Publications by authors named "Hung-Wen Tsai"

97 Publications

Comparing the Clinicopathological Characteristics of Combined Hepatocellular-Cholangiocarcinoma with Other Primary Liver Cancers Using the Updated WHO Classification.

Histopathology 2021 Apr 10. Epub 2021 Apr 10.

Department of Pathology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

Background: Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is an uncommon hepatic malignancy with a poor outcome. The 2019 WHO classification modified the definition and discarded the subtypes harboring stem cell features. However, the differences among cHCC-CCA, hepatocellular carcinoma (HCC), HCC with stem cell features (HCCscf) and intrahepatic cholangiocarcinoma (iCCA) remain undetermined. The aim of the study is to investigate the characteristics of cHCC-CCA in comparisons with other primary liver cancers utilizing the updated WHO classification.

Methods And Results: We retrospectively analyzed 64 cHCC-CCA and 55 HCCscf patients from Dec2007 to May2018. A propensity score matching was conducted to compare with HCC and iCCA patients. Clinicopathological characteristics, event-free (EFS) and overall survival (OS) were evaluated with multivariate Cox proportional hazard regression. In a median follow-up of 55.9 months, patients with cHCC-CCA had a significantly poor survival as compared with HCCscf and an intermediate survival outcome between HCC and iCCA. HBV infection and high tumor infiltrating lymphocytes (TILs) were associated with a favorable survival in cHCC-CCA. In the multivariate analysis, poor hepatic reserve, absence of HBV infection, stage IV disease and low TILs were significant negative prognostic factors in cHCC-CCA. After pooling with other primary liver cancers, tumor type of cHCC-CCA and iCCA predicted the worse survival results.

Conclusion: cHCC-CCA have an intermediate survival between HCC and iCCA and HBV infection and high TILs predict the favorable survival. Our study provides clinical correlations for the new 2019 WHO classification.
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http://dx.doi.org/10.1111/his.14384DOI Listing
April 2021

Urothelial carcinoma with trophoblastic differentiation: Reappraisal of the clinical implication and immunohistochemically features.

Urol Oncol 2021 Mar 24. Epub 2021 Mar 24.

Departments of Pathology, College of Medicine, National Cheng Kung University, Tainan, TW; Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, TW. Electronic address:

Purpose: To investigate the clinical implications of identifying urothelial carcinoma (UC) with trophoblastic differentiation (UCTD).

Materials And Methods: A prospective cohort study was performed from 2010 to 2016 to examine the incidence of UCTD in urinary tract cancer and association with clinicopathological indicators and patient outcome.

Results: UCTD was detected in 47 of 859 (5.5%) cases of UC of the bladder and 65 of 635 (10.2%) cases in the upper urinary tract. UCTD of the bladder was significantly associated with non-papillary, multiple, larger size ( > 3 cm), muscle invasion, and nodal metastasis (P ≤ 0.0001, respectively). A higher risk of recurrence (P = 0.005), progression (P < 0.0001), and patient death (P < 0.0001) was observed for UCTD than those with traditional, high-grade UC of the bladder. Among four patterns of expression, focal expression of β-human chorionic gonadotropin was frequently detected in papillary tumor (P < 0.005) and UCs of smaller than 3 cm (P = 0.03). Significant indicators in predicting poor disease-specific overall survival in multivariate statistical model were tumor staging (P = 0.001), followed by non-focal β-hCG expression (P = 0.049).

Conclusion: UCTD is more often identified in the upper urinary tract than in the bladder. UCTD of the bladder was significantly associated with higher risk of recurrence, progression, and patient death. Expression of β-hCG in non-focal patterns predicts a worse prognosis for patients with UCTD and deserves an individualized treatment planning.
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http://dx.doi.org/10.1016/j.urolonc.2021.03.006DOI Listing
March 2021

Anti- and non-tumor necrosis factor-α-targeted therapies effects on insulin resistance in rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis.

World J Diabetes 2021 Mar;12(3):238-260

Department of Pathology, National Cheng Kung University Hospital, Tainan 70403, Taiwan.

In addition to β-cell failure with inadequate insulin secretion, the crucial mechanism leading to establishment of diabetes mellitus (DM) is the resistance of target cells to insulin, . insulin resistance (IR), indicating a requirement of beyond-normal insulin concentrations to maintain euglycemic status and an ineffective strength of transduction signaling from the receptor, downstream to the substrates of insulin action. IR is a common feature of most metabolic disorders, particularly type II DM as well as some cases of type I DM. A variety of human inflammatory disorders with increased levels of proinflammatory cytokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-6 and IL-1β, have been reported to be associated with an increased risk of IR. Autoimmune-mediated arthritis conditions, including rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ankylosing spondylitis (AS), with the involvement of proinflammatory cytokines as their central pathogenesis, have been demonstrated to be associated with IR, especially during the active disease state. There is an increasing trend towards using biologic agents and small molecule-targeted drugs to treat such disorders. In this review, we focus on the effects of anti-TNF-α- and non-TNF-α-targeted therapies on IR in patients with RA, PsA and AS. Anti-TNF-α therapy, IL-1 blockade, IL-6 antagonist, Janus kinase inhibitor and phospho-diesterase type 4 blocker can reduce IR and improve diabetic hyper-glycemia in autoimmune-mediated arthritis.
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http://dx.doi.org/10.4239/wjd.v12.i3.238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7958474PMC
March 2021

Role of tumor endothelial marker 1 (Endosialin/CD248) lectin-like domain in lipopolysaccharide-induced macrophage activation and sepsis in mice.

Transl Res 2021 Jun 16;232:150-162. Epub 2021 Mar 16.

Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee. Electronic address:

Deleterious hyper-inflammation resulting from macrophage activation may aggravate sepsis and lead to lethality. Tumor endothelial marker 1 (TEM1), a type I transmembrane glycoprotein containing six functional domains, has been implicated in cancer and chronic sterile inflammatory disorders. However, the role of TEM1 in acute sepsis remains to be determined. Herein we explored the functional significance of the TEM1 lectin-like domain (TEM1D1) in monocyte/macrophage activation and sepsis using TEM1D1-deleted (TEM1) transgenic mice and recombinant TEM1D1 (rTEM1D1) protein. Under stimulation with lipopolysaccharides (LPS) or several other toll-like receptor agonists, TEM1 macrophages produced lower levels of tumor necrosis factor (TNF)-α and interleukin (IL)-6 than wild-type TEM1 macrophages. Compared with TEM1 macrophages, LPS-macrophage binding and intracellular mitogen-activated protein kinase (MAPK)/nuclear factor (NF)-κB activation were suppressed in TEM1 macrophages. In vivo, TEM1D1 deletion improved survival in LPS-challenged mice with reduction of circulating TNF-α and IL-6 and alleviation of lung injury and pulmonary leukocyte accumulation. In contrast, rTEM1D1 could bind to LPS and markedly suppress LPS-macrophage binding, MAPK/NF-κB signaling in macrophages and proinflammatory cytokine production. Treatment with rTEM1D1 improved survival and attenuated circulating TNF-α and IL-6, lung injury and pulmonary accumulation of leukocytes in LPS-challenged mice. These findings demonstrated differential roles for the TEM1 lectin-like domain in macrophages and soluble TEM1 lectin-like domain in sepsis. TEM1 in macrophages mediates LPS-induced inflammation via its lectin-like domain, whereas rTEM1D1 interferes with LPS-induced macrophage activation and sepsis.
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http://dx.doi.org/10.1016/j.trsl.2021.03.009DOI Listing
June 2021

Human hepatitis viruses-associated cutaneous and systemic vasculitis.

