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"This thesis presents the first report of the comprehensive and quantitative analysis of the effects of tumor-derived mutations on the tetrameric structure of tumor suppressor protein p53, which plays a central role in maintaining genomic integrity. Inactivation of p53 via mutation of its gene is a key step in tumorigenesis. Biophysical analyses revealed that the stability of the mutant peptides varied widely. Formation of a tetrameric structure is to be critical for protein–protein interactions, DNA binding, and the post-translational modification of p53. A small destabilization of the tetrameric structure therefore could result in dysfunction of tumor suppressor activity. This work suggests that the threshold for loss of tumor suppressor activity, in terms of the disruption of p53’s tetrameric structure, could be extremely low. Furthermore, functional control of p53 via tetramer formation was demonstrated, based on the structure–function analysis of mutant p53. The results disclosed that relatively small changes in tetramer formation, induced by the stabilization or inhibition of homo-tetramerization, could control p53 function."

"Pembentukan dan perkembangbiakan sel tumor terjadi jika protein khusus yang mengatur pembelahan sel mengalami perubahan fungsi, ekspresi gen atau hilang keduanya. Salah satu protein penekan tumor yang berperan dalam pengendalian siklus sel adalah protein TP53. Pada sebagian besar perubahan genetik dalam tumor, baik delesi atau mutasi pada lebih dari 50% kanker pada manusia, ditemukan mutan TP53 yang merupakan faktor beresiko tinggi terhadap kanker. Oleh karena itu, penting untuk melakukan studi tentang pengelompokan interaksi protein-protein TP53. Interaksi protein secara umum disajikan dalam jaringan graf (graph network) dengan protein sebagai simpul dan interaksinya sebagai busur. Algoritma Markov Clustering (MCL) adalah satu metode graph clustering yang dibuat berdasarkan simulasi dari flow stokastik pada suatu graf. Dalam skripsi ini, dibahas mengenai implementasi algoritma MCL pada data interaksi protein-protein TP53 dengan menggunakan bahasa pemrograman Python. Algoritma MCL terdiri dari tiga operasi utama yaitu ekspansi, penggelembungan, dan pemotongan. Selanjutnya, dilakukan analisis hasil clustering dari simulasi algoritma MCL dengan menggunakan parameter ekspansi, penggelembungan dan faktor pengali yang berbeda-beda. Berdasarkan analisis hasil clustering yang dilakukan, algoritma MCL terbukti menghasilkan robust cluster dengan protein TP53 sebagai pusat cluster untuk setiap hasil clustering.

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The formation and proliferation of tumor cells occurs if a special protein that regulates cell division changing the function, gene expression or lost both. One of the tumor suppressor protein that plays a role in controlling the cell cycle is the TP53 protein. In most of the genetic changes in the tumor, either deletions or mutations in more than 50% of human cancers, it found that mutant of TP53 is a high risk factor for cancer. Therefore, it is important to conduct studies on protein-protein interactions clustering of TP53. Protein interactions are generally presented in the graph network with proteins as nodes and interactions as edges. Markov Clustering (MCL) algorithm is a graph clustering method which is based on a simulation of stochastic flow on a graph. This minithesis discussed about the implementation of the MCL process on protein-protein interaction of TP53 data using the Python programming language. MCL algorithm consists of three main operations: expansion, inflation, and prune. Furthermore, the clustering simulation is using the different parameter of expansion, inflation and the multiplier factor. Based on the analysis of the clustering results, MCL algorithm is proven to produce robust cluster with TP53 protein as a centroid for each clustering results."

"Selama ini pengobatan kanker serviks hanya menggunakan vaksin profilaktik yang bersifat preventif. Pengembangan vaksin terapeutik yang bersifat kuratif perlu dilakukan untuk penderita yang berada dalam tahap terinfeksi HPV-16 pra-kanker dan kanker. Akan tetapi, efektifitas dan keamanan kandidat vaksin terapeutik perlu diuji terlebih dahulu dengan uji interaksi onkoprotein E6 dengan protein penekan tumor p53. Oleh karena itu, tujuan penelitian ini adalah melakukan ekspresi protein p53. Protein p53 merupakan salah satu komponen sistem pendeteksi interaksi antigen E6 dengan p53. Ekspresi p53 menggunakan sel E. coli transforman dilakukan dengan pemberian induksi IPTG 1 mM selama 4 jam. Plasmid rekombinan pQE-80L_p53 mampu mengekspresikan protein p53 di dalam sel E. coli BL21 cp dengan berat molekul 54 KDa. Hasil western blotting menunjukkan sebuah pita berukuran 54 KDa yang sesuai dengan berat protein p53.

