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1.
J Contemp Dent Pract ; 23(3): 343-350, 2022 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-35781441

RESUMO

AIM: The aim of the in vitro study was to comparatively evaluate the bond strength of CAD/CAM monolithic zirconia copings using three luting agents and two different finish lines. MATERIALS AND METHODS: For the evaluation of bond strength, 60 extracted human maxillary first premolars were prepared to receive CAD/CAM monolithic zirconia copings. They were randomly divided into six groups of 10 samples each to receive CAD/CAM monolithic zirconia copings to bond with three different luting agents on two different finish lines. The luting agents used were RelyX U200, RMGIC, and Maxcem Elite with finish lines which were incorporated were 90° shoulder and radial shoulder finish lines. The tensile bond strength for all 60 samples was tested using the universal testing machine. RESULTS: Between and within the group differences in tensile bond strength were analyzed using one-way ANOVA test of significance with Tukey's post-hoc analysis. The statistical analysis revealed that the CAD/CAM zirconia copings used a combination of 90° shoulder and RelyX U200 as the luting agent (Group II) which offered the maximum bond strength. CONCLUSION: Within the constraints of this study, it could be concluded that CAD/CAM monolithic zirconia copings luted with RelyX U200 cement on a 90° shoulder finish line is the preferred method, taking the bond strength into consideration. CLINICAL SIGNIFICANCE: The results of this study can be extrapolated into a clinical scenario to help the clinician decide the most apt combination of finish line design and the luting agent to achieve superior bond strengths in CAD/CAM zirconia crowns and fixed dental prosthesis.


Assuntos
Cimentos Dentários , Zircônio , Adaptação Psicológica , Humanos , Teste de Materiais , Zircônio/química
2.
Cell Rep ; 16(10): 2565-2575, 2016 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-27568553

RESUMO

Through an RNAi-based screen for previously uncharacterized regulators of genome stability, we have identified the human protein C5orf45 as an important factor in preventing the accumulation of DNA damage in human cells. Here, we functionally characterize C5orf45 as a binding partner of the MRE11-RAD50-NBS1 (MRN) damage-sensing complex. Hence, we rename C5orf45 as MRNIP for MRN-interacting protein (MRNIP). We find that MRNIP is rapidly recruited to sites of DNA damage. Cells depleted of MRNIP display impaired chromatin loading of the MRN complex, resulting in reduced DNA end resection and defective ATM-mediated DNA damage signaling, a reduced ability to repair DNA breaks, and radiation sensitivity. Finally, we show that MRNIP phosphorylation on serine 115 leads to its nuclear localization, and this modification is required for MRNIP's role in promoting genome stability. Collectively, these data reveal that MRNIP is an important component of the human DNA damage response.


Assuntos
Proteínas de Transporte/metabolismo , Dano ao DNA , Complexos Multiproteicos/metabolismo , Proteínas Nucleares/metabolismo , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Quinase do Ponto de Checagem 2/metabolismo , Cromatina/metabolismo , Quebras de DNA de Cadeia Dupla/efeitos da radiação , Reparo do DNA/efeitos da radiação , Endodesoxirribonucleases , Células HCT116 , Células HEK293 , Células HeLa , Humanos , Ligação Proteica/efeitos da radiação , Tolerância a Radiação/efeitos da radiação , Radiação Ionizante , Homologia de Sequência de Aminoácidos , Transdução de Sinais/efeitos da radiação
3.
Nucleic Acids Res ; 44(18): 8772-8785, 2016 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-27382066

RESUMO

Cyclin-dependent kinases (CDKs) coordinate cell cycle checkpoints with DNA repair mechanisms that together maintain genome stability. However, the myriad mechanisms that can give rise to genome instability are still to be fully elucidated. Here, we identify CDK18 (PCTAIRE 3) as a novel regulator of genome stability, and show that depletion of CDK18 causes an increase in endogenous DNA damage and chromosomal abnormalities. CDK18-depleted cells accumulate in early S-phase, exhibiting retarded replication fork kinetics and reduced ATR kinase signaling in response to replication stress. Mechanistically, CDK18 interacts with RAD9, RAD17 and TOPBP1, and CDK18-deficiency results in a decrease in both RAD17 and RAD9 chromatin retention in response to replication stress. Importantly, we demonstrate that these phenotypes are rescued by exogenous CDK18 in a kinase-dependent manner. Collectively, these data reveal a rate-limiting role for CDK18 in replication stress signalling and establish it as a novel regulator of genome integrity.