World J Gastroenterol 2021 Jan;27(1):19-36

Department of Pathology, National Cheng Kung University Hospital, Tainan 70403, Taiwan.

Human hepatitis viruses (HHVs) include hepatitis A virus, hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis delta virus, and hepatitis E virus and can cause liver inflammation in their common human host. Usually, HHV is rapidly cleared by the immune system, following acute HHV invasion. The morbidities associated with hepatitis A virus and hepatitis E virus infection occur shortly after their intrusion, in the acute stage. Nevertheless, the viral infectious process can persist for a long period of time, especially in HBV and HCV infection, leading to chronic hepatitis and further progressing to hepatic cirrhosis and liver cancer. HHV infection brings about complications in other organs, and both acute and chronic hepatitis have been associated with clinical presentations outside the liver. Vascular involvement with cutaneous and systemic vasculitis is a well-known extrahepatic presentation; moreover, there is growing evidence for a possible causal relationship between viral pathogens and vasculitis. Except for hepatitis delta virus, other HHVs have participated in the etiopathogenesis of cutaneous and systemic vasculitis different mechanisms, including direct viral invasion of vascular endothelial cells, immune complex-mediated vessel wall damage, and autoimmune responses with stimulation of autoreactive B-cells and impaired regulatory T-cells. Cryoglobulinemic vasculitis and polyarteritis nodosa are recognized for their association with chronic HHV infection. Although therapeutic guidelines for HHV-associated vasculitis have not yet been established, antiviral therapy should be initiated in HBV and HCV-related systemic vasculitis in addition to the use of corticosteroids. Plasma exchange and/or combined cyclophosphamide and corticosteroid therapy can be considered in patients with severe life-threatening vasculitis manifestations.
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http://dx.doi.org/10.3748/wjg.v27.i1.19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7789062PMC
January 2021

Clinicopathological features of mismatch repair protein expression patterns in colorectal cancer.

Pathol Res Pract 2021 Jan 16;217:153288. Epub 2020 Nov 16.

Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan. Electronic address:

Microsatellite instability (MSI) is reflective of a deficient mismatch repair (dMMR) system, which is mostly associated with the methylation of mismatch repair (MMR) genes and BRAF mutations in sporadic colorectal cancers (CRCs). We performed a retrospective study to analyze the clinicopathological features of dMMR CRCs and their association with the BRAF V600E mutation. The incidence of dMMR CRCs in our cohort was 7.4 % (118/1603). Immunohistochemistry (IHC) revealed four common dMMR IHC patterns in 116 dMMR CRCs from 110 patients. dMMR type 1 (MLH1-/PMS2-) CRCs were the most frequent pattern, usually showing typical proximal location and MSI histology. The BRAF V600E mutation was almost exclusively observed in dMMR type 1 (32 of 72) and dMMR type 2 (PMS- only, 7 of 18) CRCs (p = 0.001). Patients with dMMR type 3 (MSH2-/MSH6-) CRCs were usually diagnosed at younger ages (p < 0.001) and had the strongest family history of Lynch syndrome-associated tumors (p = 0.002). dMMR type 3 CRCs frequently presented at advanced stages (p = 0.005) with perineural invasion (p = 0.021). We also found a significant positive association of dMMR type 1 and type 3 with advanced stages of CRC, whereas dMMR types 2 and 4 (MSH6- only) were usually diagnosed at early stages of CRC (p < 0.001). In conclusion, BRAF V600E mutations almost exclusively occurred in dMMR type 1 and 2 CRCs. Patterns of MMR protein expression display distinct associations with tumor staging and age at diagnosis.
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http://dx.doi.org/10.1016/j.prp.2020.153288DOI Listing
January 2021

FGF primes angioblast formation by inducing ETV2 and LMO2 via FGFR1/BRAF/MEK/ERK.

Cell Mol Life Sci 2021 Mar 10;78(5):2199-2212. Epub 2020 Sep 10.

Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, No. 35, Xiaodong Rd., Tainan, 70457, Taiwan.

It is critical to specify a signal that directly drives the transition that occurs between cell states. However, such inferences are often confounded by indirect intercellular communications or secondary transcriptomic changes due to primary transcription factors. Although FGF is known for its importance during mesoderm-to-endothelium differentiation, its specific role and signaling mechanisms are still unclear due to the confounding factors referenced above. Here, we attempted to minimize the secondary artifacts by manipulating FGF and its downstream mediators with a short incubation time before sampling and protein-synthesis blockage in a low-density angioblastic/endothelial differentiation system. In less than 8 h, FGF started the conversion of KDR/PDGFRA nascent mesoderm into KDR/PDGFRA angioblasts, and the priming by FGF was necessary to endow endothelial formation 72 h later. Further, the angioblastic conversion was mediated by the FGFR1/BRAF/MEK/ERK pathway in mesodermal cells. Finally, two transcription factors, ETV2 and LMO2, were the early direct functional responders downstream of the FGF pathway, and ETV2 alone was enough to complement the absence of FGF. FGF's selective role in mediating the first-step, angioblastic conversion from mesoderm-to-endothelium thus allows for refined control over acquiring and manipulating angioblasts. The noise-minimized differentiation/analysis platform presented here is well-suited for studies on the signaling switches of other mesodermal-lineage fates as well.
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http://dx.doi.org/10.1007/s00018-020-03630-8DOI Listing
March 2021

Safety and effectiveness of new embolization microspheres SCBRM for intermediate-stage hepatocellular carcinoma: A feasibility study.

Bosn J Basic Med Sci 2020 Aug 25. Epub 2020 Aug 25.

