A Preliminary Analysis of Combined Liver Resection With New Chemotherapy for Synchronous and Metachronous Colorectal Liver Metastasis

ObjectiveTo compare the survival between patients with synchronous and metachronous colorectal liver metastases after hepatectomy with new generation of perioperative chemotherapy.MethodsFrom October 2002 to January 2008, patients receiving hepatectomy for synchronous or metachronous colorectal liver metastasis were studied retrospectively.ResultsFifty-five patients (synchronous group = 35, metachronous group = 20) underwent hepatectomy for colorectal liver metastases. Besides younger age with male predominance, patients in the synchronous group had more tumour multinodularity and bilobe liver involvement. They had received less hepatic curative hepatectomy (81.1% vs. 100%) with a higher rate of peri-operative chemotherapy (91.4% vs. 50%) and postoperative morbidity (25.7% vs. 0%). However both groups had no statistical significant difference in median overall survival (OS) and disease free survival (DFS). Inferior OS and DFS were observed in the synchronous group for patients who had no peri-operative chemotherapy or those showing poor response to chemotherapy. The most favourable OS is observed in both groups after performing globally curative hepatectomy.ConclusionSynchronous colorectal liver metastasis is not a poor prognostic factor for survival when compared with the metachronous metastasis. Globally curative hepatectomy in combination of new generation of chemotherapy is recommended for the management of resectable colorectal liver metastasis

Carboxyl-terminal truncated HBx regulates a distinct microRNA transcription program in Hepatocellular carcinoma development

Background: The biological pathways and functional properties by which misexpressed microRNAs (miRNAs) contribute to liver carcinogenesis have been intensively investigated. However, little is known about the upstream mechanisms that deregulate miRNA expressions in this process. In hepatocellular carcinoma (HCC), hepatitis B virus (HBV) X protein (HBx), a transcriptional trans-activator, is frequently expressed in truncated form without carboxyl-terminus but its role in miRNA expression and HCC development is unclear. Methods: Human non-tumorigenic hepatocytes were infected with lentivirus-expressing full-length and carboxyl-terminal truncated HBx (Ct-HBx) for cell growth assay and miRNA profiling. Chromatin immunoprecipitation microarray was performed to identify the miRNA promoters directly associated with HBx. Direct transcriptional control was verified by luciferase reporter assay. The differential miRNA expressions were further validated in a cohort of HBV-associated HCC tissues using real-time PCR. Results: Hepatocytes expressing Ct-HBx grew significantly faster than the full-length HBx counterparts. Ct-HBx decreased while full-length HBx increased the expression of a set of miRNAs with growth-suppressive functions. Interestingly, Ct-HBx bound to and inhibited the transcriptional activity of some of these miRNA promoters. Notably, some of the examined repressed-miRNAs (miR-26a, -29c, -146a and -190) were also significantly down-regulated in a subset of HCC tissues with carboxyl-terminal HBx truncation compared to their matching non-tumor tissues, highlighting the clinical relevance of our data. Conclusion: Our results suggest that Ct-HBx directly regulates miRNA transcription and in turn promotes hepatocellular proliferation, thus revealing a viral contribution of miRNA deregulation during hepatocarcinogenesis. © 2011 Yip et al.published_or_final_versio

Albumin-bilirubin grade predicts the outcomes of liver resection versus radiofrequency ablation for very early/early stage of hepatocellular carcinoma

