Ching-Chih Chang

Androgen receptor (AR) differential roles in hormone-related tumors including prostate, bladder, kidney, lung, breast and liver

The androgen receptor (AR) is expressed in many cell types and the androgen/AR signaling has been found to have important roles in modulating tumorigenesis and metastasis in several cancers including prostate, bladder, kidney, lung, breast and liver. However, whether AR has differential roles in the individual cells within these tumors that contain a variety of cell types remains unclear. Generation of AR knockout (ARKO) mouse models with deletion of AR in selective cells within tumors indeed have uncovered many unique AR roles in the individual cell types during cancer development and progression. This review will discuss the results obtained from various ARKO mice and different human cell lines with special attention to the cell type- and tissue-specific ARKO models. The understanding of various results showing the AR indeed has distinct and contrasting roles in each cell type within many hormone-related tumors (as stimulator in bladder, kidney and lung metastases vs as suppressor in prostate and liver metastases) may eventually help us to develop better therapeutic approaches by targeting the AR or its downstream signaling in individual cell types to better battle these hormone-related tumors in different stages.

Caffeine ameliorates hemodynamic derangements and portosystemic collaterals in cirrhotic rats

Portal hypertension (PH), a pathophysiological derangement of liver cirrhosis, is characterized by hyperdynamic circulation, angiogenesis, and portosystemic collaterals. These may lead to lethal complications, such as variceal bleeding. Caffeine has been noted for its effects on liver inflammation, fibrogenesis, and vasoreactiveness. However, the relevant influences of caffeine in cirrhosis and PH have not been addressed. Spraque‐Dawley rats with common bile duct ligation–induced cirrhosis or sham operation received prophylactic or therapeutic caffeine treatment (50 mg/kg/day, the first or 15th day since operation, respectively) for 28 days. Compared to vehicle (distilled water), caffeine decreased cardiac index, increased systemic vascular resistance, reduced portal pressure (PP), superior mesenteric artery flow, mesenteric vascular density, portosystemic shunting (PSS), intrahepatic angiogenesis, and fibrosis without affecting liver and renal biochemistry. The beneficial effects were reversed by selective adenosine A1 agonist N6‐cyclopentyladenosine (CPA) or A2A agonist GCS21680. Both prophylactic and therapeutic caffeine treatment decreased portal resistance and PP in thioacetamide (200mg/kg, thrice‐weekly for 8 weeks)‐induced cirrhotic rats. Caffeine down‐regulated endothelial nitric oxide synthase, vascular endothelial growth factor (VEGF), phospho‐VEGFR2, and phospho–Akt mesenteric protein expression. Caffeine adversely affected viability of hepatic stellate and sinusoidal endothelial cells, which was reversed by CPA and GCS21680. On the other hand, caffeine did not modify vascular response to vasoconstrictors in splanchnic, hepatic, and collateral vascular beds. Conclusions: Caffeine decreased PP, ameliorated hyperdynamic circulation, PSS, mesenteric angiogenesis, hepatic angiogenesis, and fibrosis in cirrhotic rats. Caffeine may be a feasible candidate to ameliorate PH‐related complications in cirrhosis. (Hepatology 2015;61:1672‐1684)

Investigation of Hepatoprotective Activity of Induced Pluripotent Stem Cells in the Mouse Model of Liver Injury

To date liver transplantation is the only effective treatment for end-stage liver diseases. Considering the potential of pluripotency and differentiation into tridermal lineages, induced pluripotent stem cells (iPSCs) may serve as an alternative of cell-based therapy. Herein, we investigated the effect of iPSC transplantation on thioacetamide- (TAA-) induced acute/fulminant hepatic failure (AHF) in mice. Firstly, we demonstrated that iPSCs had the capacity to differentiate into hepatocyte-like cells (iPSC-Heps) that expressed various hepatic markers, including albumin, α-fetoprotein, and hepatocyte nuclear factor-3β, and exhibited biological functions. Intravenous transplantation of iPSCs effectively reduced the hepatic necrotic area, improved liver functions and motor activity, and rescued TAA-treated mice from lethal AHF. 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate cell labeling revealed that iPSCs potentially mobilized to the damaged liver area. Taken together, iPSCs can effectively rescue experimental AHF and represent a potentially favorable cell source of cell-based therapy.