Department of Medical Imaging, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

Transarterial chemoembolization (TACE) is currently the recommended treatment for hepatocellular carcinoma (HCC). However, long-term chemoembolization triggers the inflammatory response and may lead to postembolization syndrome (PES). Although several types of degradable microspheres have been developed to reduce drug toxicity and PES incidence, the clinical outcomes remain unsatisfactory. Previously, we have developed a new type of spherical, calibrated, biodegradable, radiopaque microspheres (SCBRM) and demonstrated their safety and efficacy in a pig model. Thus, the goal of this feasibility study was to determine the clinical safety and efficacy of the new SCBRM in intermediate-stage HCC patients. In this study, 12 intermediate-stage HCC patients underwent TACE using SCBRM with a calibrated size of 100-250 μm. The disease control rates at 1 month and 3 months after TACE-SCBRM treatment were 100% and 75.0%, respectively. The objective response rates at 1 month and 3 months after treatment were 66.7% and 58.3%, respectively. Very few adverse events were observed with one patient developing nausea. One day after the treatment, alanine aminotransferase, alanine aminotransferase, and total bilirubin levels were slightly elevated in the patients, but all returned to baseline on day 7. The median and mean overall survival times were 33 months (interquartile range, 12.8-42.0) and 29.2 ± 14.3 months, respectively. The 1-year and 2-year survival rates were 91.7% and 58.3%, respectively. In conclusion, TACE with the new SCBRM microspheres is clinically safe and effective, and it represents a promising approach in the management of intermediate-stage HCC.
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http://dx.doi.org/10.17305/bjbms.2020.4770DOI Listing
August 2020

Detection of hepatitis B virus pre-S mutants in plasma by a next-generation sequencing-based platform determines their patterns in liver tissues.

PLoS One 2020 19;15(6):e0234773. Epub 2020 Jun 19.

Organ Transplantation Center, China Medical University Hospital, Taichung, Taiwan.

Hepatocellular carcinoma (HCC) is among the leading causes of cancer-related death worldwide. Patients with hepatitis B virus (HBV) pre-S mutants in liver tissues or blood have been regarded as a high-risk population for HCC development and recurrence. Detection of pre-S mutants in clinical specimens is thus important for early diagnosis and prognosis of HCC to improve patient survival. Recently, we have developed a next-generation sequencing (NGS)-based platform that can quantitatively detect pre-S mutants in patient plasma with superior sensitivity and accuracy. In this study, we compared the pre-S genotyping results from plasma by the NGS-based analysis with those from liver tissues by the immunohistochemistry (IHC)-based analysis in 30 HBV-related HCC patients. We demonstrated that the detection rate of pre-S mutants was significantly higher by NGS- than by IHC-based analysis. There was a moderate to good agreement between both analyses in detection of pre-S mutants. Compared with the IHC, the NGS-based detection of pre-S mutants in patient plasma could determine the patterns of pre-S mutants in liver tissues more efficiently in a noninvasive manner. Our data suggest that the NGS-based platform may represent a promising approach for detection of pre-S mutants as biomarkers of HBV-related HCC in clinical practice.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0234773PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7304603PMC
September 2020

Diagnostic Dilemma in Discriminating Between Spinal Neurenteric Cysts and Simple Arachnoid Cysts Based on Embryogenesis and Surgical Correlation.

World Neurosurg 2020 Feb 19;134:489-494. Epub 2019 Nov 19.

Section of Neurosurgery, Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan, Taiwan. Electronic address:

Background: Neurenteric cyst (NEC) is a rare intradural spinal tumor, but a correct preoperative diagnosis remains challenging. A misdiagnosis of arachnoid cyst (AC) often leads to conflicting surgical management and significantly higher recurrence.

Case Description: We report the case of a 26-year-old woman who presented with progressive spastic quadriparesis with myelopathy below the C4 level, which was caused by a ventral intradural extramedullary cystic tumor at the C3-4 level. Magnetic resonance images showed the cystic content as identical to cerebrospinal fluid, which prompted the tentative diagnosis of spinal AC. Surgical fenestration was scheduled. However, intraoperative findings of a thick-walled cyst and severe adhesion to the neural structure without a history of trauma and inflammation were more compatible with the pathogenesis of an NEC. Because of the high recurrence rate after an incomplete resection of an NEC, we did a complete resection of the cyst with adhesive rootlets instead. Pathology analysis and immunohistochemical staining confirmed the diagnosis of an endodermal-derived NEC.

Conclusions: NECs must be differentiated from ACs because they are different diseases and require different surgical management. In cases with clear cystic content, however, the diagnosis is likely to be AC, but a thick cystic wall and structural adhesions should suggest the differential diagnosis of NEC. Gross total removal of NECs should be attempted to reduce NEC recurrence.
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http://dx.doi.org/10.1016/j.wneu.2019.11.069DOI Listing
February 2020

Acute Myocarditis in Patients with Antineutrophil Cytoplasmic Antibody-positive Microscopic Polyangiitis and Receiving Rituximab Therapy.

J Rheumatol 2019 12 1;46(12):1645-1646. Epub 2019 Nov 1.

Department of Pathology, National Cheng Kung University Hospital, Tainan, Taiwan.

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http://dx.doi.org/10.3899/jrheum.190569DOI Listing
December 2019

Immune-related adverse reactions in the hepatobiliary system: second-generation check-point inhibitors highlight diverse histological changes.

Histopathology 2020 Feb 1;76(3):470-480. Epub 2019 Dec 1.

Department of Pathology, University of Washington School of Medicine, Seattle, WA, USA.

Aims: Immune check-point inhibitors are known to cause immune-mediated adverse liver injury, but our knowledge is mainly based on cases treated with ipilimumab or nivolumab.

Methods And Results: Clinicopathological features of 10 patients with hepatobiliary adverse reactions caused by second-generation drugs, pembrolizumab (n = 6) and atezolizumab (n = 4), were reviewed. Liver dysfunction developed during a median period of 3.5 weeks after administration of the check-point inhibitor (3 days-1 year). Antinuclear antibodies were detected in two patients at a low titre (1/80), and serum IgG concentrations were also only mildly elevated in two patients. Liver biopsies showed panlobular hepatitis (n = 5), cholangiopathic changes (n = 2), granulomatous injury (n = 2) and bland cholestasis (n = 1). Two cases of cholangiopathy (both pembrolizumab-treated) showed diffuse sclerosing cholangitis on imaging, and one also presented lymphocytic cholangitis resembling primary biliary cholangitis on biopsy. In two atezolizumab-treated cases, Küpffer cells were hyperplastic and aggregated, forming microgranulomas. Confluent necrosis and eosinophilic or plasma cell infiltration were rare. On immunostaining, the ratio of CD8 /CD4 cells was 12.2 ± 5.1, which was significantly higher than that in autoimmune hepatitis (2.7 ± 1.1; P < 0.001) or idiosyncratic drug-induced liver injury (5.0 ± 1.1; P = 0.014). All patients responded to steroid therapy, but it was less effective in patients with sclerosing cholangitis.

