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1.  Microwave ablation of liver metastasis complicated by Clostridium perfringens gas-forming pyogenic liver abscess (GPLA) in a patient with past gastrectomy 
•GPLA is one rare complication of liver microwave ablation.•It can be diagnosed with CT scan which shows gas-containing infective focus.•Patients with gastrectomy may have an increased risk of such infection due to gut flora change.•To date, data on effectiveness of empirical antibiotic is not convincing.•Close monitoring following ablation should be prioritised to allow timely intervention and prevent escalation of infection.
Gas-forming pyogenic liver abscess (GPLA) caused by C. perfringens is rare but fatal. Patients with past gastrectomy may be prone to such infection post-ablation.
Presentation of case
An 84-year-old male patient with past gastrectomy had MW ablation of his liver tumors complicated by GPLA. Computerised tomography scan showed gas-containing abscess in the liver and he was managed successfully with antibiotic and percutaneous drainage of the abscess.
C. perfringens GPLA secondary to MW ablation in a patient with previous gastrectomy has not been reported in the literature. Gastrectomy may predispose to such infection. Even in high-risk patients, empirical antibiotic before ablation is not a standard of practice. Therefore following the procedure, close observation of patients’ conditions is necessary to allow early diagnosis and intervention that will prevent progression of infection.
Potential complication of liver abscess following MW ablation can never be overlooked. The risk may be enhanced in patients with previous gastrectomy. Early diagnosis and management may minimise mortality and morbidity.
PMCID: PMC4987502  PMID: 27529833
Clostridium perfringens infection; Gas-containing abscess; Microwave ablation; Liver tumor; Gastrectomy; Prophylactic antibiotic
3.  Genome-wide association meta-analysis in Chinese and European individuals identifies ten new loci associated with systemic lupus erythematosus 
Nature genetics  2016;48(8):940-946.
Systemic lupus erythematosus (SLE; OMIM 1 152700) is a genetically complex autoimmune disease. Genome-wide association studies (GWASs) have identified more than 50 loci as robustly associated with the disease in single ancestries, but genome-wide transancestral studies have not been conducted. We combined three GWAS data sets from Chinese (1,659 cases and 3,398 controls) and European (4,036 cases and 6,959 controls) populations. A meta-analysis of these studies showed that over half of the published SLE genetic associations are present in both populations. A replication study in Chinese (3,043 cases and 5,074 controls) and European (2,643 cases and 9,032 controls) subjects found ten previously unreported SLE loci. Our study provides further evidence that the majority of genetic risk polymorphisms for SLE are contained within the same regions across both populations. Furthermore, a comparison of risk allele frequencies and genetic risk scores suggested that the increased prevalence of SLE in non-Europeans (including Asians) has a genetic basis.
PMCID: PMC4966635  PMID: 27399966
4.  Genetic association analyses implicate aberrant regulation of innate and adaptive immunity genes in the pathogenesis of systemic lupus erythematosus 
Nature genetics  2015;47(12):1457-1464.
Systemic lupus erythematosus (SLE; OMIM 152700) is a genetically complex autoimmune disease characterized by loss of immune tolerance to nuclear and cell surface antigens. Previous genome-wide association studies (GWAS) had modest sample sizes, reducing their scope and reliability. Our study comprised 7,219 cases and 15,991 controls of European ancestry: a new GWAS, meta-analysis with a published GWAS and a replication study. We have mapped 43 susceptibility loci, including 10 novel associations. Assisted by dense genome coverage, imputation provided evidence for missense variants underpinning associations in eight genes. Other likely causal genes were established by examining associated alleles for cis-acting eQTL effects in a range of ex vivo immune cells. We found an over-representation (n=16) of transcription factors among SLE susceptibility genes. This supports the view that aberrantly regulated gene expression networks in multiple cell types in both the innate and adaptive immune response contribute to the risk of developing SLE.
PMCID: PMC4668589  PMID: 26502338
5.  Identification of SH2B2β as an Inhibitor for SH2B1- and SH2B2α-Promoted Janus Kinase-2 Activation and Insulin Signaling 
Endocrinology  2007;148(4):1615-1621.