Background and purposeWhether liver resection or ablation should be the first-line treatment for very early/early hepatocellular carcinoma (HCC) in patients who are candidates for both remains controversial. The aim of this study was to determine if the newly-developed Albumin-Bilirubin (ALBI) grade might help in treatment selections and to evaluate the survival of patients treated with liver resection and radiofrequency ablation (RFA).MethodsPatients with BCLC stage 0/A HCC who were treated with curative liver resection and RFA from 2003 to 2013 were included. Baseline clinical and laboratory parameters were retrieved and reviewed from the hospital database. Liver function and its impact on survival was assessed by the ALBI score. Overall and disease-free survivals were compared between the two groups.Results488 patients underwent liver resection (n = 318) and RFA (n = 170) for BCLC stage 0/A HCC during the study period. Liver resection offered superior survival to RFA in patients with BCLC stage 0/A HCC in the whole cohort. After propensity score matching, liver resection offered superior overall survival and disease-free survival to RFA in patients with ALBI grade 1 (P = 0.0002 and P ConclusionsLiver resection offered superior survival to RFA in patients with BCLC stage 0/A HCC. The ALBI grade could identify those patients with worse liver function who did not gain any survival advantage from curative liver resection

Early intervention for incipient insanity: early notions from the 19th century English literature.

AIM: Early intervention programmes in mental illnesses started to bloom in the 1990s, and many programmes have been established worldwide during the past twenty years. However, the concept of early intervention has emerged during the 19th century but it did not make much impact on practice. The aim of this review is to identify the difficulties appeared during that period of time which could provide insight into the modern development of early intervention initiatives. METHODS: A narrative review which focused on English literature about early intervention for insanity during the 19th century was undertaken. RESULTS: Clinicians during the 19th century recognized that treatment would be the most effective at the early stage of the mental illness and they had emphasized the importance of early intervention. However, because of a number of factors, such as the limited roles of asylums, lack of knowledge about mental disorder and the lack of effective treatment, the idea of early intervention did not make impact in clinical service during that period of time. CONCLUSION: During the past two hundred years, understanding towards mental illness has advanced and more effective treatments, such as the use of anti-psychotic medications, have been developed. Reflecting on the past experience and difficulties might shed light on the development of today early intervention in mental disorder.This is the author accepted manuscript. It is currently under an indefinite embargo pending publication by Wiley

Constitutively Nuclear FOXO3a Localization Predicts Poor Survival and Promotes Akt Phosphorylation in Breast Cancer

Background: The PI3K-Akt signal pathway plays a key role in tumorigenesis and the development of drug-resistance. Cytotoxic chemotherapy resistance is linked to limited therapeutic options and poor prognosis. Methodology/Principal Findings: Examination of FOXO3a and phosphorylated-Akt (P-Akt) expression in breast cancer tissue microarrays showed nuclear FOXO3a was associated with lymph node positivity (p = 0.052), poor prognosis (p = 0.014), and P-Akt expression in invasive ductal carcinoma. Using tamoxifen and doxorubicin-sensitive and -resistant breast cancer cell lines as models, we found that doxorubicin- but not tamoxifen-resistance is associated with nuclear accumulation of FOXO3a, consistent with the finding that sustained nuclear FOXO3a is associated with poor prognosis. We also established that doxorubicin treatment induces proliferation arrest and FOXO3a nuclear relocation in sensitive breast cancer cells. Induction of FOXO3a activity in doxorubicin-sensitive MCF-7 cells was sufficient to promote Akt phosphorylation and arrest cell proliferation. Conversely, knockdown of endogenous FOXO3a expression reduced PI3K/Akt activity. Using MDA-MB-231 cells, in which FOXO3a activity can be induced by 4-hydroxytamoxifen, we showed that FOXO3a induction up-regulates PI3K-Akt activity and enhanced doxorubicin resistance. However FOXO3a induction has little effect on cell proliferation, indicating that FOXO3a or its downstream activity is deregulated in the cytotoxic drug resistant breast cancer cells. Thus, our results suggest that sustained FOXO3a activation can enhance hyperactivation of the PI3K/Akt pathway. Conclusions/Significance: Together these data suggest that lymph node metastasis and poor survival in invasive ductal breast carcinoma are linked to an uncoupling of the Akt-FOXO3a signaling axis. In these breast cancers activated Akt fails to inactivate and re-localize FOXO3a to the cytoplasm, and nuclear-targeted FOXO3a does not induce cell death or cell cycle arrest. As such, sustained nuclear FOXO3a expression in breast cancer may culminate in cancer progression and the development of an aggressive phenotype similar to that observed in cytotoxic chemotherapy resistant breast cancer cell models. © 2010 Chen et al.published_or_final_versio

Repurposing hyperpolarization-activated cyclic nucleotide-gated channels as a novel therapy for breast cancer.