Conclusions: Pembrolizumab and atezolizumab manifested not only lobular hepatitis but also sclerosing cholangitis, lymphocytic duct injury and granulomatous hepatitis, probably representing various impaired cellular functions in CD8 lymphocytes and macrophages due to blockage of PD-1-PD-L1 interaction.
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http://dx.doi.org/10.1111/his.14000DOI Listing
February 2020

An in situ slow-releasing HS donor depot with long-term therapeutic effects for treating ischemic diseases.

Mater Sci Eng C Mater Biol Appl 2019 Nov 16;104:109954. Epub 2019 Jul 16.

Department of Chemical Engineering and Frontier Research Center on Fundamental and Applied Sciences of Matters, National Tsing Hua University, Hsinchu, Taiwan, ROC. Electronic address:

Therapeutic angiogenesis is essential for rescuing necrotic tissues in cases of ischemic disease. The exogenous hydrogen sulfide (HS) donor, diallyl trisulfide (DATS), has been investigated as a therapeutic agent that promotes angiogenesis. However, the short half-life of generated HS limits its therapeutic efficacy. In an attempt to overcome this difficulty, a poly(D,L-lactic-co-glycolic acid) microparticle system that contains DATS (DATS@MPs) is prepared as an in situ depot for the controlled release of HS, providing slow release and long-term effectiveness. The results of in vitro investigations indicate that the slow-released DATS from the DATS@MPs depot yields a longer intracellular production of HS than that from a free DATS depot. The intracellular generation of HS favors the translocation of the transcription factor, Nrf2, from the cytosol to nuclei, potentially upregulating the gene expressions of antioxidant enzymes, ultimately increasing cellular resistance to oxidative stress. Intramuscular injection of the slow-releasing HS donor depot DATS@MPs in an ischemic limb that is experimentally generated in a mouse model promotes therapeutic angiogenesis and protects cells from apoptosis and tissues from necrosis, ultimately salvaging the limb. These analytical results reveal that DATS@MPs is potentially useful in HS-based therapy for treating ischemic diseases.
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http://dx.doi.org/10.1016/j.msec.2019.109954DOI Listing
November 2019

Single-injecting, bioinspired nanocomposite hydrogel that can recruit host immune cells in situ to elicit potent and long-lasting humoral immune responses.

Biomaterials 2019 09 12;216:119268. Epub 2019 Jun 12.

Department of Chemical Engineering and Institute of Biomedical Engineering, Frontier Research Center on Fundamental and Applied Sciences of Matters, National Tsing Hua University, Hsinchu, Taiwan, ROC. Electronic address:

Vaccination is an effective medical intervention for preventing disease. However, without an adjuvant, most subunit vaccines are poorly immunogenic. This work develops a bioinspired nanocomposite hyaluronic acid hydrogel system that incorporates N-trimethyl chitosan nanoparticles (TMC/NPs) that carry a model subunit vaccine ovalbumin (OVA) that can elicit a potent and prolonged antigen-specific humoral response. Experimental results indicate that the nanocomposite hydrogel system (NPs-Gel) can retain a large proportion of its TMC/NPs that are bonded by covalent/electrostatic interactions and extend the release of the encapsulated OVA, enabling their localization at the site of hydrogel injection. The positively charged TMC/NPs can be effectively internalized by dendritic cells, significantly augmenting their maturation, suggesting that TMC can function as an adjuvant-based OVA delivery system. Upon subcutaneous implantation in mice, the NPs-Gel acts as an in situ depot that recruits and concentrates immune cells. The TMC/NPs that do not have any specific interactions with the hydrogel network are released rapidly and internalized by the neighboring immune cells, providing a priming dose, while those retained inside the NPs-Gel are ingested by the recruited and concentrated immune cells over time, acting as a booster dose, eliciting high titers of OVA-specific antibody responses. These experimental results suggest particulate vaccines that are integrated in such a bioinspired hydrogel system may be used as single-injection prime-boost vaccines, enabling effective and persistent humoral immune responses.
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http://dx.doi.org/10.1016/j.biomaterials.2019.119268DOI Listing
September 2019

Plasma proteome plus site-specific N-glycoprofiling for hepatobiliary carcinomas.

J Pathol Clin Res 2019 07 25;5(3):199-212. Epub 2019 Jun 25.

Department of Medical Laboratory Science, College of Medicine, I-Shou University, Kaohsiung City, Taiwan.

Hepatobiliary cancer is the third leading cause of cancer death worldwide. Appropriate markers for early diagnosis, monitoring of disease progression, and prediction of postsurgical outcome are still lacking. As the majority of circulating N-glycoproteins are originated from the hepatobiliary system, we sought to explore new markers by assessing the dynamics of N-glycoproteome in plasma samples from patients with hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA), or combined HCC and CCA (cHCC-CCA). Using a mass spectrometry-based quantitative proteomic approach, we found that 57 of 5358 identified plasma proteins were differentially expressed in hepatobiliary cancers. The levels of four essential proteins, including complement C3 and apolipoprotein C-III in HCC, galectin-3-binding protein in CCA, and 72 kDa inositol polyphosphate 5-phosphatase in cHCC-CCA, were highly correlated with tumor stage, tumor grade, recurrence-free survival, and overall survival. Postproteomic site-specific N-glycan analyses showed that human complement C3 bears high-mannose and hybrid glycoforms rather than complex glycoforms at Asn85. The abundance of complement C3 with mannose-5 or mannose-6 glycoform at Asn85 was associated with HCC tumor grade. Furthermore, stepwise Cox regression analyses revealed that HCC patients with a hybrid glycoform at Asn85 of complement C3 had a lower postsurgery tumor recurrence rate or mortality rate than those with a low amount of complement C3 protein. In conclusion, our data show that particular plasma N-glycoproteins with specific N-glycan compositions could be potential noninvasive markers to evaluate oncological status and prognosis of hepatobiliary cancers.
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http://dx.doi.org/10.1002/cjp2.136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6648390PMC
July 2019

Fully galactosyl-fucosyl-bisected IgG reduces anti-HBV efficacy and liver histological improvement.

Antiviral Res 2019 03 3;163:1-10. Epub 2019 Jan 3.

Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan. Electronic address:

N-glycosylation on the crystallizable fragment (Fc) governs antibody-mediated immune responses. This study addressed the relevance of N-acetylglucosamine (GlcNAc)-bisected IgG on the disease progression and treatment efficacy in the immune active phase of chronic hepatitis B virus (HBV) infection. Serum IgGN-glycan patterns from 166 HBV e antigen (HBeAg)-positive patients were analyzed using liquid chromatography-tandem mass spectrometry. The proportion of GlcNAc-bisected IgG on the disease severity and efficacy of nucleos(t)ide analogue treatment were investigated. Cytokine-dependent regulations of IgG GlcNAc bisection were also addressed using mouse IgG-producing hybridoma cells. We found that IgG bearing a fully galactosyl-fucosyl-N-acetylglucosamine-bisected (G2FN) glycoform in HBeAg-positive patients was associated with high levels of HBV DNA or HBV surface antigen, alanine aminotransferase <2 upper limits of normal, and a mild liver injury. Moreover, baseline IgG-G2FN ≧ 1.5% was linked to lower probabilities of virological response (HBV DNA undetectable in serum), HBeAg seroconversion, HBV core antigen loss, and liver histological improvement after treatment. Cox and logistic regression analyses revealed that IgG-G2FN was an unfavorable factor for the virological response (hazard ratio = 0.620, 95% confidence interval = 0.466-0.825, P = 0.001) or liver histological improvement (odds ratio = 0.513, 95% confidence interval = 0.279-0.943, P = 0.032), respectively. Results from in vitro studies showed that transforming growth factor (TGF)-β1 treatment downregulated mannosyl β-1,4-N-acetylglucosaminyltransferase 3 and β-1,4-galactosyltransferase 1 activities and thereby IgG-G2FN production, and this phenomenon reflected an inverse correlation between IgG-G2FN and TGF-β1 in sera of patients (r = -0.431, P < 0.001). In conclusion, IgG-G2FN was related to an attenuated liver inflammation and unfavorable treatment responses in patients with HBeAg-positive chronic hepatitis B.
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http://dx.doi.org/10.1016/j.antiviral.2018.12.021DOI Listing
March 2019

Fucosyl-Agalactosyl IgG₁ Induces Cholangiocarcinoma Metastasis and Early Recurrence by Activating Tumor-Associated Macrophage.

Cancers (Basel) 2018 Nov 21;10(11). Epub 2018 Nov 21.

Department of Medical Laboratory Science, College of Medicine, I-Shou University, Kaohsiung 82445, Taiwan.

Concern over roles of serum IgG agalactosylation in chronic inflammatory diseases has been mounting for years but less touched in cancers. The present study addressed the underlying role of agalactosylated IgG beyond tumorigenesis. Liquid-chromatography-tandem mass spectrometry was leveraged for the analysis of IgG₁ and IgG₂ -glycomes. We found that a high percentage of serum fucosyl-agalactosyl IgG₁ (IgG₁-G0F) in patients with cholangiocarcinoma was associated with poor tumor differentiation and tumor metastasis. Results from Kaplan⁻Meier analyses and a stepwise Cox regression analysis showed that patients with serum IgG₁-G0F ≥40% were highly correlated with poor recurrence-free survivals and overall survivals. Interestingly, patients with cholangiocarcinoma whose serum IgG₁-G0F ≥40% had more CD163+ tumor-associated macrophages in cancerous tissues than adjacent non-cancerous counterparts. In vitro assays revealed that agalactosylated IgG upregulated tumor-associated macrophage markers CD163 and CD204 in human U-937 cells and peripheral macrophages. Moreover, a positive and a negative feedback loop of transforming growth factor-β1 and interferon-γ, respectively, on IgG agalactosylation was identified using hybridoma cells and verified in sera of the patients. In conclusion, agalactosylated IgG activates tumor-associated macrophages, thereby promoting tumor metastasis and recurrence of cholangiocarcinoma.
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http://dx.doi.org/10.3390/cancers10110460DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6267046PMC
November 2018

Effect of Retrograde Cerebral Protection Strategy on Outcome of Patients with Stanford Type A Aortic Dissection.

Acta Cardiol Sin 2018 Jul;34(4):328-336

Cardiovascular Center, Taichung Veterans General Hospital, Taichung, Taiwan.

Background: Neurological complications are an important concern in the repair of type A aortic dissection. Supra-aortic involvement is considered to be an important risk factor for neurological injuries. However, the optimal brain protection strategy still remains controversial. The aim of the present study was to assess the efficacy and short-term results of retrograde cerebral protection techniques in the treatment of acute type A aortic dissection.

Methods: Between 2005 and 2013, 185 patients who underwent repair of acute type A aortic dissection were enrolled in this study, all of whom received retrograde cerebral perfusion. The patients were divided into two group: 102 patients who had at least one carotid artery involved as the carotid dissection group, and 83 patients who had no carotid artery involvement as the non-carotid dissection group.

Results: The mean age of the patients was 57.8 years and 69% were male. The 30-day mortality rate was 10.3%, and the overall in-hospital mortality rate was 11.9%. Eight patients (4.3%) developed new permanent neurological deficits (PNDs) including two in the non-carotid dissection group and six in the carotid dissection group. Although new PND was milder in the carotid dissection group, there was no significant difference (p = 0.248). The proportion of patients who received a coronary artery bypass graft was significantly higher in the carotid dissection group (1 vs. 8, p = 0.037).

Conclusions: According to our study, the retrograde cerebral perfusion technique is an easy and safe procedure, especially for patients with concomitant carotid dissection.
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http://dx.doi.org/10.6515/ACS.201807_34(4).20180301BDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6066949PMC
July 2018

Intrahepatic hepatitis B virus large surface antigen induces hepatocyte hyperploidy via failure of cytokinesis.

J Pathol 2018 08 4;245(4):502-513. Epub 2018 Jul 4.

Institute of Molecular and Cellular Biology, National Tsing Hua University, Hsinchu, Taiwan.

Hepatitis B virus (HBV) is an aetiological factor for liver cirrhosis and hepatocellular carcinoma (HCC). Despite current antiviral therapies that successfully reduce the viral load in patients with chronic hepatitis B, persistent hepatitis B surface antigen (HBsAg) remains a risk factor for HCC. To explore whether intrahepatic viral antigens contribute directly to hepatocarcinogenesis, we monitored the mitotic progression of HBV-positive cells. Cytokinesis failure was increased in HBV-positive HepG2.2.15 and 1.3ES2 cells, as well as in HuH-7 cells transfected with a wild-type or X-deficient HBV construct, but not in cells transfected with an HBsAg-deficient construct. We show that expression of viral large surface antigen (LHBS) was sufficient to induce cytokinesis failure of immortalized hepatocytes. Premitotic defects with DNA damage and G /M checkpoint attenuation preceded cytokinesis in LHBS-positive cells, and ultimately resulted in hyperploidy. Inhibition of polo-like kinase-1 (Plk1) not only restored the G /M checkpoint in these cells, but also suppressed LHBS-mediated in vivo tumourigenesis. Finally, a positive correlation between intrahepatic LHBS expression and hepatocyte hyperploidy was detected in >70% of patients with chronic hepatitis B. We conclude that HBV LHBS provokes hyperploidy by inducing DNA damage and upregulation of Plk1; the former results in atypical chromatin structures, and the latter attenuates the function of the G /M DNA damage checkpoint. Our data uncover a mechanism by which genomic integrity of hepatocytes is disrupted by viral LHBS. These findings highlight the role of intrahepatic surface antigen as an oncogenic risk factor in the development of HCC. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/path.5102DOI Listing
August 2018

Liver regeneration accelerates hepatitis B virus-related tumorigenesis of hepatocellular carcinoma.

