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Peran Th17 dalam keganasan, khususnya karsinoma sel hati, masih menjadi perdebatan. Sel Th17, sel penghasil IL-17, dilaporkan berhubungan dengan efek protumor dan antitumor sekaligus. Di lain sisi, sel Th1 yang menyekresikan IFN-γ memiliki sifat antitumor. Kemoembolisasi transarterial / transarterial chemo-embolization (TACE) diketahui dapat menyebabkan nekrosis tumor, namun peran TACE dalam memengaruhi sel Th17, Th1, IL-17, IFN-γ, dan rasio neutrofil limfosit (RNL) masih belum diketahui. Penelitian ini bertujuan untuk menentukan perubahan Th17, Th1, IL-17, IFN-γ, dan nilai RNL pada pasien KSH yang menjalani TACE.

Penelitian ini dilakukan sepanjang Juni 2015–Januari 2019 di RSCM dan beberapa rumah sakit jejaring di Jakarta. Desain potong lintang digunakan untuk membandingkan respons imun pasien KSH dengan sirosis hati. Desain kohort prospektif diterapkan untuk menilai hubungan respons imun dengan keberhasilan TACE. Pengambilan darah dilakukan sebelum dan 30 hari setelah tindakan TACE pada pasien KSH dan satu kali pada pasien sirosis. Nilai Th17 dan Th1 dianalisis menggunakan teknik flowcytometry, sedangkan nilai IL-17 dan IFN-γ diukur dengan teknik enzyme-linked immunosorbent assay (ELISA). Nilai RNL dihitung dari pembagian kadar neutrofil dengan limfosit yang diperoleh dari pemeriksaan hitung jenis. Respons terhadap TACE dievaluasi berdasarkan kriteria mRECIST.

Sebanyak 40 pasien sirosis dan 41 pasien KSH berpartisipasi dalam penelitian ini. Sebanyak 12 pasien dan 29 pasien termasuk ke dalam kelompok respons dan nonrespons, secara berurutan. Penurunan kadar AFP dan ukuran tumor secara bermakna ditemukan pada kelompok respons. Pada kelompok ini, juga ditemukan peningkatan bermakna kadar Th1, Th17, dan sel T CD4+/IFN-γ+/IL-17+ setelah TACE. Nilai IL-17, IFN-γ, dan RNL tidak berhubungan dengan respons TACE. Di samping itu, didapatkan peningkatan bermakna kadar CD4+/IFN-γ+/IL-17- pada kelompok nonrespons.

Simpulan: Peningkatan kadar Th1 dan Th17 dalam darah perifer yang diiringi dengan peningkatan sel T CD4+/IFN-γ+/IL-17+ didapatkan pada pasien KSH yang berespons baik terhadap TACE.

 

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The role of Th17 cells in malignancy, especially hepatocellular carcinoma, remains controversial. Th17 cells, IL-17 producing cells, were reported to be associated with both protumor and antitumor effects. On the other hand, Th1 cells, IFN-γ producing cells, had antitumor properties. Transarterial chemoembolization (TACE) is known for its potency to cause tumor necrosis, but its impact on Th17, Th1, IL-17, IFN-γ, and neutrophil-to-lymphocyte ratio (NLR) is still unclear. This study aims to determine the changes in Th17, Th1, IL-17, IFN-γ, and NLR levels in HCC patients treated with TACE.

This study was conducted from June 2015 to January 2019 at Cipto Mangunkusumo National General Hospital dan several affiliated hospitals in Jakarta. A cross-sectional study design was used to compare the immune response between HCC and liver cirrhotic patients. A prospective cohort study design was applied to assess the relationship between immune response and tumor response to TACE. Plasma sampling was obtained from HCC and cirrhotic patients that fulfilled the inclusion and exclusion criteria. Blood samples were collected immediately before and 30 days after TACE. Th17 and Th1 levels were measured using flowcytometry technique, while IL-17 and IFN-γ levels were quantified by using enzyme-linked immunosorbent assay (ELISA). The value of NLR was calculated by dividing the neutrophil count by the lymphocyte count. Responses to TACE were evaluated based on mRECIST.

A total of 40 cirrhotic and 41 HCC patients participated in this study. As many as 12 and 29 patients were included in the response and nonresponse group, respectively. In the response group, there were significant reduction of AFP levels and tumor size, as well as significant increase of Th1, Th17 and CD4+/IFN-γ+/IL-17+ T cells levels after TACE. Furthermore, there was an increase of CD4+/IFN-γ+/IL-17- levels in the non-response group. The values of IL-17, IFN-γ, and NLR were not related to TACE response.

Conclusion: Patients with good response to TACE had increased levels of circulating Th1, Th17, and CD4+/IFN-γ+/IL-17+ T cells.

