Correction: Chen et al. Hydroxychloroquine (HCQ) Modulates Autophagy and Oxidative DNA Damage Stress in Hepatocellular Carcinoma to Overcome Sorafenib Resistance via TLR9/SOD1/hsa-miR-30a-5p/Beclin-1 Axis. Cancers 2021, 13, 3227.

Error in Figure [...].

Hydroxychloroquine (HCQ) Modulates Autophagy and Oxidative DNA Damage Stress in Hepatocellular Carcinoma to Overcome Sorafenib Resistance via TLR9/SOD1/hsa-miR-30a-5p/Beclin-1 Axis.

Sorafenib is used for treating advanced hepatocellular carcinoma (HCC), but some patients acquire sorafenib resistance. We investigated the mechanisms underlying acquired sorafenib resistance in HCC cells and targeted them to re-sensitize them to sorafenib. In silico analysis indicated that toll-like receptor (TLR)-9 was significantly overexpressed, and that miRNA (hsa-miR-30a-5p) was downregulated in sorafenib-resistant HCC cells, which modulated HCC cell proliferation, oxidative stress, and apoptosis. TLR9 overexpression increased HCC cell proliferation, whereas TLR9 inhibition from hydroxychloroquine (HCQ) decreased HCC cell proliferation, tumor growth, oxidative stress marker (SOD1), and the formation of autophagosome bodies (reduced ATG5 and Beclin-1 expression). Moreover, HCQ treatment reduced epithelial-mesenchymal transition, leading to decreased clonogenicity, migratory ability, and invasiveness. HCQ targeted and reduced the self-renewal capacity phenotype by inhibiting tumorsphere generation. Both in vitro and in vivo results demonstrated the synergistic effect of the HCQ-sorafenib combination on sorafenib-resistant HCC (Huh7-SR) cells, increasing their sensitivity to treatment by modulating TLR9, autophagy (ATG5 and Beclin-1), oxidative stress (SOD1), and apoptosis (c-caspase3) expression and thus overcoming the drug resistance. This study's findings indicate that TLR9 overexpression occurs in sorafenib-resistant HCC cells and that its downregulation aids HCC suppression. Moreover, HCQ treatment significantly increases sorafenib's effect on sorafenib-resistant HCC cells.

Induced Mitochondrial Alteration and DNA Damage via IFNGR-JAK2-STAT1-PARP1 Pathway Facilitates Viral Hepatitis Associated Hepatocellular Carcinoma Aggressiveness and Stemness.

BACKGROUND: Hepatitis virus is a major risk factor for liver cancer. The mitochondrial dysfunction IFN gamma-related pathways are activated after virus infection. Jak family-related protein is involved in the downstream of IFN gamma-related pathways. However, the effect of the IFNGR-JAK-STAT pathway acting as functional regulators of their related protein expression on virus infection and hepatocellular carcinoma (HCC) remains unclear. Interestingly, the role of the DNA repair gene (PARP1) in therapy resistant cancers also has not been studied and explored well. In this study, we hypothesized that momelotinib could suppress the progression of HCC by targeting Jak family related and PARP1 DNA repair protein. Based on this observation, we link the relevant targets of the JAK family and the potential applications of targeted therapy inhibitors. METHODS: We analyzed possible synergism between momelotinib and sorafenib in hepatitis virus-associated liver cancer. Immunostaining, colony formation assay, cell invasion, migration, and tumorsphere-formation assay were used for drug cytotoxicity, cell viability, and possible molecular mechanism. RESULT: We first demonstrated that the expression of Jak1 and 2 is significantly upregulated in vHCC than in nvHCC/normal liver tissues. In addition, the gene expression of IFN gamma-related pathways is activated after virus infection. Additionally, we found that momelotinib significantly inhibited the growth of HCC cells and reduces the expression of Jak2, which showed the importance of momelotinib in targeting Jak2 and reducing tumorigenesis in HCC. Meanwhile, momelotinib effectively inhibited the IFNGR-JAK-STAT pathway and reduced the migratory/invasive ability of vHCC cells through down-regulating EMT biomarkers (E-cadherin and vimentin), transcription factor (Slug), and significantly inhibits the DNA damage repair enzyme PARP1. It also induced cell apoptosis of vHCC cells. Furthermore, the combined effect of momelotinib and sorafenib both at in vitro and in vivo synergistically suppresses the proliferation of vHCC cells and effectively reduces the tumor burden. CONCLUSIONS: Our results showed that momelotinib effectively suppressed the expression of the IFNGR-JAK-STAT-PARP1 pathway, which results in the downregulation of cancer stem cell genes and enhances the antitumor efficacy of sorafenib by initiating the expression of apoptosis-related genes and inhibiting the DNA repair gene in vHCC cells, thus maximizing its therapeutic potential for patients with HCC.

Transplant Recipients Using Tacrolimus Had Higher Utilization of Healthcare Services Than Those Receiving Cyclosporine in Taiwan.

To date, population-based studies on the healthcare service utilization among stable heart, kidney, and liver transplant recipients with different calcineurin inhibitors are still scarce. Therefore, we used the Taiwan National Health Insurance Research Database to conduct a nationwide cross-sectional study to estimate the healthcare utilization of stable transplant recipients with tacrolimus or cyclosporine (n = 3,482). The sampled patients in this study comprised 377 heart, 1,693 kidney, and 1,412 liver transplant recipients between 1 January 2011 and 31 December 2011. Each subject was followed for a 1-year period to evaluate his/her healthcare service utilization. Outcome variables of the healthcare service utilization were stated as below: numbers of outpatient visits, outpatient costs, numbers of inpatient days, inpatients costs, and total costs of all healthcare services. As for all healthcare service utilization, stable transplant recipients on tacrolimus had significantly more outpatient visits (40.7 vs. 38.6), outpatient costs (US$10,383 vs. US$8,155), and total costs (US$12,516 vs. US$10,372) of all healthcare services than those on cyclosporine during the 1-year follow-up period. Additionally, further analysis showed that heart transplant recipients receiving tacrolimus incurred 1.7-fold higher inpatient costs compared to patients receiving cyclosporine. We concluded that transplant recipients using tacrolimus had significantly higher utilization of all healthcare services than those receiving cyclosporine as immunosuppressive therapy.