Mol Oncol 2018 06 29;12(7):1175-1187. Epub 2018 May 29.

Division of General and Transplant Surgery, Department of Surgery, National Cheng Kung University Hospital, Tainan, Taiwan.

Although partial hepatectomy (PH) to remove tumors provides a potential cure of hepatocellular carcinoma (HCC), long-term survival of hepatitis B virus (HBV)-related HCC patients after PH remains a big challenge. Early recurrence within 2 years post-PH is associated with the dissemination of primary HCC. However, late recurrence after 2 years post-PH is supposed due to the de novo or a secondary tumor. Since PH initiates liver regeneration (LR), we hypothesize that LR may accelerate tumorigenesis through activation of pre-existing precancerous lesions in the remaining liver. In this study, we explored the potential role of several LR-related factors in the de novo recurrence in a HBV X protein (HBx) transgenic mouse model receiving PH to mimic human HCC development. Following PH, we observed that tumor development was significantly accelerated from 16.9 to 10.4 months in HBx transgenic mice. The expression of suppressor of cytokine signaling (SOCS) family proteins was remarkably suppressed in livers of HBx transgenic relative to non-transgenic mice from early to late stages after PH as compared with non-PH mice. The expression of transforming growth factor-β (TGF-β)/Smad pathway, hepatocyte growth factor (HGF), Myc, signal transducer and activator of transcription 3 (STAT3), and β-Catenin also showed a significant difference between livers of HBx transgenic and non-transgenic mice at variable time points after PH in comparison with non-PH mice. Taken together, our results provide an explanation for the high de novo recurrence of HBV-related HCC after PH, probably through induction of the sequential changes of LR-related SOCS family proteins, growth factors, and transcription factors, which may promote growth on the precancerous remnant liver.
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http://dx.doi.org/10.1002/1878-0261.12318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6026873PMC
June 2018

Progesterone receptor membrane component 1 as a potential prognostic biomarker for hepatocellular carcinoma.

World J Gastroenterol 2018 Mar;24(10):1152-1166

Department of Pathology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70403, Taiwan.

Aim: To investigate the clinicopathological significance of progesterone receptor membrane component 1 (PGRMC1) and PGRMC2 in hepatocellular carcinoma (HCC).

Methods: We performed immunohistochemical staining to evaluate the estrogen receptor (ER), progesterone receptor (PR), PGRMC1, and PGRMC2 in a clinical cohort consisting of 89 paired HCC and non-tumor liver samples. We also analyzed HCC data ( = 373) from The Cancer Genome Atlas (TCGA). We correlated the expression status of PGRMC1 and PGRMC2 with clinicopathological indicators and the clinical outcomes of the HCC patients. We knocked down or overexpressed PGRMC1 in HCC cell lines to evaluate its biological significance in HCC cell proliferation, differentiation, migration, and invasion.

Results: We found that few HCC cases expressed ER (5.6%) and PR (4.5%). In contrast, most HCC cases expressed PGRMC1 (89.9%) and PGRMC2 (100%). PGRMC1 and PGRMC2 exhibited significantly lower expression in tumor tissue than in non-tumor tissue ( < 0.001). Lower PGRMC1 expression in HCC was significantly associated with higher serum alpha-fetoprotein expression ( = 0.004), poorer tumor differentiation ( = 0.045) and liver capsule penetration ( = 0.038). Low PGRMC1 expression was an independent predictor for worse disease-free survival ( = 0.002, HR = 2.384, CI: 1.377-4.128) in our cases, as well as in the TCGA cohort ( < 0.001, HR = 2.857, CI: 1.781-4.584). The expression of PGRMC2 did not relate to patient outcome. PGRMC1 knockdown promoted a poorly differentiated phenotype and proliferation of HCC cells , while PGRMC1 overexpression caused the opposite effects.

Conclusion: PGRMC1 is a non-classical hormonal receptor that negatively regulates hepatocarcinogenesis. PGRMC1 down-regulation is associated with progression of HCC and is a poor prognostic indicator.
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http://dx.doi.org/10.3748/wjg.v24.i10.1152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5850134PMC
March 2018

Hepatitis B virus surface gene pre-S mutant as a high-risk serum marker for hepatoma recurrence after curative hepatic resection.

Hepatology 2018 09 21;68(3):815-826. Epub 2018 May 21.

Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

Chronic hepatitis B virus (HBV) infection is the major cause of hepatocellular carcinoma (HCC). The pre-S mutant large HBV surface antigen (LHBS) is highly associated with HCC. This study analyzed the expression of the large form of surface protein in tumors and evaluated the LHBS with mutations within the pre-S region as a high-risk recurrence marker in HCC patients after curative hepatic resection. By analyses using immunohistochemical staining (n = 12) and western blotting (n = 22), the HBV surface protein, which is mainly comprised of the major form of HBV surface antigen, was greatly diminished in the tumors. However, LHBS was not significantly decreased in tumorous regions, suggesting that LHBS maintains its expression in cancer development. A cohort of 175 patients with HBV-related HCC who underwent curative hepatic resection was analyzed for pre-S gene mutations using Pre-S Gene Chip. Results of the multivariate regression analysis showed that the serum pre-S mutant level and the American Joint Committee on Cancer stage were the two main independent high-risk factors for recurrence. A Cox proportional hazards analysis also revealed a prediction model, which indicated the recurrence-free survival rate along with the time after surgery; this was developed and further validated in an independent HCC cohort. Receiver operating characteristic curve analysis revealed that the model showed close sensitivities in the main and validation cohorts (area under the curve values, 0.741 and 0.704, respectively). Conclusion: Unlike the major HBV surface antigen, LHBS is mostly expressed in the tumorous regions of HBV-induced HCC, indicating that it plays a unique role in tumor progression; the relative level of pre-S mutant in serum is, independently of tumor stage, an important high-risk marker for HCC recurrence after primary hepatic resection. (Hepatology 2018).
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http://dx.doi.org/10.1002/hep.29790DOI Listing
September 2018

Exendin-4 improves cardiovascular function and survival in flow-induced pulmonary hypertension.

J Thorac Cardiovasc Surg 2018 04 7;155(4):1661-1669.e4. Epub 2017 Nov 7.

Department of Anesthesiology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; E-Da Hospital/I-Shou University, Kaohsiung City, Taiwan. Electronic address:

Objectives: Systemic left-to-right shunting causes pulmonary arteriopathy, leading to progressive cardiopulmonary failure and a poor prognosis. In this study, we examined the extraglycemic effect of a synthetic glucagon-like peptide, exendin-4, on pulmonary arteriopathy regression and cardiopulmonary function in nondiabetic rats.

