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Abstrak :
ABSTRAK
Kanker kolorektal KKR dianggap sebagai masalah kesehatan utama, salah satu jenis kanker yang paling sering terjadi serta penyebab kematian kedua terbesar di negara barat dan di Indonesia. Adenokarsinoma kolorektal serrated AKS merupakan salah satu tipe dari KKR. Salah satu jalur karsinogenesis kolorektal adalah jalur serrated yang diketahui melibatkan mutasi gen KRAS. Penanda tumor lain yang juga terlibat dalam proses karsinogenesis adalah P53 dan Bcl-2. Gambaran histomorfologik yang ditemukan oleh Tuppurainen dkk. saat ini digunakan sebagai penanda AKS. Terbatasnya sarana laboratorium patologi molekular di Indonesia, menekankan pentingnya membuat model skoring gambaran histomorfologik AKS dan atau ekspresi protein P53 serta Bcl-2 untuk memprediksi mutasi KRAS.Penelitian potong lintang terhadap 39 kasus AKS didapatkan dari Arsip Departemen Patologi Anatomik FKUI/RSCM selama tahun 2013 ndash;2015. Setiap kasus dikumpulkan data klinisnya, dan dinilai ulang karakteristik histomorfologik dan penanda tumor Bcl2 dan P53 , serta dilakukan pemeriksaan status KRAS. Penelitian histomorfologik dilakukan per kasus dan per contoh yaitu terhadap 100 kelenjar/kasus.Pada penelitian ini, kasus AKS ditemukan paling banyak pada laki-laki 51,3 , usia ge; 40 tahun 71,8 , lokasi di kolon kiri 84,6 , tidak memiliki metastasis 92,3 , status mutasi KRAS 71,8 . Ekspresi protein P53 didapatkan pada 69,2 dan protein Bcl-2 51,3 , tidak didapatkan hubungan bermakna ekspresi protein tersebut dengan status KRAS. Gambaran histomorfologik status KRAS didapatkan hubungan pada epitel serrated, lokasi inti sel, kondisi inti, sitoplasma dan musin. Odds ratio tertinggi ditemukan pada epitel serrated OR 2,7; IK 95 2,30 ndash;3,07 dan musin OR 2,0; IK 95 , 1,15 ndash;3,65 . Berdasarkan uji statistik didapatkan model nilai skoring yang terdiri dari epitel serrated, keadaan lokasi inti, kondisi inti dan adanya musin CI 95 antara 61 ndash;65 . Nilai sensitivitas dan spesifisitas berdasarkan nilai titik potong pada angka 16 sensitivitasnya sebesar 72 dan spesifisitasnya sebesar 48 .Simpulan: Didapatkan model sistem skor dengan titik potong 16 untuk memprediksi adanya mutasi KRAS berdasarkan, epitel serrated, lokasi inti sel, kondisi inti, dan adanya musin.Kata kunci: Adenokarsinoma kolorektal serrated, Bcl-2, jalur serrated, Kanker kolorektal, mutasi KRAS, P53

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ABSTRACT
Colorectal cancer CRC is considered as major health problem, one type of cancer that most often occurs as well as the second largest cause of death in western countries and in Indonesia. Serrated colorectal adenocarcinoma SA is one type of CRC. One of colorectal carcinogenesis pathway is serrated pathway that known to involve KRAS gene mutation. Other tumor markers that also involved in the process of its carcinogenesis were P53 and Bcl 2. Histomorphological criteria found by Tuppurainen et al currently used as marker of SA. Limited facilities of molecular pathology laboratory in Indonesia emphasize the needs of making scoring model by using histomorphological features of SA and or P53 and Bcl 2 protein expression to predict KRAS mutation.A cross sectional study conducted to 39 cases of SA registered in Departement of Anatomical Pathology FMUI Ciptomangunkusumo Hospital from 2013 ndash 2015. All clinical data related to the cases were collected. Each case was reevaluated based on Tuppurainen histomorphological criteria, tumor markers Bcl 2 and P53 , and KRAS status. Histomorphological examination is conducted per case and per instance to 100 nodes case.Present study showed that most cases of SA was found in male 51.3 , aged ge 40 years 71.8 , located in left colon 84.6 , did not have metastasis 92.3 , with KRAS mutation status 71.8 . P53 and Bcl 2 protein expressions were found in 69.2 and 51.3 respectively, with no significant association with KRAS status. Histomorphological features of KRAS status found in epithelial serration, nucleus location, nucleus condition, cytoplasm and mucin. Epithelial serration has the highest odds ratio OR 2.7 IK 95 2.30 ndash 3.07 followed by mucin OR 2.0 IK 95 , 1.15 ndash 3.65 . Statistical values showed scoring models consisted of epithelial serrations, nucleus location, nucleus condition and presence of mucin CI 95 between 61 ndash 65 . The sensitivity and specificity cut off point located on the number 16, with sensitivity value was 72 and specificity 48 .Conclusion A scoring system model yielded 16 as cut off score was obtained to predict KRAS mutations based on epithelial serrations, nucleus location, nucleus condition and presence of mucin.Keywords Bcl2, Colorectal cancer, colorectal serrated adenocarcinoma, KRAS mutation, P53, serrated pathway