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Over the last few years, cervix medication depends only on prophylactic vaccination. The development of therapeutic vaccination needs to be improved in order to treat HPV 16 infected patients. However, vaccines safety needs to be tested by examining interaction between E6 oncoprotein and p53 tumour suppressor protein. Therefore, p53 protein needs to be expressed as one of the system components. pQE 80L recombinant plasmid is capable to express p53 6xhis tagged using E. coli BL21 Codon Plus as a cell host. Western blot result showed that 4 hours of 1 mM IPTG induction produced a single band with the size of 54 kDa."

"Metilasi DNA merupakan perubahan epigenetik yang umum terjadi sebagai penyebab inaktivasi gen pada tumor suppressor genes (TSGs). Metilasi pada promoter TSG memiliki asosiasi dengan pembentukan kanker tiroid. Metode methylation-specific multiplex ligation dependent-probe amplification (MS-MLPA) merupakan salah satu metode berbasis PCR yang dapat melakukan identifikasi metilasi pada beberapa gen dan analisis copy number variant secara simultan. Tujuan dari penelitian ini adalah untuk mengoptimasi metode MS-MLPA dan mengidentifikasi metilasi TSG pada kanker tiroid dengan metode MS-MLPA. Sebanyak 40 sampel fine needle aspiration biopsy (FNAB) dikumpulkan secara retrospektif di Rumah Sakit Kanker Dharmais. Sampel FNAB berasal dari pasien yang memiliki kelainan nodul tiroid. Metilasi TSG dianalisis dengan metode MS-MLPA menggunakan probemix Tumour Suppressor Mix 1 ME001-C2 (MRC-Holland). Sampel FNAB dibandingkan dengan reference sample berupa sampel darah yang berasal dari individu sehat. Penelitian ini berhasil mengoptimasi metode MS-MLPA dan mendeteksi metilasi pada 4 jenis tumor suppressor genes, yaitu gen RASSF1A, gen CASP8, gen FHIT, dan gen CHFR. Hasil identifikasi menunjukkan bahwa terdapat 20 sampel tumor ganas dan 2 sampel tumor jinak mengalami metilasi.

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DNA methylation is a common epigenetic change that causes gene inactivation in tumor suppressor genes (TSGs). TSGpromoter methylation has an association with the formation of thyroid cancer. Methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) is a PCR-based method that can identify methylation in several genes and copy number variant simultaneously. The aim of this study is to optimize methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) and to identify tumor suppressor genes methylation of thyroid cancer using MS-MLPA. Retrospectively 40 Fine Needle Aspiration Biopsy samples were collected in Dharmais Cancer Hospital. FNAB samples were collected from patients with thyroid nodules abnormalities. Tumor suppressor genes methylation were analyzed using Tumour Suppressor Mix 1 ME001-C2 probemix (MRC-Holland) as MS-MLPA reagents. FNAB samples were compared with reference sample from blood that were collected from healthy people. This study has successfully optimizing MS-MLPA method and detecting 4 methylated tumor suppressor genes, RASSF1A, CAPS8, FHIT and CHFR. Methylation identification shows 20 malignant histopathology samples and 2 benign histopathology samples were methylated.

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"Pendahuluan : Giant Cell Tumor tulang (GCT) merupakan tumor tulang jinak yang dapat secara lokal bersifat agresif dengan tingkat rekurensi mencapai 20%. Antigen Ki-67 dan p53 adalah penanda imunohistokimia pada GCT yang menandakan proliferasi sel dan supresi tumor. Penelitian ini menganalisis hubungan antara penanda Ki-67 dan p53 dengan rekurensi pada kasus GCT.