The SH2B family has three members (SH2B1, SH2B2, and SH2B3) that contain conserved dimerization (DD), pleckstrin homology, and SH2 domains. The DD domain mediates the formation of homo- and heterodimers between members of the SH2B family. The SH2 domain of SH2B1 (previously named SH2-B) or SH2B2 (previously named APS) binds to phosphorylated tyrosines in a variety of tyrosine kinases, including Janus kinase-2 (JAK2) and the insulin receptor, thereby promoting the activation of JAK2 or the insulin receptor, respectively. JAK2 binds to various members of the cytokine receptor family, including receptors for GH and leptin, to mediate cytokine responses. In mice, SH2B1 regulates energy and glucose homeostasis by enhancing leptin and insulin sensitivity. In this work, we identify SH2B2β as a new isoform of SH2B2 (designated as SH2B2α) derived from the SH2B2 gene by alternative mRNA splicing. SH2B2β has a DD and pleckstrin homology domain but lacks a SH2 domain. SH2B2β bound to both SH2B1 and SH2B2α, as demonstrated by both the interaction of glutathione S-transferase-SH2B2β fusion protein with SH2B1 or SH2B2α in vitro and coimmunoprecipitation of SH2B2β with SH2B1 or SH2B2α in intact cells. SH2B2β markedly attenuated the ability of SH2B1 to promote JAK2 activation and subsequent tyrosine phosphorylation of insulin receptor substrate-1 by JAK2. SH2B2β also significantly inhibited SH2B1- or SH2B2α-promoted insulin signaling, including insulin-stimulated tyrosine phosphorylation of insulin receptor substrate-1. These data suggest that SH2B2β is an endogenous inhibitor of SH2B1 and/or SH2B2α, negatively regulating insulin signaling and/or JAK2-mediated cellular responses.
PMCID: PMC4710543  PMID: 17204555
6.  Adipose tissue macrophages: phenotypic plasticity and diversity in lean and obese states 
Purpose of review
Proinflammatory adipose tissue macrophages (ATMs) contribute to obesity-associated disease morbidity. We will provide an update of the current state of knowledge regarding the phenotypic and functional diversity of ATMs in lean and obese mice and humans.
Recent findings
The phenotypic diversity of ATMs is now known to include more than two types requiring an expansion of the simple concept of an M2 to M1 shift with obesity. Potential functions for ATMs now include the regulation of fibrosis and response to acute lipolysis in states of caloric restriction. Novel pathways that can potentiate ATM action have been identified, which include inflammasome activation and the response to lipodystrophic adipose tissue. Studies provide a new appreciation for the ability of ATMs to respond dynamically to the adipose tissue microenvironment.
ATMs play a key role in shaping the inflammatory milieu within adipose tissue, and it is now apparent that ATM heterogeneity is acutely shaped by the adipose tissue environment. To account for the new findings, we propose a new nomenclature for ATM subtypes that takes into account their diversity.
PMCID: PMC4690541  PMID: 21587064
adipose tissue macrophages; inflammation; obesity
7.  Sprouty 1 predicts prognosis in human epithelial ovarian cancer 
American Journal of Cancer Research  2015;5(4):1531-1541.
Sprouty proteins are evolutionary-conserved modulators of receptor tyrosine kinase (RTK) signaling. We have previously reported inverse correlation of the Sprouty 1 (Spry1) protein expression with ovarian cancer cell proliferation, migration, invasion and survival. In the present study, the expression status of Spry1 protein and its clinical relevance in patients with epithelial ovarian cancer were explored. Matched tumor and normal tissue samples from 100 patients with epithelial ovarian cancer were immunohistochemically stained for Spry1. Expression of ERK, p-ERK, Ki67, FGF-2, VEGF and IL-6 and their correlation with Spry1 were also evaluated. In addition, correlation between Spry1 and clinicopathological characteristics and predictive significance of Spry1 for overall survival (OS) and disease-free survival (DFS) were analysed. Our data indicated that Spry1 was significantly downregulated in tumor tissues (p=0.004). Spry1 showed significant inverse correlation with p-ERK/ERK (p=0.045), Ki67 (p=0.010), disease stage (p=0.029), tumor grade (p=0.037), recurrence (p=0.001) and lymphovascular invasion (p=0.042). It was revealed that Spry1 low-expressing patients had significantly poorer OS (p=0.010) and DFS (p=0.012) than those with high expression of Spry1. Multivariate analysis showed that high Spry1 (p=0.030), low stage (p=0.048) and no residual tumor (p=0.007) were independent prognostic factors for a better OS, among which high Spry1 (p=0.035) and low stage (p=0.035) remained as independent predictors of DFS, too. We also found that the expression of Spry1 significantly correlates with the expression of Spry2 (p<0.001), but not that of Spry4. In conclusion, we report for the first time to our knowledge that Spry1 protein is downregulated in human epithelial ovarian cancer. Spry1 expression significantly impacts tumor behavior and shows predictive value as an independent prognostic factor for survival and recurrence.