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"HIV coinfection in HCV-infected patients accelerates the course of disease and affects the outcome of Peg-IFN/RBV combination treatment. HCV-HIV coinfected patients are suspected to have HCV mutation in NS5A-ISDR/PKR-BD region that had a role to the successfulness of Peg-IFN/RBV therapy. SNP IL-28B polymorphism is predicted to have an effect on the HCV quasi-species evolution. However, until now the effect of HCV NS5A mutation and SNP IL-28B of the host to the response of treatment is still unclear.This study aimed to determine the presence and role of HCV NS5A-ISDR/PKR-BD region mutation and host SNP IL-28B on the succes of Peg-IFN/RBV combination treatment in HCV-HIV coinfected patients.Prospective cohort study design was conducted in this study. Plasma sample was collected from 22 monoinfected and 134 HCV-HIV coinfected patients prior to therapy. All of them were treated with Peg-IFN/RBV for 48 weeks. The examination of HCV RNA was performed 24 weeks after the end of therapy. PCR nucleotide sequencing was performed after the RNA virus extraction and cDNA synthesis had been performed. Analysis of secondary structure and prediction of mutation function were assessed by PredictProtein (PP) program.Sixteen from thirthy HCV-HIV co-infection patients and none from eight HCV patients achieved SVR. Nonneutral mutation ≥ 1 was found in 23/30 subjects with HCV-HIV co-infection. The presence of nonneutral mutation ≥ 1 was observed more frequent in SVR group than non-SVR group. Nonneutral mutation ≥ 1 was associated with SVR achievement, regardless the monoinfection or coinfection status (p = 0.04). Interaction of CC gene and nonneutral mutation was not associated with SVR. Secondary structure transformation of VHC NS5A was not associated with SVR in coinfected subjects. NS5A binding site structure was different from consensus in SVR group, while the structure was similar to consensus in non-SVR group.Nonneutral mutation ≥ 1 has the most important role on the SVR achievement in patients treated with Peg-IFN/RBV. The interaction of CC-gene and nonneutral mutation was not associated with SVR. The change of secondary structure was also not associated with SVR achievement, however, the changes of NS5A binding site structure were found in HCV-HIV coinfected patients who achieved SVR.

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Koinfeksi HIV pada pasien dengan infeksi VHC dapat memperberat perjalanan penyakit dan memengaruhi keberhasilan terapi kombinasi Peg-IFN/RBV. Pasien koinfeksi VHC-HIV diduga mengalami mutasi VHC pada regio NS5A-ISDR/PKR-BD yang mempunyai peran terhadap keberhasilan terapi Peg-IFN/RBV. Polimorfisme SNP IL-28B diprediksi berpengaruh terhadap evolusi quasi-spesies VHC, namun hingga saat ini keberadaan dan peran mutasi VHC NS5A serta SNP IL-28B pejamu pada koinfeksi VHC-HIV terhadap keberhasilan terapi masih belum diketahui secara jelas.Penelitian ini bertujuan untuk mengetahui keberadaan dan peran mutasi VHC NS5A-ISDR/PKR-BD serta SNP IL-28B pejamu terhadap keberhasilan terapi dengan kombinasi Peg-IFN/RBV pada pasien koinfeksi VHC-HIV.Penelitian ini menggunakan desain studi kohort prospektif. Sampel plasma dikumpulkan dari 22 subjek monoinfeksi dan 134 subjek koinfeksi sebelum menjalani terapi. Seluruh pasien mendapatkan terapi Peg-IFN/RBV selama 48 minggu. Pemeriksaan VHC RNA setelah 24 minggu dari akhir terapi dilakukan untuk menilai respons terapi (sustained virological response/SVR 24). Sekuensing nukleotida menggunakan PCR dilakukan setelah ekstraksi RNA virus dan sintesis cDNA dari sampel plasma. Analisis struktur sekunder dan prediksi fungsi mutasi menggunakan program PredictProtein (PP).Sebanyak 16 pasien dari 30 pasien koinfeksi VHC-HIV yang mengalami SVR serta tidak ada dari 8 pasien monoinfeksi VHC yang mengalami SVR. Mutasi nonnetral ≥ 1 ditemukan pada 23/30 pasien koinfeksi VHC-HIV. Keberadaan mutasi nonnetral ≥ 1 didapatkan lebih tinggi pada kelompok SVR (14 pasien) dibandingkan dengan non-SVR (9 pasien). Mutasi nonnetral ≥1 berhubungan dengan kejadian SVR, tanpa memandang status monoinfeksi dan koinfeksi (p = 0,04). Interaksi antara gen CC dan mutasi nonnetral tidak berhubungan dengan SVR. Perubahan struktur sekunder NS5A tidak berhubungan dengan SVR pada pasien koinfeksi. Struktur binding site NS5A pada kelompok SVR didapatkan berbeda dengan konsensus, sedangkan pada kelompok non-SVR mirip dengan konsensus.Mutasi nonnetral ≥ 1 berperan terhadap kejadian SVR pada pasien yang mendapat terapi Peg-IFN/RBV. Interaksi mutasi nonnetral dan gen CC tidak berhubungan dengan pencapaian SVR. Perubahan struktur sekunder juga tidak berhubungan dengan pencapaian SVR, akan tetapi perubahan struktur binding site NS5A-ISDR/PKR-BD ditemukan pada pasien koinfeksi VHC-HIV yang mencapai SVR dengan terapi Peg-IFN/RBV."

