and defective in DNA DSB repair. AIM: To determine the genetic defect causing cellular radiation hypersensitivity in XP14BRneo17 cells. METHODS: Functional genetic complementation whereby copies of human chromosomes containing genes involved in DNA DSB repair (chromosomes 2, 5, 8 10, 13 and 22) were individually transferred to XP14BRneo17 cells in an attempt to correct the radiation hypersensitivity. Clonogenic survival assays and gamma-H2AX immunofluorescence were conducted to measure radiation sensitivity and repair of DNA DSBs. DNA sequencing of defective DNA repair genes was performed. RESULTS: Transfer of chromosome 8 (location of DNA-PKcs gene) and transfection of a mammalian expression construct containing the DNA-PKcs cDNA restored normal ionising radiation sensitivity and repair of DNA DSBs in XP14BRneo17 cells. DNA sequencing of the DNA-PKcs coding region revealed a 249-bp deletion (between base pairs 3656 and 3904) encompassing exon 31 of the gene. CONCLUSION: We provide evidence of a novel splice variant of the DNA-PKcs gene associated with radiosensitivity in a patient with xeroderma pigmentosum and report the first double mutant in distinct DNA repair pathways being consistent with viability.


Assuntos
Proteína Quinase Ativada por DNA/fisiologia , Neoplasias de Cabeça e Pescoço/radioterapia , Hemangiossarcoma/radioterapia , Proteínas Nucleares/fisiologia , Tolerância a Radiação/genética , Neoplasias Cutâneas/radioterapia , Xeroderma Pigmentoso/genética , Processamento Alternativo/fisiologia , Sequência de Aminoácidos , Sobrevivência Celular/genética , Sobrevivência Celular/efeitos da radiação , Células Cultivadas , Proteína Quinase Ativada por DNA/genética , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/patologia , Hemangiossarcoma/genética , Hemangiossarcoma/patologia , Humanos , Isoenzimas/genética , Isoenzimas/fisiologia , Dados de Sequência Molecular , Proteínas Nucleares/genética , Isoformas de Proteínas/genética , Isoformas de Proteínas/fisiologia , Lesões por Radiação/genética , Couro Cabeludo , Homologia de Sequência de Aminoácidos , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Xeroderma Pigmentoso/patologia
13.
Exp Cell Res ; 313(4): 753-60, 2007 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-17188678

RESUMO

Xeroderma pigmentosum (XP) is characterised by defects in nucleotide excision repair, ultraviolet (UV) radiation sensitivity and increased skin carcinoma. Compared to other complementation groups, XP-F patients show relatively mild cutaneous symptoms. DNA interstrand cross-linking agents are a highly cytotoxic class of DNA damage induced by common cancer chemotherapeutics such as cisplatin and nitrogen mustards. Although the XPF-ERCC1 structure-specific endonuclease is required for the repair of ICLs cellular sensitivity of primary human XP-F cells has not been established. In clonogenic survival assays, primary fibroblasts from XP-F patients were moderately sensitive to both UVC and HN2 compared to normal cells (2- to 3-fold and 3- to 5-fold, respectively). XP-A fibroblasts were considerably more sensitive to UVC (10- to 12-fold) but not sensitive to HN2. The sensitivity of XP-F fibroblasts to HN2 correlated with the defective incision or 'unhooking' step of ICL repair. Using the comet assay, XP-F cells exhibited only 20% residual unhooking activity over 24 h. Over the same time, normal and XP-A cells unhooked greater than 95% and 62% of ICLs, respectively. After HN2 treatment, ICL-associated DNA double-strand breaks (DSBs) are detected by pulse field gel electrophoresis in dividing cells. Induction and repair of DNA DSBs was normal in XP-F fibroblasts. These findings demonstrate that in primary human fibroblasts, XPF is required for the unhooking of ICLs and not for the induction or repair of ICL-associated DNA DSBs induced by HN2. In terms of cancer chemotherapy, people with mild DNA repair defects affecting ICL repair may be more prevalent in the general population than expected. Since cellular sensitivity of primary human fibroblasts usually reflects clinical sensitivity such patients with cancer would be at risk of increased toxicity.


Assuntos
Reagentes para Ligações Cruzadas/farmacologia , Dano ao DNA/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Xeroderma Pigmentoso/patologia , Técnicas de Cultura de Células , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , DNA/metabolismo , Quebras de DNA de Cadeia Dupla , Reparo do DNA , Humanos , Mecloretamina/farmacologia , Raios Ultravioleta/efeitos adversos
14.
Aging Cell ; 4(5): 247-55, 2005 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-16164424

RESUMO

We have examined the relationship between nucleotide excision of the main UV-induced photoproduct, the cyclobutane pyrimidine dimer and in vitro cellular senescence. An in situ semiquantitative immunocytochemical assay has demonstrated that, following a UV-C dose of 15 J m-2, young human dermal fibroblasts maintained in a high level of serum are more efficient than senescent fibroblasts in the removal of dimers. However, in G0-arrested cultures (serum-starved), young fibroblasts are compromised in their ability to remove dimers and are significantly less efficient than senescent cells in this process. Supplementation of the culture medium with 0.1 mm deoxyribonucleosides enhances the removal of dimers in both young and senescent fibroblasts in proliferating or serum-starved cells. These data indicate that overall there is a modest but significant reduction in nucleotide excision of dimer photoproducts in cells as they age in vitro. In addition, G0-arrested young cells exhibit reduced removal of dimers, although this can be complemented by deoxyribonucleoside addition. In addition, this in situ assay has revealed heterogeneity in both susceptibility to UV-C-induced damage and excision. Overall, we provide evidence of reduced UV-induced damage excision in senescent compared with young fibroblasts, and demonstrate modulation of these processes in young and senescent cells under specific growth conditions.


Assuntos
Senescência Celular , Reparo do DNA , Derme/citologia , Fibroblastos/fisiologia , Dímeros de Pirimidina , Biomarcadores , Células Cultivadas , Meios de Cultura/química , Dano ao DNA , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Desoxirribonucleosídeos/metabolismo , Relação Dose-Resposta à Radiação , Fibroblastos/citologia , Fibroblastos/efeitos da radiação , Humanos , Masculino , Reprodutibilidade dos Testes , Raios Ultravioleta , Proteína de Xeroderma Pigmentoso Grupo A
15.
Chromosoma ; 114(4): 263-74, 2005 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16133353

RESUMO

Microcell-mediated chromosome transfer (MMCT) was a technique originally developed in the 1970s to transfer exogenous chromosome material into host cells. Although, the methodology has not changed considerably since this time it is being used to great success in progressing several different fields in modern day biology. MMCT is being employed by groups all over the world to hunt for tumour suppressor genes associated with specific cancers, DNA repair genes, senescence-inducing genes and telomerase suppression genes. Some of these genomic discoveries are being investigated as potential treatments for cancer. Other fields have taken advantage of MMCT, and these include assessing genomic stability, genomic imprinting, chromatin modification and structure and spatial genome organisation. MMCT has also been a very useful method in construction and manipulation of artificial chromosomes for potential gene therapies. Indeed, MMCT is used to transfer mainly fragmented mini-chromosome between cell types and into embryonic stem cells for the construction of transgenic animals. This review briefly discusses these various uses and some of the consequences and advancements made by different fields utilising MMCT technology.


Assuntos
Cromossomos/genética , Técnicas de Transferência de Genes , Envelhecimento/genética , Animais , Reparo do DNA , Genes Supressores de Tumor , Humanos , Modelos Genéticos , Neoplasias/genética , Transfecção
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