PMCID: PMC4473329  PMID: 26101716
Disease free survival; epithelial ovarian cancer; overall survival; prognostic biomarker; Sprouty 1
8.  Depletion of mucin in mucin-producing human gastrointestinal carcinoma: Results from in vitro and in vivo studies with bromelain and N-acetylcysteine 
Oncotarget  2015;6(32):33329-33344.
Aberrant expression of membrane-associated and secreted mucins, as evident in epithelial tumors, is known to facilitate tumor growth, progression and metastasis, and to provide protection against adverse growth conditions, chemotherapy and immune surveillance. Emerging evidence provides support for the oncogenic role of MUC1 in gastrointestinal carcinomas and relates its expression to an invasive phenotype. Similarly, mucinous differentiation of gastrointestinal tumors, in particular increased or de novo expression of MUC2 and/or MUC5AC, is widely believed to imply an adverse clinicopathological feature. Through formation of viscous gels, too, MUC2 and MUC5AC significantly contribute to the biology and pathogenesis of mucin-secreting gastrointestinal tumors. Here, we investigated the mucin-depleting effects of bromelain (BR) and N-acetylcysteine (NAC), in nine different regimens as single or combination therapy, in in vitro (MKN45, KATOIII and LS174T cell lines) and in vivo (female nude mice bearing intraperitoneal MKN45 and LS174T) settings. The inhibitory effects of the treatment on cancer cell growth and proliferation were also evaluated in vivo. Our results suggest that a combination of BR and NAC with dual effects on growth and mucin products of mucin-expressing tumor cells is a promising candidate towards the development of novel approaches to gastrointestinal malignancies with the involvement of mucin pathology. This capability supports the use of this combination formulation in locoregional approaches for reducing the adverse effects of the aberrantly secreted gel-forming mucins, as in pseudomyxoma peritonei and similar pathologies with ectopic production of mucin.
PMCID: PMC4741769  PMID: 26436698
bromelain; gastrointestinal cancers; mucin; mucin-depleting effect; N-acetylcysteine
9.  Minocycline attenuates hypoxia-inducible factor-1α expression correlated with modulation of p53 and AKT/mTOR/p70S6K/4E-BP1 pathway in ovarian cancer: in vitro and in vivo studies 
Hypoxia-inducible factor (HIF)-1α is the key cellular survival protein under hypoxia, and is associated with tumor progression and angiogenesis. We have recently shown the inhibitory effects of minocycline on ovarian tumor growth correlated with attenuation of vascular endothelial growth factor (VEGF) and herein report a companion laboratory study to test if these effects were the result of HIF-1α inhibition. In vitro, human ovarian carcinoma cell lines (A2780, OVCAR-3 and SKOV-3) were utilized to examine the effect of minocycline on HIF-1 and its upstream pathway components to elucidate the underlying mechanism of action of minocycline. Mice harboring OVCAR-3 xenografts were treated with minocycline to assess the in vivo efficacy of minocycline in the context of HIF-1. Minocycline negatively regulated HIF-1α protein levels in a concentration-dependent manner and induced its degradation by a mechanism that is independent of prolyl-hydroxylation. The inhibition of HIF-1α was found to be associated with up-regulation of endogenous p53, a tumor suppressor with confirmed role in HIF-1α degradation. Further studies demonstrated that the effect of minocycline was not restricted to proteasomal degradation and that it also caused down-regulation of HIF-1α translation by suppressing the AKT/mTOR/p70S6K/4E-BP1 signaling pathway. Minocycline treatment of mice bearing established ovarian tumors, led to suppression of HIF-1α accompanied by up-regulation of p53 protein levels and inactivation of AKT/mTOR/p70S6K/4E-BP1 pathway. These data reveal the therapeutic potential of minocycline in ovarian cancer as an agent that targets the pro-oncogenic factor HIF-1α through multiple mechanisms.