Metode : Penelitian adalah suatu studi Cross-sectional kategorikal. Data yang dikumpulkan adalah data demografis pasien, keterangan terkait diagnosis dan tindakan serta hasil pemeriksaan Ki-67 dan p53. Data pasien Ekspresi Ki-67 dan p53 dievaluasi dengan teknik pewarnaan imunohistokimia menggunakan metode avidin-biotin complex perioxidase dengan menggunakan kit LSAB2.

Hasil : Terdapat 26 laki-laki dan 37 perempuan dengan usia rata-rata adalah 34,77 tahun berkisar antara 16 sampai 61 tahun. 13 kasus dengan rekurensi lokal. Tidak terdapat hubungan antara rekurensi dengan karakteristik tumor (jenis kelamin, usia, ukuran tumor, lokasi tumor, stadium tumor dan tindakan operasi). Tidak ada hubungan antara Ki-67 (p=0.524) dan rekurensi lokal serta terdapat hubungan yang signifikan antara p53 dengan rekurensi lokal (p=0.048).

Kesimpulan : Ekspresi Ki-67 tidak berhubungan dengan rekurensi, sedangkan ekspresi p53 berhubungan dengan rekurensi giant cell tumor tulang. Tidak terdapat hubungan antara rekurensi lokal dengan karakteristik tumor (jenis kelamin, usia, lokasi tumor, ukuran tumor, stadium tumor dan tindakan operasi).

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Introduction : Giant cell tumor of bone (GCTB) is a benign neoplasm that may be locally aggressive with recurrence rate reaching 20%. Ki-67 and p53 are immunochemistry markers that marked cell proliferations and tumor suppression. This research analyze the association between Ki-67 and p53 with recurrence of GCT.

Method :This study is a Cross-sectional categorical study. Demography of the patients, diagnosis and treatment related to the GCT, and Ki-67 and p53 results were taken. The expression of Ki-67 and p53 were evaluated using a immunochemistry staining with avidin-biotin complex peroxidase by using KSAB2 kit.

Result : There are 26 men and 37 women with an average age is 34.77 years ranged from 16 to 61 years. 13 cases with local recurrence. There is no association between recurrence and tumor characteristics (sex, age, tumor size, tumor location, stage and operation). There is no association between Ki-67 with local recurrence (p=0,524) and a significant association between p53 and local recurrence (p=0,048).

Conclusion : Ki-67 was not associated with recurrence, mean while p53 was associated with recurrence of GCT. There is no association between recurrence and tumor characteristics (sex, age, tumor size, tumor location, stage, and operation)."

"Latar Belakang: Karsinoma sel hati (KSH) adalah lesi neoplastik ganas pada hati tersering. Transformasi keganasan sel hati normal menjadi KSH melibatkan berbagai faktor seperti inflamasi dan perubahan genetik yang menyebabkan KSH menjadi sangat heterogen pada tingkat histologik dan molekular. Perbedaan fenotipe yang dipengaruhi berbagai perubahan molekular menghasilkan berbagai derajat diferensiasi, subtipe histologik dan gambaran klinik yang berbeda dan sebagian berhubungan dengan prognosis pada KSH. Mutasi pada gen TP53 yang berfungsi menontrol proliferasi sel melalui perbaikan DNA, apoptosis, dan penuaan sel terbukti sebagai salah satu perubahan molekular tersering pada KSH dan sering dikaitkan dengan beberapa faktor risiko, derajat diferensiasi, subtipe histologik tertentu dan prognosis. Penelitian ini bertujuan menginvestigasi ekspresi p53 pada derajat diferensiasi, subtipe histologik dan stadium patologi tumor KSH.Bahan dan cara: Penelitian dilakukan di Departemen Patologi Anatomik FKUI/RSCM, Jakarta terhadap 41 kasus KSH yang diperoleh seara reseksi. Sampel kasus diklasifikasikan berdasarkan kelompok derajat diferensiasi (WHO), subtipe histologik dan stadium patologi tumor. Selanjutnya dilakukan pulasan imunohistokimia (IHK) protein 53 (p53) pada seluruh kasus dan dilakukan analisis untuk mengetahui ekspresi p53 pada variabel penelitian.Hasil: Ekspresi p53 ditemukan pada 35 kasus (85%). Berdasarkan derajat diferensiasi, ekspresi p53 ditemukan paling banyak pada derajat diferensiasi sedang dan buruk, yaitu 21 dan 14 kasus (91% dan 93%). Ekspresi p53 berdasarkan stadium patologi tumor ditemukan paling banyak pada pT1b dan pT2, yaitu 8 dan 14 kasus ( 88% dan 93%). Berdasarkan subtipe histologik, seluruh kasus macrotrabecular massive (MTM) menunjukkan ekspresi p53 (4 kasus, 100%), subtipe clear cell (CC) terpulas pada 15 kasus (93%), klasik (CL) ditemukan 16 kasus (88%) dan tidak ditemukan ekspresi p53 pada seluruh kasus steatohepatitic (SH). Terdapat perbedaan rerata bermakna ekspresi p53 pada kelompok baik dan sedang (p=0,011), baik dan buruk (p=0,015) dan tidak terdapat perbedaan rerata bermakna antara kelompok sedang dan buruk (p=0,339). Tidak ditemukan perbedaan rerata bermakna ekspresi p53 pada seluruh kelompok stadium patologi tumor (p=0,948) dan subtipe histologik (p=0,076).Kesimpulan: Terdapat perbedaan bermakna ekspresi p53 pada KSH kelompok diferensiasi baik dan sedang serta baik dan buruk.