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are members of the voltage-gated cation channel family known to be expressed in the heart and central nervous system. Ivabradine, a small molecule HCN channel-blocker, is FDA-approved for clinical use as a heart rate-reducing agent. We found that HCN2 and HCN3 are overexpressed in breast cancer cells compared with normal breast epithelia, and the high expression of HCN2 and HCN3 is associated with poorer survival in breast cancer patients. Inhibition of HCN by Ivabradine or by RNAi, aborted breast cancer cell proliferation in vitro and suppressed tumour growth in patient-derived tumour xenograft models established from triple-negative breast cancer (TNBC) tissues, with no evident side-effects on the mice. Transcriptome-wide analysis showed enrichment for cholesterol metabolism and biosynthesis as well as lipid metabolism pathways associated with ER-stress following Ivabradine treatment. Mechanistic studies confirmed that HCN inhibition leads to ER-stress, in part due to disturbed Ca2+ homeostasis, which subsequently triggered the apoptosis cascade. More importantly, we investigated the synergistic effect of Ivabradine and paclitaxel on TNBC and confirmed that both drugs acted synergistically in vitro through ER-stress to amplify signals for caspase activation. Combination therapy could suppress tumour growth of xenografts at much lower doses for both drugs. In summary, our study identified a new molecular target with potential for being developed into targeted therapy, providing scientific grounds for initiating clinical trials for a new treatment regimen of combining HCN inhibition with chemotherapy

Nonvirally Modified Autologous Primary Hepatocytes Correct Diabetes and Prevent Target Organ Injury in a Large Preclinical Model

BACKGROUND: Current gene- and cell-based therapies have significant limitations which impede widespread clinical application. Taking diabetes mellitus as a paradigm, we have sought to overcome these limitations by ex vivo electrotransfer of a nonviral insulin expression vector into primary hepatocytes followed by immediate autologous reimplantation in a preclinical model of diabetes. METHODS AND RESULTS: In a single 3-hour procedure, hepatocytes were isolated from a surgically resected liver wedge, electroporated with an insulin expression plasmid ex vivo and reimplanted intraparenchymally under ultrasonic guidance into the liver in each of 10 streptozotocin-induced diabetic Yorkshire pigs. The vector was comprised of a bifunctional, glucose-responsive promoter linked to human insulin cDNA. Ambient glucose concentrations appropriately altered human insulin mRNA expression and C-peptide secretion within minutes in vitro and in vivo. Treated swine showed correction of hyperglycemia, glucose intolerance, dyslipidemia and other metabolic abnormalities for > or = 47 weeks. Metabolic correction correlated significantly with the number of hepatocytes implanted. Importantly, we observed no hypoglycemia even under fasting conditions. Direct intrahepatic implantation of hepatocytes did not alter biochemical indices of liver function or induce abnormal hepatic lobular architecture. About 70% of implanted hepatocytes functionally engrafted, appeared histologically normal, retained vector DNA and expressed human insulin for > or = 47 weeks. Based on structural tissue analyses and transcriptome data, we showed that early correction of diabetes attenuated and even prevented pathological changes in the eye, kidney, liver and aorta. CONCLUSIONS: We demonstrate that autologous hepatocytes can be efficiently, simply and safely modified by electroporation of a nonviral vector to express, process and secrete insulin durably. This strategy, which achieved significant and sustained therapeutic efficacy in a large preclinical model without adverse effects, warrants consideration for clinical development especially as it could have broader future applications for the treatment of other acquired and inherited diseases for which systemic reconstitution of a specific protein deficiency is critical