Methods: Pulmonary hypertension (PH) was induced by monocrotaline (60 mg/kg, subcutaneous) injection followed by the creation of an aortocaval fistula. After 4 weeks, exendin-4 (1 μg/kg/day) was administered intraperitoneally for 3 consecutive weeks, followed by an assessment of cardiopulmonary function, pulmonary artery vasoreactivity, tissue and blood biochemistry, and lung histology.

Results: Exendin-4 significantly reduced right ventricle mass and pulmonary artery pressure, which improved right ventricle function and the survival rate in rats with PH. Tissue and blood interleukin-1β levels decreased, whereas pulmonary artery cyclic adenosine monophosphate levels were restored by exendin-4. Smooth muscle-myosin heavy chain-II and α-smooth muscle actin protein levels increased in the pulmonary arteries of exendin-4-treated rats. Histology showed that exendin-4 decreased the main and intra-acinar pulmonary artery medial thickness.

Conclusions: Exendin-4 treatment improved pulmonary artery function in flow-induced PH via its direct vasoactive properties, anti-inflammatory effects, and vascular smooth muscle cell phenotypic modulation. Mitigation of pulmonary arteriopathy further potentiated right ventricle performance and reduced overall mortality. These responses were associated with suppressed expression and activity of interleukin-1β and its downstream signaling molecules. Glucagon-like peptide analogs may possess pleiotropic therapeutic potential in flow-induced PH.
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http://dx.doi.org/10.1016/j.jtcvs.2017.10.085DOI Listing
April 2018

Case report: term birth after fertility-sparing treatments for stage IB1 small cell neuroendocrine carcinoma of the cervix.

BMC Womens Health 2017 07 28;17(1):56. Epub 2017 Jul 28.

Department of Obstetrics & Gynecology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, 138, Sheng-Li Rd. Northern District, Tainan, 70403, Taiwan.

Background: Advances in cervical cancer management for childbearing women have led to less radical approaches. Use of fertility-sparing treatment to treat small cell neuroendocrine carcinoma (SCNEC) is challenging owing to the aggressive nature of the disease, even in early stage disease.

Case Presentation: A 25-year-old nulligravida woman presented with malodorous vaginal discharge and was diagnosed to have an exophytic cervical SCNEC. A magnetic resonance image scan showed no evidence of parametrial invasion or distant metastasis. Clinical staging allocated her to stage IB1 disease. She underwent radical abdominal trachelectomy for reproductive purpose. Preoperative and postoperative chemotherapy with ifosfamide/etoposide/cisplatin combining gonadotropin-releasing hormone agonist were administered. She had a spontaneous, uneventful pregnancy and successfully delivered a term baby via cesarean section 7 years after treatment.

Conclusion: To our knowledge, we describe the first success in offering a fertility-preserving multimodality strategy to present favorable oncologic, reproductive, and obstetric outcomes in a fertile woman of stage I SCNEC. Individualized multimodality therapy may be utilized in specific patients with early-stage cervical cancer to preserve their fertility.
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http://dx.doi.org/10.1186/s12905-017-0404-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5534099PMC
July 2017

Favorable Response to Long-term Nucleos(t)ide Analogue Therapy in HBeAg-positive Patients with High Serum Fucosyl-Agalactosyl IgG.

Sci Rep 2017 05 16;7(1):1957. Epub 2017 May 16.

Department of Chemistry, National Cheng Kung University, Tainan, Taiwan.

Aberrant IgG glycosylation is a feature of hepatitis B virus (HBV) infection but its effect on a long-term efficacy of antiviral therapy has never been addressed. After a screening of 1,085 patients, 132 eligible HBV e antigen (HBeAg)-positive and 101 HBeAg-negative patients with anti-HBV nucleos(t)ide analogue monotherapy were enrolled with on-treatment follow-ups for at least one year. IgG1 N-glycome was profiled using mass spectrometry and evaluated for its relevance in treatment responses. The results indicated that a high level of serum fucosyl-agalactosyl IgG1 (IgG1-G0F) at baseline was associated with the severity of liver inflammation and damage but advanced treatment responses, including HBV DNA loss, HBeAg seroconversion, a reduced drug resistance rate, and a liver histological improvement at year 1, thereby improving the long-term treatment efficacy and the probability of treatment discontinuation in HBeAg-positive patients. Stepwise Cox regression analyses revealed that baseline IgG1-G0F >30% was an independent factor that links to virological response (HR 3.071, 95% CI 1.835-5.141, P < 0.001) or HBeAg seroconversion (HR 2.034, 95% CI 1.011-4.093, P = 0.046). Furthermore, a high IgG1-G0F level at the treatment endpoint was associated with an off-treatment sustained virological response. In conclusion, IgG1-G0F favors the medication outcome for HBeAg-positive chronic hepatitis B.
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http://dx.doi.org/10.1038/s41598-017-02158-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5434008PMC
May 2017

Serrated adenocarcinoma morphology in colorectal mucinous adenocarcinoma is associated with improved patient survival.

Oncotarget 2017 May;8(21):35165-35175

Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70403, Taiwan.

Colorectal mucinous adenocarcinoma (MAC) and serrated adenocarcinoma (SAC) share many characteristics, including right-side colon location, frequent mucin production, and various molecular features. This study examined the frequency of SAC morphology in MACs. We assessed the correlation of SAC morphology with clinicopathological parameters, molecular characteristics, and patient prognosis. Eighty-eight colorectal MACs were collected and reviewed for SAC morphology according to Makinen's criteria. We sequenced KRAS and BRAF, assessed CpG island methylator phenotype (CIMP) frequency, and analyzed DNA mismatch repair enzyme levels using immunohistochemistry in tumor samples. SAC morphology was observed in 38% of MACs, and was associated with proximal location (P=0.001), BRAF mutation (P=0.042), CIMP-positive status (P=0.023), and contiguous traditional serrated adenoma (P=0.019). Multivariate analysis revealed that MACs without both SAC morphology and CIMP-positive status exhibited 3.955 times greater risk of cancer relapse than MACs having both characteristics or either one (P=0.035). Our results show that two MAC groups with distinct features can be identified using Makinen's criteria, and suggest a favorable prognostic role for the serrated neoplastic pathway in colorectal MAC.
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http://dx.doi.org/10.18632/oncotarget.16815DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5471043PMC
May 2017

Prediction of early hepatocellular carcinoma recurrence using germinal center kinase-like kinase.