Involvement of Bcl-XL deamidation in E1A-mediated cisplatin sensitization of ovarian cancer cells

The adenovirus E1A protein has been shown to be involved in the potentiation of apoptosis induced by chemotherapeutic agents, yet the molecular events of E1A-mediated apoptosis are not very clear. A recent report has suggested that deamidation of the Bcl-XL protein inhibits its antiapoptotic ability and leads to apoptosis induced by alkylating agents in Rb-deficient tumor cells. Since Rb is known to interact with E1A, which interrupts Rbs normal function, we examined Bcl-XL deamidation and cell death induced by cisplatin in E1A transfectants. We found that the E1A transfectants became sensitive to cisplatin-induced apoptosis compared to the parental cells, SKOV3.ip1. Our data show that cisplatin treatment induced the modification of Bcl-XL in the E1A transfectants in dosage and time-dependent manner. Furthermore, phosphatase treatment had no effect on the level of Bcl-XL modification, whereas alkaline lysis buffer appeared to induce the same modification of Bcl-XL. Ectopic expression of the deamidated forms of Bcl- XL in SKOV3.ip1 cells revealed that the modification to the Bcl- XL protein molecules was deamidation. Expression of the E1A mutant (dl1108) which contains deletion at CR2 domain suppressed Bcl-XL deamidation and apoptosis induced by cisplatin. We also found that expression of the nondeamidated Bcl-XL protected E1A transfectants from apoptosis. These findings suggest that Bcl-XL deamidation contributes to E1A-mediated cisplatin sensitization in SKOV3.ip1 cells.

Clinical instructors' perception of a faculty development programme promoting postgraduate year-1 (PGY1) residents' ACGME six core competencies: a 2-year study

Objective The six core competencies designated by Accreditation Council for Graduate Medical Education (ACGME) are essential for establishing a patient centre holistic medical system. The authors developed a faculty programme to promote the postgraduate year 1 (PGY1) resident, ACGME six core competencies. The study aims to assess the clinical instructors perception, attitudes and subjective impression towards the various sessions of the ‘faculty development programme for teaching ACGME competencies.’ Methods During 2009 and 2010, 134 clinical instructors participated in the programme to establish their ability to teach and assess PGY1 residents about ACGME competencies. Results The participants in the faculty development programme reported that the skills most often used while teaching were learnt during circuit and itinerant bedside, physical examination teaching, mini-clinical evaluation exercise (mini-CEX) evaluation demonstration, training workshop and videotapes of ‘how to teach ACGME competencies.’ Participants reported that circuit bedside teaching and mini-CEX evaluation demonstrations helped them in the interpersonal and communication skills domain, and that the itinerant teaching demonstrations helped them in the professionalism domain, while physical examination teaching and mini-CEX evaluation demonstrations helped them in the patients care domain. Both the training workshop and videotape session increase familiarity with teaching and assessing skills. Participants who applied the skills learnt from the faculty development programme the most in their teaching and assessment came from internal medicine departments, were young attending physician and had experience as PGY1 clinical instructors. Conclusions According to the clinical instructors response, our faculty development programme effectively increased their familiarity with various teaching and assessment skills needed to teach PGY1 residents and ACGME competencies, and these clinical instructors also then subsequently apply these skills.

Evolution of portal-systemic collateral vasopressin response in endotoxemic portal hypertensive rats.