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Background: Hepatocellular cell carcinoma (HCC) is the most common malignant neoplastic lesion of the liver. Malignant transformation of hepatocytes involves various factors such as inflammation and genetic causing HCC to be very heterogeneous at the histological and molecular level. Differences in phenotypes affected by various molecular changes produce different differentiation grade, histological subtype, clinical features and prognosis. TP53 as one of the most common molecular changes in HCC play an important role in cycle cell by controlling cell proliferation through DNA repair, apoptosis and cellular senescence, associates with several risk factors such as certain differentiation grade, histologic subtypes, and prognosis. This current study aimed to investigate p53 expression at HCC’s differentiation grade, tumor pathology stage and histologic subtype.

Materials and methods: The study was conducted at the Department of Anatomical Pathology FKUI / RSCM, Jakarta on 41 cases of resected HCC. Case samples are classified based on groups of differentiation grade (WHO), histologic subtypes and tumour pathology stage. Furthermore immunohistochemical (IHC) staining of protein 53 (p53) carry out in all cases and an analysis statistic was performed to evaluated the expression of p53.

Results: p53 expression was found in 35 cases (85%). Based on the differentiation grade, the expression of p53 was found mostly in the moderate and poor differentiation (91%, 21 cases and 93%, 14 cases). Based on tumour pathology stage, p53 expression was found mostly in pT1b and pT2, which were 8 and 14 cases (88% and 93%). Based on histologic subtypes, all macrotrabecullar massive (MTM) cases showed p53 expression (4 cases, 100%), clear cell (CC) subtypes were in 15 cases (93%), classic (CL) 16 cases (88%) and negative expression was found in all cases of steatohepatitic (SH). There were significant differences in mean expression of p53 in the well and moderate groups (p = 0.011), well and poor (p = 0.015) and there were no significant mean differences between the moderate and poor groups (p = 0.339). There were no significant mean differences in p53 expression in all groups of tumour pathology stages (p = 0.948) and histologic subtypes (p = 0.076).

Conclusion: There is significant difference mean of p53 expression in well and moderate as well as well and poor differentiation."