Assuntos
Quinases Ciclina-Dependentes/metabolismo , Replicação do DNA , Instabilidade Genômica , Transdução de Sinais , Estresse Fisiológico , Pontos de Checagem do Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Cromatina/genética , Cromatina/metabolismo , Aberrações Cromossômicas , Quinases Ciclina-Dependentes/química , Quinases Ciclina-Dependentes/genética , Dano ao DNA , Humanos , Fosforilação , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Interferência de RNA , RNA Interferente Pequeno/genética
4.
Cell Cycle ; 13(21): 3450-9, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25485589

RESUMO

We previously identified and characterized TELO2 as a human protein that facilitates efficient DNA damage response (DDR) signaling. A subsequent yeast 2-hybrid screen identified LARG; Leukemia-Associated Rho Guanine Nucleotide Exchange Factor (also known as Arhgef12), as a potential novel TELO2 interactor. LARG was previously shown to interact with Pericentrin (PCNT), which, like TELO2, is required for efficient replication stress signaling. Here we confirm interactions between LARG, TELO2 and PCNT and show that a sub-set of LARG co-localizes with PCNT at the centrosome. LARG-deficient cells exhibit replication stress signaling defects as evidenced by; supernumerary centrosomes, reduced replication stress-induced γH2AX and RPA nuclear foci formation, and reduced activation of the replication stress signaling effector kinase Chk1 in response to hydroxyurea. As such, LARG-deficient cells are sensitive to replication stress-inducing agents such as hydroxyurea and mitomycin C. Conversely we also show that depletion of TELO2 and the replication stress signaling kinase ATR leads to RhoA signaling defects. These data therefore reveal a level of crosstalk between the RhoA and DDR signaling pathways. Given that mutations in both ATR and PCNT can give rise to the related primordial dwarfism disorders of Seckel Syndrome and Microcephalic osteodysplastic primordial dwarfism type II (MOPDII) respectively, which both exhibit defects in ATR-dependent checkpoint signaling, these data also raise the possibility that mutations in LARG or disruption to RhoA signaling may be contributory factors to the etiology of a sub-set of primordial dwarfism disorders.


Assuntos
Fatores de Troca de Nucleotídeo Guanina Rho/metabolismo , Transdução de Sinais , Antígenos/metabolismo , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Centrossomo/metabolismo , Quinase 1 do Ponto de Checagem , Reparo do DNA , Replicação do DNA/efeitos dos fármacos , Células HCT116 , Células HEK293 , Células HeLa , Humanos , Hidroxiureia/farmacologia , Mitomicina/farmacologia , Fosforilação/efeitos dos fármacos , Proteínas Quinases/metabolismo , RNA Interferente Pequeno/metabolismo , Fatores de Troca de Nucleotídeo Guanina Rho/antagonistas & inibidores , Fatores de Troca de Nucleotídeo Guanina Rho/genética , Proteínas de Ligação a Telômeros/antagonistas & inibidores , Proteínas de Ligação a Telômeros/genética , Proteínas de Ligação a Telômeros/metabolismo , Proteína rhoA de Ligação ao GTP/metabolismo
5.
Oncotarget ; 5(15): 6414-24, 2014 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-25071006

RESUMO

Brain tumours kill more children and adults under 40 than any other cancer. Around half of primary brain tumours are glioblastoma multiforme (GBMs) where treatment remains a significant challenge, where survival rates have improved little over the last 40 years, thus highlighting an unmet need for the identification/development of novel therapeutic targets and agents to improve GBM treatment. Using archived and fresh glioma tissue, we show that in contrast to normal brain or benign schwannomas GBMs exhibit re-expression of FANCD2, a key protein of the Fanconi Anaemia (FA) DNA repair pathway, and possess an active FA pathway. Importantly, FANCD2 expression levels are strongly associated with tumour grade, revealing a potential exploitable therapeutic window to allow inhibition of the FA pathway in tumour cells, whilst sparing normal brain tissue. Using several small molecule inhibitors of the FA pathway in combination with isogenic FA-proficient/deficient glioma cell lines as well as primary GBM cultures, we demonstrate that inhibition of the FA pathway sensitises gliomas to the chemotherapeutic agents Temozolomide and Carmustine. Our findings therefore provide a strong rationale for the development of novel and potent inhibitors of the FA pathway to improve the treatment of GBMs, which may ultimately impact on patient outcome.