PMCID: PMC4396050  PMID: 25973298
Minocycline; HIF-1; p53; AKT; mTOR; VEGF; ovarian cancer
10.  Trans-arterial embolisation therapies for unresectable intrahepatic cholangiocarcinoma: a systematic review 
Unresectable intrahepatic cholangiocarcinoma (ICC) portends a poor prognosis despite standard systemic treatments which confer minimal survival benefits and significant adverse effects. This study aimed to assess clinical outcomes, complications and prognostic factors of TAE therapies using chemotherapeutic agents or radiation.
A literature search and article acquisition was conducted on PubMed (MEDLINE), OVID (MEDLINE) and EBSCOhost (EMBASE). Original articles published after January 2000 on trans-arterial therapies for unresectable ICC were selected using strict eligibility criteria. Radiological response, overall survival, progression-free survival, safety profile, and prognostic factors for overall survival were assessed. Quality appraisal and data tabulation were performed using pre-determined forms. Results were synthesized by narrative review and quantitative analysis.
Twenty articles were included (n=929 patients). Thirty three percent of patients presented with extrahepatic metastases. After treatment, the average rate of complete and partial radiological response was 10% and 22.2%, respectively. Overall median survival time was 12.4 months with a median 30-day mortality and 1-year survival rate of 0.6% and 53%, respectively. Acute treatment toxicity (within 30 days) was reported in 34.9% of patients, of which 64.3% were mild to moderate in severity. The most common clinical toxicities were abdominal pain, nausea and vomiting, and fatigue. Multiplicity, localization and vascularity of the tumor may predict worse overall survival.
Trans-arterial therapies are safe and effective treatment options which should be considered routinely for unresectable ICC. Consistent and standardized methodology and data collection is required to facilitate a meta-analysis. Randomized controlled trials will be valuable in the future.
PMCID: PMC4570915  PMID: 26487951
Intrahepatic cholangiocarcinoma (ICC); unresectable; embolization; survival
11.  Vascular endothelial growth factor expression correlates with serum CA125 and represents a useful tool in prediction of refractoriness to platinum-based chemotherapy and ascites formation in epithelial ovarian cancer 
Oncotarget  2015;6(29):28491-28501.
There is an increasing need for the identification of novel biological markers and potential therapeutic targets in epithelial ovarian cancer (EOC). Given the critical role of growth factors in the biology of EOC, we aimed in the present study to evaluate the intratumoral expressions of vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) proteins and their clinical relevance in a cohort of 100 patients with EOC. All patients received platinum-based chemotherapy after surgery. A comparative immunohistochemical study of normal ovarian and EOC tissues showed that both growth factors were expressed at higher levels in tumor samples. In our statistical analysis, while no association existed between the FGF expression status and the clinicopathological characteristics of patients, intratumoral VEGF was identified as a potential biomarker for the prediction of ascites formation. In addition, the expression status of VEGF appeared to independently predict overall survival and response to chemotherapy. Furthermore, a direct association was demonstrated between the pre-treatment VEGF expression and serum CA125 after three cycles of chemotherapy. In sum, we report for the first time to our knowledge the correlation between intratumoral VEGF and serum CA125 in EOC. Our data also shows the prognostic value of VEGF expression in EOC. These results suggest the potential value of intratumoral VEGF in patient stratification. Dual inhibition of VEGF and CA125 might bring about a better outcome for patients with EOC.
PMCID: PMC4695074  PMID: 26143638
ascites; CA125; epithelial ovarian cancer; fibroblast growth factor; chemorefractoriness
12.  Cytoreductive surgery and perioperative intraperitoneal chemotherapy for peritoneal carcinomatosis in the elderly 
Peritoneal carcinomatosis is life-threatening without cytoreductive surgery (CRS) and perioperative intraperitoneal chemotherapy (PIC). Only a few studies in the literature addressed the relationship between age and outcomes of peritonectomy. This study was designed to review the clinical outcomes in elderly patients who underwent CRS and PIC.