Abstrak :
Fenomena utama pada pasien MDS adalah sitopenia di darah tepi, namun disertai kondisi hiperselular di sumsum tulang. sCD40L dianggap sebagai sitokin yang dapat memicu sintesis TNFα sebagai sitokin proapoptosis dan memicu sintesis VEGF sebagai sitokin proangiogenesis pada MDS. Oleh sebab itu sCD40L dianggap berpotensi sebagai biopenanda untuk memperkirakan perburukan pada MDS. Penelitian ini bertujuan untuk membuktikan peran pajanan rh-sCD40L dalam menginduksi sintesis TNFα dan VEGF pada sel progenitor hematopoesis, serta membuktikan peran pajanan TNFα dalam memicu apoptosis pada sel progenitor hematopoesis dan sel mesenkim MDS. Penelitian ini merupakan penelitian eksperimental in vitro komparatif. Subjek penelitian adalah pasien MDS yang didiagnosis dan diklasifikasikan berdasarkan kriteria WHO 2008. Pada bone marrow mononuclear cells (BMMC) dipajankan dengan rh-sCD40L dan antiCD40L, kemudian dilakukan pemeriksaan ekspresi mRNA TNFα dan mRNA VEGF yang dikuantifikasi dengan qRT-PCR, serta pemeriksaan kadar TNFα dan VEGF yang diperiksa dengan metode ELISA. Pada sel CD34+, CD33+, CD41+, dan CD73+ dipajankan rhTNFα kemudian dilakukan pemeriksaan aktivitas kaspase-3 dengan imunoflowsitometri. Terdapat 15 sampel MDS terdiri dari 4 dengan diagnosis RCUD, 7 RCMD, dan 4 RAEB1, serta 7 sampel kontrol. Pajanan rh-sCD40L meningkatkan ekspresi mRNA TNFα secara bermakna dibandingkan pajanan antiCD40L. Pajanan rh-sCD40L meningkatkan kadar TNFα secara bermakna dibandingkan kontrol. Namun pajanan rh-sCD40L tidak meningkatkan mRNA VEGF dan kadar protein VEGF. Pajanan rhTNFα meningkatkan aktivitas kaspase-3 pada sel progenitor MDS terutama yang berdiferensiasi menjadi mieloid (CD33+) dan megakariosit-trombosit (CD41+). Pajanan rhTNFα meningkatkan aktivitas kaspase-3 pada sel mesenkim (CD73+) MDS Simpulan: sCD40L berperan dalam meningkatkan sintesis sitokin proapoptosis TNFα di level mRNA dan protein, namun tidak terbukti berperan dalam meningkatkan sintesis proangiogenesis VEGF. TNFα berperan dalam meningkatkan apoptosis terutama pada sel hematopoesis yang telah berdiferensiasi menjadi seri mieloid dan seri megakariosit-trombosit, dan berperan dalam meningkatkan apoptosis pada sel mesenkim.

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Cytopenia is the primary phenomenon in Myelodysplastic Syndrome (MDS) patients, amidst hypercellular bone marrow. The soluble CD40 ligand (sCD40L) is considered as a cytokine that can trigger synthesis of TNFα and VEGF. The former is known as a cytokine that promotes apoptosis while the latter promotes angiogenesis in MDS patients. Therefore, the sCD40L may serve as a potential biomarker to predict worsening of MDS. This study aims to prove the role of rh-sCD40L exposure in inducing the synthesis of TNFα and VEGF in hematopoietic progenitor cells, as well as to establish the role of TNFα exposure in triggering apoptotic activity in hematopoietic progenitor and mesenchymal cells of MDS. The study was a comparative in vitro experimental study. Subjects were MDS patients diagnosed and classified using the WHO 2008 criteria. Bone marrow mononuclear cells (BMMC) were exposed to rh-sCD40L and antiCD40L. The expressions of TNFα and VEGF mRNAs were then quantified by qRT-PCR, and the level of TNFα and VEGF were measured using the ELISA method. The CD34+, CD33+, CD41+, and CD73+ cells were exposed to rhTNFα, then the activity of enzyme caspase-3 was measured using the immunoflowcytometry. There were 7 control and 15 MDS samples with the following diagnoses: 4 RCUD, 7 RCMD, and 4 RAEB1. Compared to antiCD40L, it is found that exposure of rh-sCD40L significantly increased the expression of TNFα mRNA. The similar exposure also significantly increased the level of TNFα compared to controls. However, the exposure of rh-sCD40L did not increase the expression of VEGF mRNA as well as the level of VEGF. The exposure of rhTNFα was found to increase the activity of caspase-3 in MDS progenitor cells, particularly those differentiated into myeloid cells (CD33+) and megakaryocyte-thrombocyte cells (CD41+). The exposure of rhTNFα was found to increase the activity of caspase-3 in MDS mesenchymal (CD73+) cells. Conclusion: The sCD40L plays a role in increasing the synthesis of TNFα which favors apoptotic activity in mRNA and protein level, but not in improving the synthesis of VEGF that promotes angiogenesis. Furthermore, TNFα plays a role in increasing apoptotic activity of hematopoietic cells, particularly those that have differentiated into myeloid series and megakaryocyte-thrombocyte series cells. Also TNFα plays a role in increasing apoptotic activity of mesenchymal cells.