Cirrhotic patients with portal hypertension and variceal hemorrhage are vulnerable to endotoxemia. However, the direct influence of endotoxemia on portal-systemic collateral vasculature remains unexplored. In this study, portal hypertension was induced in Sprague-Dawley rats by partial portal vein ligation. On the 7th day after portal vein ligation, at 0.5, 1.5, and 5 h post endotoxin (LPS; Escherichia coli serotype O111:B4, 3 mg/kg, i.p., E0.5, E1.5 and E5, respectively) or saline (control, C0.5, C1.5, and C5, respectively) injection, hemodynamic measurements and concentration-response relationships to arginine vasopressin (AVP; 10−10-10−7 mol/L) in collateral vascular bed were obtained. In another six parallel groups, reverse-transcriptase-polymerase chain reaction of iNOS, eNOS, and endothelin 1 (ET-1) mRNA expressions for splenorenal shunt, the most prominent intra-abdominal collateral vessel, was performed. The results showed that E0.5 had lower perfusion pressure changes to AVP and higher splenorenal shunt eNOS expression than C0.5 group (P < 0.05). Compared with C1.5, tachycardia, higher perfusion pressure changes and enhanced splenorenal shunt iNOS and ET-1 expression were observed in E1.5 group (P < 0.05). In E5, systemic and portal hypotension with markedly enhanced collateral AVP responsiveness and splenorenal shunt iNOS and ET-1 expressions were noted (P < 0.05). In conclusion, vasoactive substances counterregulation participates, at least in part, the time-dependent changes of collateral AVP responsiveness in endotoxemic portal hypertensive rats.

Chronic Thalidomide Administration Enhances Vascular Responsiveness to Vasopressin in Portal-systemic Collaterals of Bile Duct-ligated Rats

Background: Arginine vasopressin (AVP) controls gastroesophageal variceal bleeding, partly due to its vasoconstrictive effect on portal‐systemic collaterals. It has been shown that chronic thalidomide treatment decreases portal pressure, attenuates hyperdynamic circulation and inhibits vascular endothelial growth factor (VEGF) and tumor necrosis factor (TNF)‐α in partially portal vein‐ligated rats. This study investigated the effects of chronic thalidomide treatment on portal‐systemic collateral vascular responsiveness to AVP in common bile duct‐ligated (CBDL) cirrhotic rats. Methods: In the first series, CBDL‐induced cirrhotic rats received thalidomide (50 mg/kg/day orally) or distilled water (control) from the 35th to 42nd day after ligation. On the 43rd day after ligation, the body weight, mean arterial pressure, portal pressure, and heart rate were measured. An in situ collateral vascular perfusion model was used to obtain the cumulative concentration–response curves of collateral vessels to AVP (10−10 to 3 × 10−7 M). Plasma levels of VEGF and TNF‐α were measured, and expressions of VEGF and TNF‐α mRNA in the left adrenal veins were also determined. In the second series, the cumulative concentration–response curves of collateral vessels to AVP in CBDL rats with or without thalidomide (10−5 M) preincubation in the perfusate were obtained. Results: The thalidomide and control groups were not significantly different in terms of heart rate, mean arterial pressure and portal pressure (p > 0.05). The collateral vascular perfusion pressure change to AVP was significantly enhanced at 10−8 M after thalidomide treatment (p = 0.041). Compared with the control group, thalidomide‐treated rats had significantly lower plasma VEGF levels (p < 0.001), accompanied by an insignificant reduction in plasma TNF‐α levels (p > 0.05). The expressions of VEGF and TNF‐α mRNA in the left adrenal veins of thalidomide‐treated CBDL rats were not significantly changed compared with those of the control group. In addition, thalidomide did not significantly elicit changes in vascular responsiveness to AVP in collateral vessels of CBDL rats when it was added into the perfusate. Conclusion: In cirrhotic rats, chronic thalidomide treatment improves the portal‐systemic collateral vascular responsiveness to AVP, which was partly related to VEGF inhibition.

Vasopressin response and shunting modulation in cirrhotic rats by chronic nitric oxide inhibition.