This is a retrospective study of prospectively collected data of 611 consecutive patients with peritoneal carcinomatosis who underwent CRS and PIC by the same surgical team at St George Hospital in Sydney, Australia, between January 1996 and December 2013. Patients were divided into two groups; group 1 (<65 years old, n = 487) and group 2 (≥ 65 years old, n = 124). Subgroup analysis was performed in patients who were ≥75 years old (n = 20). A significant difference was defined as p < 0.05.
There was no significant statistical difference in terms of mean total hospital stay, intensive care unit stay, high dependency unit stay and complication rates. Postoperative mortality was 2 and 3 % in groups 1 and 2, respectively. Overall survival did not reach a statistical significance between the two groups. In subgroup analysis, patients showed similar morbidity results to patients who were <65 years old.
CRS and PIC can be safely done in the elderly. Age alone should not be the single exclusion criterion but rather taken into consideration along with other factors to determine the suitability of elderly patients.
PMCID: PMC4551766  PMID: 26311565
Cytoreductive surgery; Peritonectomy; Peritoneal carcinomatosis; Elderly
13.  Intratumoral interleukin-6 predicts ascites formation in patients with epithelial ovarian cancer: A potential tool for close monitoring 
The implication of IL-6 in the pathogenesis of epithelial ovarian cancer (EOC) is well documented. Accordingly, the clinicopathological significance of this cytokine in patients’ ascites fluid or serum has largely been investigated. Since the main source of IL-6 secreted into the biological fluids is the tumor tissue, this study was designed to investigate the status and possible clinical relevance of the IL-6 expression in an array of EOC tissue specimens.
Tissue samples obtained from ninety-eight consecutive patients with EOC were studied using immunohistochemistry. Clinicopathological characteristics and treatment related factors were collected from patient files. The relationship between the expression of the protein of interest and the study endpoints of disease-free survival (DFS) and overall survival (OS) were analyzed using the Kaplan-Meier method. For evaluating the predictive value of IL-6, logistic regression and cox proportional hazards models were employed.
An upregulation of IL-6 expression was observed in EOC tissues as compared with the normal samples (p < 0.0001). As regards the clinical relevance, IL-6 failed to predict OS, DFS and response to the platinum-based chemotherapy in EOC patients. In multivariate analysis, however, IL-6 was identified as an independent predictive factor for the development of post-treatment ascites (p:0.033).
Having the capability to predict the ascites formation, IL-6 might serve as a biomarker and a useful tool in EOC for monitoring purposes. IL-6 targeting for the prevention of the ascites development is a potential avenue for further investigation.
PMCID: PMC4539669  PMID: 26282935
Ascites; Chemorefractoriness; Disease free survival; Epithelial ovarian cancer; Interleukin-6; Overall survival
14.  Anticancer properties of novel aminoacetonitrile derivative monepantel (ADD 1566) in pre-clinical models of human ovarian cancer 
Monepantel (MPL) is a new anthelmintic agent approved for the treatment of nematode infections in farm animals. As a nematicide, it acts through a nematode-specific nicotinic receptor subtype which explains its exceptional safety in rodents and mammals. In the present study, we evaluated its potential as an anticancer agent. In vitro treatment of epithelial ovarian cancer cells with MPL resulted in reduced cell viability, inhibition of cell proliferation and suppression of colony formation. Proliferation of human ovarian surface epithelial cells and other non-malignant cells were however minimally affected. MPL-induced inhibition was found to be independent of the acetylcholine nicotinic receptor (nAChR) indicating that, its target in cancer cells is probably different from that in nematodes. Analysis of MPL treated cells by flow cytometry revealed G1 phase cell cycle arrest. Accordingly, MPL treated cells expressed reduced levels of cyclins D1 and A whereas cyclin E2 expression was enhanced. Consistent with a G1 phase arrest, cellular levels of cyclin dependent kinases (CDKs) 2 and 4 were lower, whereas expression of CDK inhibitor p27kip was increased. In cells expressing the wild-type p53, MPL treatment led to increased p53 expression. In line with these results, MPL suppressed cellular thymidine incorporation thus impairing DNA synthesis and inducing cleavage of poly (ADP-ribose) polymerase (PARP-1). Combined these pre-clinical findings reveal for the first time the anticancer potential of monepantel.
