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Chung Y.-L.,Koo Foundation Sun Yat Sen Cancer Center | Chung Y.-L.,National Yang Ming University | Pui N.N.M.,ASAN Laboratories Inc.
Journal of Dermatological Science | Year: 2011

Background: Epidermal growth factor receptor inhibitors (EGFRIs) cause skin inflammation, and understanding the factors that mediate this reaction is fundamental for designing therapies for EGFRI-related cutaneous side effects. Objective: We characterized EGFRI-enhanced skin reactions and evaluated the therapeutic efficacy of phenylbutyrate, a histone deacetylase inhibitor. Methods: PD168393, an EGFRI, was applied topically to the ear skin of mice with or without mast cell deficiency. The skin was then irritated once or pre-sensitized and repeatedly challenged with 2,4-dinitrofluorobenzene (DNFB). The reaction pattern, the type and number of infiltrating cells, changes in protein, cytokine (TNF-α) and chemokine (CCL2) expression, and the immune response were analyzed. Phenylbutyrate, formulated as a gel for topical treatment or dissolved in water for intraperitoneal administration, was tested as a treatment. Results: EGFRI rapidly upregulated the mast cell chemotactic factor, stem cell factor (SCF) and augmented DNFB-induced immediate contact dermatitis within hours of treatment in the presence of mast cells. Topical phenylbutyrate treatment suppressed EGFRI-induced SCF expression in the epithelium, inhibited DNFB-induced mast cell recruitment in the dermis, and ameliorated the EGFRI-enhanced acute skin reaction. EGFRI also enhanced the delayed-type DNFB-induced hypersensitive reaction that was mast-cell independent but was associated with T lymphocytes. Systemic phenylbutyrate administration suppressed EGFRI-enhanced delayed-type skin hypersensitivity by increasing the number and function of Foxp3 + T regulatory suppressor cells, which inhibited T helper cell proliferation. Conclusions: Our data suggest that phenylbutyrate has dual beneficial therapeutic effects on EGFRI-enhanced acute (local inflammatory) and late (systemic immune) skin reactions. © 2011 Japanese Society for Investigative Dermatology. Source


ABSTRACT: Autologous cord blood transplantations are rarely applied in patients with hematologic as well as metastatic solid cancers since contamination of malignant clones is a concern.We report a case of therapy-related myelodysplasia after metastatic neuroblastoma who suffered from graft rejection and life-threatening infections after a myeloablative unrelated cord blood transplantation.The patient experiences long-term survival, free from leukemia/neuroblastoma after infusion of autologous cord blood cells.It suggests that autologous cord blood transplantation after high dose therapy might be a curative strategy for certain hematologic or metastatic solid cancers. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. Source


Chung Y.-L.,Koo Foundation Sun Yat Sen Cancer Center | Wu M.-L.,Foundation Medicine
Oncotarget | Year: 2016

Proteasome-mediated degradation of promyelocytic leukemia tumor suppressor (PML) is upregulated in many viral infections and cancers. We previously showed that PML knockdown promotes early-onset hepatocellular carcinoma (HCC) in hepatitis B virus surface antigen (HBsAg)-transgenic mice. Here we report the effects of PML restoration on late-onset HBsAg-induced HCC. We compared protein expression patterns, genetic mutations and the effects of pharmacologically targeting PML in wild-type, PML-/-, PML+/+HBsAgtg/o and PML-/-HBsAgtg/o mice. PML-/- mice exhibited somatic mutations in DNA repair genes and developed severe steatosis and proliferative disorders, but not HCC. PML-/-HBsAgtg/o mice exhibited early mutations in cancer driver genes and developed hyperplasia, fatty livers and indolent adiposelike HCC. In PML+/+HBsAg-transgenic mice, HBsAg expression declined over time, and HBsAg-associated PML suppression was concomitantly relieved. Nevertheless, these mice accumulated mutations in genes contributing to oxidative stress pathways and developed aggressive late-onset angiogenic trabecular HCC. PML inhibition using non-toxic doses of arsenic trioxide selectively killed long-term HBsAg-affected liver cells in PML+/+HBsAgtg/o mice with falling HBsAg and rising PML levels, but not normal liver cells or early-onset HCC cells in PML-/-HBsAgtg/0 mice. These findings suggest dual roles for PML as a tumor-suppressor lost in early-onset HBsAg-induced hepatocarcinogenesis and as an oncogenic promoter in late-onset HBsAg-related HCC progression. Source


Chung Y.-L.,Koo Foundation Sun Yat Sen Cancer Center | Wu M.-L.,Foundation Medicine
Journal of Pathology | Year: 2013

DNA damage response and repair pathways are important barriers to carcinogenesis. Here, we show that promyelocytic leukaemia (PML, also known as TRIM19), involved in sensing DNA damage and executing homologous recombination repair, is down-regulated in non-tumour liver cells surrounding hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). No PML mutation or deletion was found in HBV-infected liver or HCC cells. Immunohistochemical analysis of liver biopsies from patients with breast or liver cancer and HBV reactivation after chemotherapy revealed PML up-regulation and HBV exacerbation in normal liver tissue in response to DNA damage (functional PML), PML down-regulation in HCC peritumour cells associated with high HBsAg accumulation and low HBV replication activity (suppressive PML), and heterogeneous nuclear PML expression in HCC cells that lost HBV DNA and HBsAg and were non-reactive to DNA damage (dysregulated PML). Loss of PML in HBsAg-transgenic mice promoted chromosome breaks in liver cells and accelerated the accumulation of body and liver fat and the development of a liver steatosis-dysplasia-adenoma-carcinoma sequence in an inflammation-independent and male-predominant manner, compared to PML knock-out or HBsAg-transgenic mice during the same time period. These results indicate that PML deficiency facilitates genomic instability and promotes HBsAg-related hepatocarcinogenesis, which also involves androgen and lipid metabolism. These findings uncover a novel PML link between HBV-related tumourigenesis, DNA repair, and metabolism. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Source


Chung Y.-L.,Koo Foundation Sun Yat Sen Cancer Center
FASEB Journal | Year: 2013

Hepatitis B virus (HBV) is implicated in liver cancer. The aim of this study was to find out whether HBV or its components [HBV surface antigen (HBsAg), HBV core protein (HBc), and HBV X protein (HBx)] could interfere with the host DNA damage response and repair pathway. The full HBV genome or individual HBV open-reading frame (ORF) was introduced into HepG2 cells to examine the effect on host genomic stability, DNA repair efficacy in response to double-strand DNA damage, and DNA damage-induced cell death. Responses to apoptosis induction in the HBV ORF-transfected HepG2 cells were also compared with those in HBVpositive and HBV-negative human hepatocellular carcinoma (HCC) cells. In the absence of HBV replication, accumulation of HBsAg in liver cells without other HBV proteins enhanced DNA repair protein and tumor suppressor promyelocytic leukemia (PML) degradation, which resulted in resistance to apoptosis induction and deficient double-strand DNA repair. However, HBsAg-positive cells exhibited increased cell death with exposure to the poly(ADP-ribose) polymerase inhibitor that blocks single-strand DNA repair. These results indicate that suppression of PML by HBsAg disrupts cellular mechanisms that respond to double-strand DNA damage for DNA repair or apoptosis induction, which may facilitate hepatocarcinogenesis and open up a synthetic lethality strategy for HBsAg-positive HCC treatment. © FASEB. Source

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