"Pendahuluan: Endometriosis merupakan suatu kelainan jinak ginekologi yang dapat mengalami transformasi menjadi kanker. Stres oksidatif diduga berperan dalam perkembangan penyakit endometriosis. Gen supresor tumor ARID1A banyak ditemukan termutasi dan inaktif pada kanker ovarium yang berhubungan dengan endometriosis. Tujuan penelitian adalah untuk menganalisis peran stres oksidatif terhadap ekspresi gen supresor tumor ARID1A dalam transformasi endometriosis menjadi ganas. Metoda: Penelitian dimulai dengan 10 sampel jaringan kanker ovarium, 10 sampel endometriosis dan3 jaringan endometrium eutopik sebagai kontrol yang diisolasi mRNA dan proteinnya. Analisis ekspresi gen ARID1A pada tingkat mRNA dilakukan dengan pemeriksaan RT-qPCR dan pada tingkat protein dengan ELISA. Pada sel endometriosis dan kanker ovarium dilakukan analisis stres oksidatif dengan pemeriksaan aktivitas antioksidan MnSOD dan pemeriksaan kadar MDA sebagai salah bukti kerusakan salah satu komponen sel. Setelah itu dilakukan uji eksperimental pada kultur sel endometriosis dan endometrium eutopik sebagai kontrol. Kedua sel kultur diinduksi dengan H2O2 konsentrasi 0 nM, 100 nM, dan 1000 nM. Analisis dilakukan terhadap ketahanan hidup sel, kadar ROS dan ekspresi gen ARID1A pada tingkat mRNA dan protein. Hasil: Efek induksi H2O2 dalam menekan ekspresi gen ARID1A sel endometriosis dan sel endometrium eutopik pada tingkat mRNA dan protein, bermakna, meskipun pada kanker ovarium tidak bermakna pada penelitian ini. Kesimpulan: Stres oksidatif berperan dalam menekan ekspresi gen supresor tumor ARID1A ditingkat mRNA dan protein pada endometriosis.

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Introduction: Endometriosis as a gynecologic benign lesion, can transform itself into cancer. Oxidative stress is considered as an important factor in endometriosis development. Studies found that ARID1A as tumor suppressor gene, was frequently mutated and inactivated in endometriosis associated ovarian cancer. The aim of the study is to analyze the role of oxidative stress on ARID1A expresion in endometriosis malignant transformation.

Methods: This study started with ten samples of ovarian cancer, ten samples of endometriosis, and 3 samples of eutopic endometrioid tissues as control. They were analyzed for the expression of ARID1A by RT-qPCR and ELISA, then analyzed for the activity of MnSOD as antioxidant enzyme and level of malondialdehyde as one of the oxidative stress damage effect evidence on cell's components. The second part of the study was experimental study on cultured eutopic endometrial and endometriosis cells. They were induced by H2O2 of 0, 100, and 1000 nM concentration. Analysis of the expression of ARID1A by RTqPCR and ELISA, and the DCFH-DA for the level of Reactive oxygen species were done.

Result: The impact of the H2O2 induction in repressing ARID1A gene expression on the endometriosis as well on the eutopic endometrium cells are significant, but not on the ovarian cancer in this study.

Conclusion: Oxidative stress has a role in repressing the expression of ARID1A gene at the mRNA and protein levels on the endometriosis."

"This book will cover primary roles of NKT cells in immunity to cancer, in both mouse tumor models and cancer patients. There are several chapters describing general aspects of NKT cells."

"Bacterial lipopolysaccharide (LPS) is impacted in the etiology of inflammatory periodontal disease. Aside from immunopathologic reactions which may be involved in the pathogenesis of the disease, the possibility exist that direct cytotoxic effect on cultured human gingival fibroblasts may be equally destructive. The expression of P53 protein can be one of markers to examine the state of impaired DNA. The purpose of this study was to investigate the effect of LPS toward expression of P53 protein on cultured human gingival fibroblasts. Cultured human gingival fibroblasts were exposed to LPS in concentrations of 50 and 200 ug/ml and untreated medium for a period of 24 and 48 hours. Cells were harvested and prepared for immunohistochemical evaluation. After exposure for 24 and 48 hours, the fraction of P53-positive cells was 81.7% in case of 50 ug/ml LPS, and 88.8% in case of 200 ug/ml LPS. After exposure for 48 hours, the fraction of P53-positive cells was 32.2% in case of 50 ug/ml LPS, and 21.1% in case of 200 ug/ml LPS. None of untreated group showed p53-positive cells. Up-regulation of p53 protein during the initial logarithmic phase of growth may be a consequence of on-going DNA damage."