Oncotarget 2016 Aug;7(31):49765-49776

Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

Germinal center kinase-like kinase (GLK) is a key controller of autoimmunity. In this study, we assessed the clinical relevance and tumorigenic effects of GLK in hepatocellular carcinoma (HCC). Using immunohistochemistry, we showed that the GLK proportion score increased in both cancerous and adjacent non-cancerous liver tissue from patients with HCC recurrence. A Kaplan-Meier analysis revealed that patients with a wide distribution of GLK in non-cancerous liver tissue had a higher rate of HCC recurrence than those with very low or no GLK expression. Multivariate Cox regression analyses indicated that a high GLK proportion score in non-cancerous liver tissue was an independent predictor of early HCC recurrence after resection. Lentiviral vector-mediated overexpression of GLK activated the nuclear factor kappa B (NFκB) signaling cascade and accelerated cell cycle progression in primary human hepatocytes, thereby promoting proliferation. An increase in GLK expression coincided with NFκB activation and enhanced expression of proliferating cell nuclear antigen in HCC tissue. Our findings demonstrate a potential hepatocarcinogenic effect of GLK and the feasibility of using GLK to predict early HCC recurrence.
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http://dx.doi.org/10.18632/oncotarget.10176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5226546PMC
August 2016

Resistance of ground glass hepatocytes to oral antivirals in chronic hepatitis B patients and implication for the development of hepatocellular carcinoma.

Oncotarget 2016 May;7(19):27724-34

Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan.

Ground glass hepatocytes (GGHs) have been shown to predict the development of hepatocellular carcinoma (HCC). Type I GGH and type II GGH harbor hepatitis B virus (HBV) pre-S1 and pre-S2 deletion mutants, respectively. Whether anti-HBV therapy can inhibit the expression of GGHs and potentially reduce HCC development is explored in this study. Two sets of liver specimens were included: the first contained 31 paired biopsy specimens obtained from chronic HBV patients receiving oral nucleos(t)ide analogue (NA) treatment; the second contained 186 resected liver tissues obtained from HBV-related HCC patients receiving surgery: 82 received NA before surgery and 104 did not. Compared with the baseline biopsy specimens, type I (P=0.527) and type II GGH (P=0.077) were not significantly decreased after 48 weeks of NA treatment in the first set of patients. In the second set, despite suppression of viral load (P<0.001) and periportal necrosis (P=0.006) in treated patients, GGH (P=0.594), cccDNA (P=0.172) and serum pre-S mutants (p=0.401) were not significantly suppressed. A significant decrease of type I (P=0.049) and type II GGH (P=0.029) could only be observed in patients after long duration of treatment (median duration: 4.3 years). In the treated patients, the persisted type II GGH remained an independent variable associated with decreased local recurrence-free survival of HCC (P=0.019) as in non-treated patients (P=0.001). In conclusion, the persistence of GGHs could explain the residual risk of HCC development under anti-HBV treatment. Therefore, intrahepatic GGHs and pre-S mutant are potential additional targets for HCC prevention in patients already receiving anti-HBV treatment.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5053683PMC
http://dx.doi.org/10.18632/oncotarget.8388DOI Listing
May 2016

Toll-Like Receptor 4 Is Essential in the Development of Abdominal Aortic Aneurysm.

PLoS One 2016 7;11(1):e0146565. Epub 2016 Jan 7.

Cardiovascular Research Center, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

Toll-like receptor (TLR) family plays a key role in innate immunity and various inflammatory responses. TLR4, one of the well-characterized pattern-recognition receptors, can be activated by endogenous damage-associated molecular pattern molecules such as high mobility group box 1 (HMGB1) to sustain sterile inflammation. Evidence suggested that blockade of TLR4 signaling may confer protection against abdominal aortic aneurysm (AAA). Herein we aimed to obtain further insight into the mechanism by which TLR4 might promote aneurysm formation. Characterization of the CaCl2-induced AAA model in mice revealed that upregulation of TLR4 expression, localized predominantly to vascular smooth muscle cells (VSMCs), was followed by a late decline during a 28-day period of AAA development. In vitro, TLR4 expression was increased in VSMCs treated with HMGB1. Knockdown of TLR4 by siRNA attenuated HMGB1-enhanced production of proinflammatory cytokines, specifically interleukin-6 and monocyte chemoattractant protein-1 (MCP-1), and matrix-degrading matrix metalloproteinase (MMP)-2 from VSMCs. In vivo, two different strains of TLR4-deficient (C57BL/10ScNJ and C3H/HeJ) mice were resistant to CaCl2-induced AAA formation compared to their respective controls (C57BL/10ScSnJ and C3H/HeN). Knockout of TLR4 reduced interleukin-6 and MCP-1 levels and HMGB1 expression, attenuated macrophage accumulation, and eventually suppressed MMP production, elastin destruction and VSMC loss. Finally, human AAA exhibited higher TLR4 expression that was localized to VSMCs. These data suggest that TLR4 signaling contributes to AAA formation by promoting a proinflammatory status of VSMCs and by inducing proteinase release from VSMCs during aneurysm initiation and development.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0146565PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4711799PMC
July 2016

The B56γ3 regulatory subunit-containing protein phosphatase 2A outcompetes Akt to regulate p27KIP1 subcellular localization by selectively dephosphorylating phospho-Thr157 of p27KIP1.

Oncotarget 2016 Jan;7(4):4542-58

Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

The B56γ-containing protein phosphatase 2A (PP2A-B56γ) has been postulated to have tumor suppressive functions. Here, we report regulation of p27KIP1 subcellular localization by PP2A-B56γ3. B56γ3 overexpression enhanced nuclear localization of p27KIP1, whereas knockdown of B56γ3 decreased p27KIP1 nuclear localization. B56γ3 overexpression decreased phosphorylation at Thr157 (phospho-Thr157), whose phosphorylation promotes cytoplasmic localization of p27KIP1, whereas B56γ3 knockdown significantly increased the level of phospho-Thr157. In vitro, PP2A-B56γ3 catalyzed dephosphorylation of phospho-Thr157 in a dose-dependent and okadaic acid-sensitive manner. B56γ3 did not increase p27KIP1 nuclear localization by down-regulating the upstream kinase Akt activity and outcompeted a myristoylated constitutively active Akt (Aktca) in regulating Thr157 phosphorylation and subcellular localization of p27KIP1. In addition, results of interaction domain mapping revealed that both the N-terminal and C-terminal domains of p27 and a domain at the C-terminus of B56γ3 are required for interaction between p27 and B56γ3. Furthermore, we demonstrated that p27KIP1 levels are positively correlated with B56γ levels in both non-tumor and tumor parts of a set of human colon tissue specimens. However, positive correlation between nuclear p27KIP1 levels and B56γ levels was found only in the non-tumor parts, but not in tumor parts of these tissues, implicating a dysregulation in PP2A-B56γ3-regulated p27KIP1 nuclear localization in these tumor tissues. Altogether, this study provides a new mechanism by which the PP2A-B56γ3 holoenzyme plays its tumor suppressor role.
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http://dx.doi.org/10.18632/oncotarget.6609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4826225PMC
January 2016