Assuntos
Antineoplásicos Alquilantes/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/metabolismo , Proteína do Grupo de Complementação D2 da Anemia de Fanconi/biossíntese , Anemia de Fanconi/metabolismo , Glioma/tratamento farmacológico , Glioma/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Carmustina/farmacologia , Linhagem Celular Tumoral , Curcumina/metabolismo , Dacarbazina/análogos & derivados , Dacarbazina/farmacologia , Anemia de Fanconi/genética , Anemia de Fanconi/patologia , Glioma/genética , Glioma/patologia , Humanos , Gradação de Tumores , Temozolomida
6.
J Cell Sci ; 127(Pt 13): 2910-9, 2014 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-24816561

RESUMO

Here, we identify coiled-coil domain-containing protein 13 (Ccdc13) in a genome-wide RNA interference screen for regulators of genome stability. We establish that Ccdc13 is a newly identified centriolar satellite protein that interacts with PCM1, Cep290 and pericentrin and prevents the accumulation of DNA damage during mitotic transit. Depletion of Ccdc13 results in the loss of microtubule organisation in a manner similar to PCM1 and Cep290 depletion, although Ccdc13 is not required for satellite integrity. We show that microtubule regrowth is enhanced in Ccdc13-depleted cells, but slowed in cells that overexpress Ccdc13. Furthermore, in serum-starved cells, Ccdc13 localises to the basal body, is required for primary cilia formation and promotes the localisation of the ciliopathy protein BBS4 to both centriolar satellites and cilia. These data highlight the emerging link between DNA damage response factors, centriolar and peri-centriolar satellites and cilia-associated proteins and implicate Ccdc13 as a centriolar satellite protein that functions to promote both genome stability and cilia formation.


Assuntos
Proteínas de Ciclo Celular/fisiologia , Centríolos/metabolismo , Cílios/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Instabilidade Genômica , Células HCT116 , Células HEK293 , Células HeLa , Humanos , Transfecção
7.
J Cell Sci ; 125(Pt 20): 4770-9, 2012 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-22797915

RESUMO

The centrosome acts as a centre for microtubule organisation and plays crucial roles in cell polarity, migration, growth and division. Cep131 has recently been described as a basal body component essential for cilium formation, but its function in non-ciliogenic cells is unknown. We identified human Cep131 (also known as AZI1) in a screen for regulators of genome stability. We show that centrosomal localisation of Cep131 is cell-cycle-regulated and requires both an intact microtubule network and a functional dynein-dynactin transport system. Cep131 is recruited to centriolar satellites by PCM1, and localised to the centriolar core region by both pericentrin and Cep290. Depletion of Cep131 results in a reduction in proliferation rate, centriole amplification, an increased frequency of multipolar mitosis, chromosomal instability and an increase in post-mitotic DNA damage. These data therefore highlight the importance of human Cep131 for maintaining genomic integrity.


Assuntos
Proteínas de Ciclo Celular , Centríolos , Centrossomo , Instabilidade Genômica , Proteínas dos Microtúbulos , Antígenos de Neoplasias/metabolismo , Autoantígenos/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular , Centríolos/genética , Centríolos/ultraestrutura , Centrossomo/metabolismo , Centrossomo/ultraestrutura , Instabilidade Cromossômica , Proteínas do Citoesqueleto , Complexo Dinactina , Dineínas/metabolismo , Humanos , Proteínas dos Microtúbulos/genética , Proteínas dos Microtúbulos/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Mitose/genética , Proteínas de Neoplasias/metabolismo
8.
J Clin Imaging Sci ; 2: 74, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23393630

RESUMO

OBJECTIVES: To study the results of magnetic resonance-guided focused ultrasound surgery (MRgFUS) treatment carried out on Indian patients in our Hospital. MATERIALS AND METHODS: Fifty Indian women (mean age = 36.2 ± 8.3 years) were treated for fibroids as outpatients using the ExAblate MRgFUS system (InSightec). Non-perfused volumes (NPVs) were measured immediately after treatment to calculate the treatment outcomes. A validated symptom-specific questionnaire to record their symptoms prior to treatment and six months following treatment was completed by patients. The size of the fibroids was measured on the day of the treatment and during the 6-month checkup to calculate shrinkage. Adverse events during and following treatment were recorded and monitored. RESULTS: The average NPV ratio measured after the treatment was 88% ± 6%, indicative of high ablated fibroid tissue. Prior to treatment, the mean Symptoms Severity Score was 56.9 ± 4.8 (n = 50), which is indicative of highly symptomatic patients. Six months following treatment, there was an average fibroid shrinkage of 30% ± 11%, and a significant decrease in the mean score to 28.6 ± 6.0 (n = 50) (P < 0.001). There were no reports of serious or unexpected adverse events at any point during treatment or during the follow-up period from any of the 50 women treated in the current study. CONCLUSIONS: The current results obtained after 6 months of treatment corroborated previous data on the safety and efficacy of MRgFUS for treating uterine fibroids. This is the first publication that provides such data for a large cohort of Indian women.

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