Background and Aim:u2002 Nitric oxide (NO) plays a significant role in the vascular hyposensitivity to vasoconstrictors in cirrhosis. Chronic NO inhibition improves the portal‐systemic collateral responsiveness to arginine8‐vasopressin (AVP) and ameliorates shunting degree in rats with prehepatic portal hypertension. This study investigated whether long‐term NO inhibition by NG‐nitro‐L‐arginine methyl ester (L‐NAME) enhances the collateral vascular responsiveness to AVP and alleviates the severity of shunting in cirrhotic rats.

Chronic Indomethacin Treatment Enhances the Portal-systemic Collateral Vascular Response to Vasopressin in Bile-duct Ligated Rats

Background: Liver cirrhosis is often accompanied by portal‐systemic collateral formation with hemorrhage and encephalopathy. Prostacyclin participates in hyperdynamic circulation and vascular hyporeactiveness to vasoconstrictors in cirrhosis. It has been shown that arginine vasopressin (AVP) induces direct collateral vasoconstriction in portal hypertensive rats, which is potentiated by indomethacin preincubation. However, the influence of chronic indomethacin administration in cirrhosis remains unexplored. Methods: This study was performed on male Sprague‐Dawley rats with liver cirrhosis induced by common bile duct ligation. They received subcutaneous indomethacin (5 mg/kg/day) or distilled water (control) injection from the 36th to 42nd day after operation. On the 43rd day, systemic and portal hemodynamics were evaluated and the following experiments were performed with an in situ collateral perfusion model: in the first series, concentration‐response curves to AVP (10−10−10−7 M) were obtained; in the second series, flow‐pressure curves were plotted (Krebs solution, 6–18 mL/min), where the slope represents an index of collateral vascular resistance (the higher the resistance, the smaller the amount of shunting vessels, that is, the lower the degree of shunting). Results: The mean arterial pressure and portal pressure were similar between indomethacin and control groups (p > 0.05). Indomethacin elevated the collateral perfusion pressure to AVP (3 × 10−9, 10−8 M, p < 0.05) but did not influence the slope of the flow‐pressure curve (p > 0.05). Conclusion: In bile duct‐ligated cirrhotic rats, indomethacin improves the portal‐systemic collateral vascular responsiveness to AVP without alleviating the severity of shunting.

Nucleos(t)ide Analogs Do Not Independently Influence Hepatic Fibrosis and Portal Hypertension beyond Viral Suppression in CBDL-Induced Cirrhotic Rat

Chronic hepatitis is the major cause of liver cirrhosis and portal hypertension. Several factors affect portal pressure, including liver fibrosis, splanchnic vasodilatation, and pathologic angiogenesis. Nucleos(t)ide analogs (NUCs), the oral antiviral agents, effectively attenuate chronic hepatitis B-related liver cirrhosis and portal hypertension via viral suppression and alleviation of hepatitis. On the other hand, NUCs affect tumor necrosis factor (TNF)-α, vascular endothelial growth factor (VEGF), and nitric oxide, which participate in fibrogenesis, vasodilatation, and angiogenesis. However, whether NUCs independently influence liver fibrosis and portal hypertension beyond viral suppression is unknown. This study thus aimed to evaluate the influences of three frequently used NUCs in rats with nonviral cirrhosis. Male Sprague-Dawley rats received common bile duct ligation (CBDL) to induce cholestatic cirrhosis and portal hypertension. The rats were randomly allocated into four groups, treated by mouth with lamivudine (30 mg/kg per day), entecavir (0.09 mg/kg per day), tenofovir (50 mg/kg per day), or distilled water (vehicle control) from the 15th day after CBDL. On the 29th day, liver cirrhosis- and portal hypertension-related parameters were evaluated. The results showed that chronic NUCs treatment did not affect hemodynamic parameters, plasma TNF-α concentration, and hepatic fibrogenesis protein expressions in rats with nonviral cirrhosis. Though the mesenteric VEGF receptor 2 phosphorylation was downregulated in NUCs-treated groups, the splanchnic angiogenesis was not influenced. In conclusion, lamivudine, entecavir, and tenofovir had no additional effects on liver cirrhosis and portal hypertension in rats with nonviral cirrhosis.