PMCID: PMC4163619  PMID: 25232496
Monepantel; ovarian cancer; cell cycle; cyclins; PARP-1
15.  Monepantel induces autophagy in human ovarian cancer cells through disruption of the mTOR/p70S6K signalling pathway 
We have recently shown that the novel anthelmintic drug monepantel (MPL) inhibits growth, proliferation and colony formation, arrests the cell cycle and induces cleavage of PARP-1 in ovarian cancer cell lines. Here we report on the mechanism behind the anticancer properties of MPL. The cytotoxic effect of MPL on ovarian cancer cells (OVCAR-3 and A2780) was investigated employing a panel of tests used for the detection of apoptosis and autophagy. Apoptosis and autophagy were defined by caspase activity, DNA-laddering, Annexin-V and acridine orange (AO) staining. Autophagy markers such as LC3B, SQSTM1/p62 and mammalian target of rapamycin (mTOR) pathway related proteins were assessed by western blotting and ELISA techniques. MPL did not activate caspases 3 or 8, nor did it alter the percentage of Annexin V positive stained cells. Failure to cause DNA laddering and the inability of z-VAD-fmk to block the MPL antiproliferative effects led to the ruling out of apoptosis as the mechanism behind MPL-induced cell death. On the other hand, accumulation of acidic vacuoles with distinct chromatin morphology and an increase in punctuate localization of green fluorescent protein-LC3B, and MPL-induced changes in the expression of SQSTM1/p62 were all indicative of MPL-induced autophagy. Consistent with this, we found inhibition of mTOR phosphorylation leading to suppression of the mTOR/p70S6K signalling pathway. Our findings provide the first evidence to show that MPL triggers autophagy through the deactivation of mTOR/p70S6K signalling pathway.
PMCID: PMC4163620  PMID: 25232497
Monepantel; ovarian cancer; apoptosis; PARP; autophagy; mTOR; p70S6K
16.  Sprouty2 protein in prediction of post-treatment ascites in epithelial ovarian cancer treated with adjuvant carbotaxol chemotherapy 
American Journal of Cancer Research  2015;5(8):2498-2507.
Ascites development and resistance to chemotherapy with carbotaxol are common clinical problems in epithelial ovarian cancer, partly due to the activation of MAPK/ERK signaling. Sprouty proteins are negative modulators of MAPK/ERK pathway, but their role in predicting resistance to carbotaxol chemotherapy and ascites development is unknown. In this study, we evaluated the expression of Sprouty protein isoforms by immunohistochemistry. The associations between the Sprouty expression and the clinicopathological features, including chemoresistance and the presence of ascites, were then explored. We found that the decreased expression of Spry2 was correlated with the post-treatment development of ascites and represented an independent predictor of this condition in carbotaxol-treated patients. However, no association was observed between the Sprouty expression and chemoresistance. In conclusion, our results suggest that Spry2 may be useful for patient follow-up and monitoring as it predicts the development of ascites in epithelial ovarian cancer cases treated with carbotaxol.
PMCID: PMC4568786  PMID: 26396926
Ascites; epithelial ovarian cancer; refractory disease; Sprouty1; Sprouty2; Sprouty4
17.  Effects of sex hormones on survival of peritoneal mesothelioma 
Previous studies have suggested the presence of steroid receptors as a favourable prognostic factor in peritoneal mesothelioma (PM). This study aims to investigate possible hormonal effects on survival of PM.
This is a retrospective study of prospectively collected data of 52 consecutive patients with PM who underwent cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) by the same surgical team at St George Hospital in Sydney, Australia, between April 1996 and April 2013. Females were arbitrarily divided into assumed premenopausal (<51 years old; n = 15) and assumed postmenopausal (≥51 years old, n = 9). In each gender group, patients were furthered divided into three age groups (<40, 40–60, >60). A significant statistical difference was defined as p < 0.05.
Females with epithelial mesothelioma had a significantly higher survival than males (p = 0.023). They also had a better overall median survival (>60 months) than males (43 months), although this difference was not statistically significant (p = 0.098). Survival of postmenopausal females became similar to males after excluding benign cystic mesothelioma.
The better survival in premenopausal females could probably be explained by higher levels of oestradiol and progesterone. Also, our data suggests that higher rates of benign cystic mesothelioma in females was not the key reason for the better survival in female patients, further supporting the hypothesis of hormonal links with survival of PM. Therapeutic effects of sex steroid hormones on PM may be a valuable area to explore.
