Major Drug Resistance Mutations on Reverse Transcriptase Gene in Human Immunodeficiency Virus Type-1 in Indonesia: A Systematic Review.

PURPOSE OF REVIEW: The prevalence of HIV-1 in Indonesia is on a concerning upward trajectory, with a concurrent rise in the development of drug-resistant strains, challenging the efficacy of antiretroviral therapy (ART). Many mutations have been found in the pol gene that makes HIV resistant to ART. We aim to review the major drug resistance mutations (DRMs) of reverse transcriptase (RT) of pol gene in HIV-1 cases in Indonesia. RECENT FINDINGS: A total of eleven articles reporting DRMs in HIV-1 subjects from various regions between 2015-2020 in Indonesia are included. The prevalence of major DRMs on the RT gene in studies included varies from 3.4% to 34%. The CRF01_AE subtype stands out as the predominant variant. Notably, the prevalence of major DRMs in ART-experienced individuals is 22.1%, while ART-naïve individuals show a lower rate of 4.4%. Among the RT gene mutations, M184I/V emerges as the most prevalent (10.5%) within the nucleos(t)ide reverse transcriptase inhibitors (NRTI) group, while K103N leads among the non-NRTI (NNRTI) group, with a frequency of 6.4%. Regionally, North Sulawesi records the highest prevalence of major DRMs in the RT gene at 21.1%, whereas Riau and Central Papua exhibit the lowest rates at 3.4%. Significant variations in drug resistance mutations within the RT gene across Indonesian regions highlight the importance of closely monitoring and evaluating the effectiveness of current antiretroviral therapy (ART) regimens. Considerably, more studies are needed to understand better and overcome the emergence of DRMs on HIV-1 patients in Indonesia.

The role of multipotent cancer associated fibroblasts in hepatocarcinogenesis.

BACKGROUND: The presence of tumor supporting cells in various cancer, including in hepatocellular carcinoma (HCC), has become an important target in the study of carcinogenesis. The cancer-associated fibroblast (CAF), one of the most important cellular components in the cancer stroma, might contribute to the progression of the disease due to its plasticity, a behavior of the stem cells. In this study, we investigate the significance of the CAF and its role in the HCC progression and metastasis. METHODS: Primary CAF and non-tumoral fibroblast (NTF) from nine paired HCC and distant non-tumoral liver tissues were isolated and cultured. The cells were characterized by flow cytometry, RT-PCR, anchorage-independent assay and in vitro cells directed trans-differentiation. Co-culture study was performed in Transwell system and xenograft assay was performed in immunodeficient mice. RESULTS: CAF and NTF were positive for CD90, CD44, αSMA, and vimentin and negative for CD34, CD45, CD117, and CD133. When stimulated, they showed the potential to differentiate into adipocytes, osteoblasts, and pancreatic cells. When co-cultured with human HCC cell lines, CAF up-regulated gene expressions of TGFB1 and FAP of HuH-7 and JHH-6 while NTF did not induced either of the genes. Xenograft assay showed that the CAF had the capacity to enter into circulation as confirmed by RT-PCR and DNA sequencing. CONCLUSION: Our data provides evidence of the plasticity of the CAF and the NTF as stem cells in the process of hepatocarcinogenesis and metastasis. These cells mutually interacts with HCC cells. Their trans-differentiation flexibility may induce a switch from normal to cancerous microenvironment.

Serum AP-endonuclease 1 (sAPE1) as novel biomarker for hepatocellular carcinoma.

Late diagnosis for Hepatocellular Carcinoma (HCC) remains one of the leading causes for the high mortality rate. The apurinic/apyrimidinic endonuclease 1 (APE1), an essential member of the base excision DNA repair (BER) pathway, contributes to cell response to oxidative stress and has other non-repair activities. In this study, we evaluate the role of serum APE1 (sAPE1) as a new diagnostic biomarker and we investigate the biological role for extracellular APE1 in HCC. sAPE1 level was quantified in 99 HCC patients, 50 non-HCC cirrhotic and 100 healthy controls. The expression level was significantly high in HCC (75.8 [67.3-87.9] pg/mL) compared to cirrhosis (29.8 [18.3-36.5] pg/mL] and controls (10.8 [7.5-13.2] pg/mL) (p < 0.001). The sAPE1 level corresponded with its protein expression in HCC tissue. sAPE1 had high diagnostic accuracy to differentiate HCC from cirrhotic (AUC = 0.87, sensitivity 88%, specificity 71%, cut-off of 36.3 pg/mL) and healthy subjects (AUC 0.98, sensibility 98% and specificity 83%, cut-off of 19.0 pg/mL). Recombinant APE1, exogenously added to JHH6 cells, significantly promotes IL-6 and IL-8 expression, suggesting a role of sAPE1 as a paracrine pro-inflammatory molecule, which may modulate the inflammatory status in cancer microenvironment. We described herein, for the first time to our knowledge, that sAPE1 might be considered as a promising diagnostic biomarker for HCC.

The expression of CD90/Thy-1 in hepatocellular carcinoma: an in vivo and in vitro study.

Although the CD90 (Thy-1) was proposed as biomarker of several tumors and cancer stem cells, the involvement of this molecule in the progression of hepatocellular carcinoma (HCC) and other less frequent hepatic neoplasms is still undefined. The distribution of CD90 was investigated both in in vivo (human tissues samples) and in vitro (human HCC cell line JHH-6). A total of 67 liver tumors were analyzed: 51 HCC, 6 cholangiocarcinoma and 10 hepatoblastoma. In all cases, paired tissue sample of both the tumor and cirrhotic liver was available. Hepatic tissue obtained in 12 healthy livers was used as control. CD90 gene expression was studied by RT-qPCR, protein expression was assessed by quantitative Western Blot, immunofluorescence and flow cytometry. The CD90 expression analysis showed a significant increment in tumor compared to both its paired cirrhotic tissue and normal liver (p<0.05 and p<0.001, respectively). This increase was accompanied by the up-regulation of stromal component in the cancer, as demonstrated by alpha smooth muscle actin staining. In vitro analysis of JHH-6 cell line showed a higher proliferation capacity of CD90(+) compared to CD90(-) cells (p<0.001), also noticed in 3D clonogenic assay (p<0.05), associated by a significant higher expression of the promoting factors (hepatocyte growth factor, fibroblast associated protein and alpha smooth muscle actin 2). A higher expression of the breast cancer resistance protein was found in CD90(+) subpopulation while the multidrug resistance protein 1 showed an opposite behavior. Collectively, these results point to the importance of CD90 in the HCC.