"Infeksi virus hepatitis B (VHB) merupakan masalah kesehatan global. Terapi yang ada saat ini hanya berdampak minimal terhadap covalently closed circular deoxyribonucleic acid (cccDNA), sehingga eradikasi sulit dicapai. Matriks Metaloproteinase-9 (MMP-9) berperan dalam meningkatkan replikasi VHB, namun belum ada penelitian yang mengevaluasi peran penghambat MMP-9 terhadap replikasi VHB. Kultur primer hepatosit diperoleh dari Tupaia javanica dan diinfeksi dengan VHB manusia, kemudian dibagi menjadi dua kelompok, yaitu kontrol dan intervensi. Kelompok intervensi diberikan penghambat MMP-9 dosis 1 nM, 3 nM, dan 7 nM. Peripheral blood mononuclear cells (PBMC) manusia diperoleh dari pasien hepatitis B kronik, kemudian dibagi menjadi dua kelompok, yaitu kontrol dan intervensi. Kelompok intervensi diberikan penghambat MMP-9 dosis 3 nM. Dilakukan pengukuran HBsAg, DNA VHB, cccDNA, MMP-9, type-1 IFN receptor 1 (IFNAR1), dan interferon-β (IFN-β) sebelum dan 72 jam setelah pemberian intervensi pada kedua kelompok. Pada kultur primer hepatosit T. javanica yang diinfeksi VHB manusia, pemberian penghambat MMP-9 dosis 1 nM, 3 nM, dan 7 nM secara konsisten menurunkan kadar HBsAg, DNA VHB, cccDNA, dan MMP-9. Dosis 3 nM meningkatkan kadar IFNAR1, sedangkan dosis 7 nM meningkatkan kadar IFN-β. Dosis 3 nM menunjukkan efek yang lebih optimal dibandingkan dosis lainnya. Pada PBMC manusia dengan infeksi VHB, pemberian penghambat MMP- 9 dosis 3 nM menurunkan kadar HBsAg, DNA VHB, cccDNA, dan MMP- 9, serta meningkatkan kadar IFN-β, namun menurunkan kadar IFNAR1. Studi ini menunjukkan bahwa pemberian penghambat MMP-9 dapat menurunkan kadar HBsAg, DNA VHB, cccDNA, dan MMP-9, serta meningkatkan kadar IFN-β pada kultur primer hepatosit T. javanica dan PBMC manusia.

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Hepatitis B virus (HBV) infection remains a significant global health concern. Current therapies have minimal impact on covalently closed circular deoxyribonucleic acid (cccDNA), making HBV eradication difficult. Matrix Metalloproteinase-9 (MMP-9) enhance HBV replication, but its inhibition has not been studied. Primary hepatocyte cultures were obtained from Tupaia javanica and infected with human HBV, then divided into control and intervention groups. The intervention groups were treated with MMP-9 inhibitors at doses of 1 nM, 3 nM, and 7 nM. Human peripheral blood mononuclear cells (PBMC) were isolated from chronic hepatitis B patients and divided into control and intervention groups. The intervention groups received MMP-9 inhibitors at dose of 3 nM. Measurements of HBsAg, HBV DNA, cccDNA, MMP-9, type-1 IFN receptor 1 (IFNAR1), and interferon-β (IFN-β) were performed before and 72 hours after intervention in both groups. In T. javanica primary hepatocyte culture infected with human HBV, MMP-9 inhibitors at doses of 1 nM, 3 nM, and 7 nM consistently decreased levels of HBsAg, HBV DNA, cccDNA, and MMP-9. The 3 nM dose increased IFNAR1 levels, while the 7 nM dose increased IFN-β levels. The 3 nM dose demonstrated the most optimal effects. In human PBMC with HBV infection, MMP-9 inhibitor at dose of 3 nM decreased levels of HBsAg, HBV DNA, cccDNA, MMP-9, increased IFN-β levels, but reduced IFNAR1 levels. This study shows that administration of MMP-9 inhibitors reduced levels of HBsAg, HBV DNA, cccDNA, and MMP-9, while increased IFN-β levels in T. javanica primary hepatocyte cultures and human PBMC."