Ovatodiolide suppresses yes-associated protein 1-modulated cancer stem cell phenotypes in highly malignant hepatocellular carcinoma and sensitizes cancer cells to chemotherapy in vitro.

The cancer stem cells (CSCs) theory recently became a focus of heightened attention in cancer biology, with the proposition that CSCs may constitute an important therapeutic target for effective anticancer therapy, because of their demonstrated role in tumor initiation, chemo-, and radio-resistance. Liver CSCs are a small subpopulation of poorly- or undifferentiated liver tumor cells, implicated in tumorigenesis, metastasis, resistance to therapy and disease relapse, enriched with and associated with the functional markers corresponding to the CSCs-enriched side population (SP), high aldehyde dehydrogenase (ALDH) activity, and enhanced formation of in vitro liver CSCs models, referred to herein as hepatospheres. In this study, we found YAP1 was significantly expressed in the SP cells, as well as in generated hepatospheres compared to non-SP or parental HCC cells, at transcript and/or protein levels. In addition, downregulation of YAP1 expression levels by small molecule inhibitor and siRNA transfection, in the HCC cell lines, PLC/PRF/5 and Mahlavu, were associated with marked loss of ability to form hepatospheres and increased sensitivity to sorafenib. Consistent with the above, we demonstrated that YAP1 expression positively correlated with that of Sox2, Oct4, c-Myc and GRP78, markers of stemness and drug resistance. This is suggestive of YAP1's role as a modulator of cancer stemness, ER stress and chemoresistance. For the first time, we demonstrate that Ovatodiolide significantly attenuates YAP1 expression and subsequently suppressed YAP1-modulated CSCs phenotypes and associated disease progression, consistent with our previous finding in breast cancer. Taken together, our findings suggest that YAP1, highly expressed in malignant liver tumours, contributes to hepatocellular CSCs phenotype and is a molecular target of interest for CSCs targeted therapy in liver cancer patients.

Cancer Incidence among Heart, Kidney, and Liver Transplant Recipients in Taiwan.

Population-based evidence of the relative risk of cancer among heart, kidney, and liver transplant recipients from Asia is lacking. The Taiwan National Health Insurance Research Database was used to conduct a population-based cohort study of transplant recipients (n = 5396), comprising 801 heart, 2847 kidney, and 1748 liver transplant recipients between 2001 and 2012. Standardized incidence ratios and Cox regression models were used. Compared with the general population, the risk of cancer increased 3.8-fold after heart transplantation, 4.1-fold after kidney transplantation and 4.6-fold after liver transplantation. Cancer occurrence showed considerable variation according to transplanted organs. The most common cancers in all transplant patients were cancers of the head and neck, liver, bladder, and kidney and non-Hodgkin lymphoma. Male recipients had an increased risk of cancers of the head and neck and liver, and female kidney recipients had a significant risk of bladder and kidney cancer. The adjusted hazard ratio for any cancer in all recipients was higher in liver transplant recipients compared with that in heart transplant recipients (hazard ratio = 1.5, P = .04). Cancer occurrence varied considerably and posttransplant cancer screening should be performed routinely according to transplanted organ and sex.

Scrub typhus cases in a teaching hospital in Penghu, Taiwan, 2006-2010.

Scrub typhus is a mite-borne infectious disease caused by Orientia tsutsugamushi (previously called Rickettsia tsutsugamushi). The severity of this disease varies from only mild symptoms to death, and its manifestations are nonspecific. Therefore, clinicians may not correctly diagnose scrub typhus early enough for successful treatment. Reports of infections in travelers returning from Asia to their home countries are increasingly common. Thus, it is important that even clinicians in nonepidemic regions be alert for this disease. Here we describe the epidemiological aspects and clinical manifestations of scrub typhus encountered at a teaching hospital in Penghu, Taiwan, over the past 5 years. A total of 126 patients were confirmed to be positive for scrub typhus at the hospital from 2006 to 2010. All cases were confirmed by the Centers for Disease Control and Prevention or its contract laboratory through pathogen isolation and an indirect immunofluorescence assay. Medical records of these patients were reviewed, and demographic and clinical characteristics, laboratory data, seasonal data, geographic distribution, complications, and outcome were analyzed. The incidence of scrub typhus peaked in individuals aged 0-10 and 51-60 years, with the highest incidence among those ≤10 years of age. No significant difference was noted between sexes. Fever was the most common symptom (93.6%), followed by chills (23.8%), cough (18.3%), and headache (14.3%). Eschars were observed in 78 (61.9%) patients, with the axilla being the most frequent site (n=17; 21.8%). Most patients were retirees (n=63; 50%), followed by students (n=16; 12.7%). Patients were more likely to live in rural areas than urban areas. Scrub typhus was epidemic in the spring (April to June) and fall (October to December) in a bimodal distribution similar to that observed in Japan. Leukocytosis was not common, but most patients had abnormal C-reactive protein levels, thrombocytopenia, and elevated liver function test results. Residents of Penghu, particularly Makung City and Husi Township, as well as travelers to the region during the spring and fall seasons should be educated about the signs and symptoms of scrub typhus. All physicians who come into contact with individuals residing in or traveling to or from epidemic regions should remain alert about the manifestations of this disease.