PMCID: PMC4491202  PMID: 26111523
Peritoneal mesothelioma; Hormone; Female; Survival
18.  Defective removal of ribonucleotides from DNA promotes systemic autoimmunity 
Genome integrity is continuously challenged by the DNA damage that arises during normal cell metabolism. Biallelic mutations in the genes encoding the genome surveillance enzyme ribonuclease H2 (RNase H2) cause Aicardi-Goutières syndrome (AGS), a pediatric disorder that shares features with the autoimmune disease systemic lupus erythematosus (SLE). Here we determined that heterozygous parents of AGS patients exhibit an intermediate autoimmune phenotype and demonstrated a genetic association between rare RNASEH2 sequence variants and SLE. Evaluation of patient cells revealed that SLE- and AGS-associated mutations impair RNase H2 function and result in accumulation of ribonucleotides in genomic DNA. The ensuing chronic low level of DNA damage triggered a DNA damage response characterized by constitutive p53 phosphorylation and senescence. Patient fibroblasts exhibited constitutive upregulation of IFN-stimulated genes and an enhanced type I IFN response to the immunostimulatory nucleic acid polyinosinic:polycytidylic acid and UV light irradiation, linking RNase H2 deficiency to potentiation of innate immune signaling. Moreover, UV-induced cyclobutane pyrimidine dimer formation was markedly enhanced in ribonucleotide-containing DNA, providing a mechanism for photosensitivity in RNase H2–associated SLE. Collectively, our findings implicate RNase H2 in the pathogenesis of SLE and suggest a role of DNA damage–associated pathways in the initiation of autoimmunity.
PMCID: PMC4382239  PMID: 25500883
19.  Impact of treatment modality and number of lesions on recurrence and survival outcomes after treatment of colorectal cancer liver metastases 
Ablative strategies have been used to treat and facilitate hepatic resection (HR) in patients with otherwise unresectable colorectal liver metastases (CLM). We evaluated the efficacy of HR, concomitant HR and ablation and isolated ablation on recurrence and survival outcomes after treatment of CLM in patients with 1-4 and ≥5 lesions, respectively.
A retrospective review of a prospectively collected hepatobiliary surgery database was performed on patients who underwent treatment for isolated CLM between 1990 and 2010. Pre-operative and treatment characteristics were compared between patients who underwent HR, concomitant HR and ablation and ablation alone. The impact of treatment modality on survival and recurrence outcomes was determined.
A total of 701 patients met inclusion criteria; 550 patients (78%) had 1-4 lesions and 151 patients (22%) had ≥5 lesions. Overall median survival for the entire cohort was 35 months with 5- and 10-year survival of 33% and 20%, respectively. Overall median and 5-year recurrence-free survival (RFS) was 13 months and 21%, respectively. For patients with 1-4 lesions, median survival was 37 months with 5-year survival of 36%. Stratified by procedure type, 5-year survival was 41% in patients who underwent HR, 35% in patients who underwent concomitant HR and ablation and 13% in patients who underwent ablation alone (P<0.001). For patients with ≥5 lesions, median survival was 28 months with 5-year survival of 23% without difference between treatment groups (P=0.078).
HR appears to be the most effective strategy for patients with 1-4 lesions. When ≥5 lesions are present, ablative strategies are useful in facilitating HR in otherwise unresectable patients.
PMCID: PMC3904025  PMID: 24490042
Colorectal cancer; hepatectomy; liver metastases; resection; survival; ablation
20.  Albumin nanoparticles increase the anticancer efficacy of albendazole in ovarian cancer xenograft model 
The poor prognosis of patients with drug resistant ovarian cancer and the lack of targeted therapy have raised the need for alternative treatments. Albendazole (ABZ) is an anti-parasite compound capable of impairing microtubule formation. We hypothesized that ABZ could be repurposed as a potential anti-angiogenic drug due to its potent inhibition of vascular endothelial growth factor (VEGF) in ovarian cancer with ascites. However, the poor aqueous solubility of ABZ limits its potential for cancer therapy. In this study, we have assembled ABZ with bovine serum albumin into nanoparticles with a size range of 7–10 nm (BSA-ABZ) and 200–250 nm (Nab-ABZ). We further examined the anticancer effects of ABZ carrying nanoparticles in ovarian cancer cells, in both in vitro and in vivo models.
Drug release studies demonstrated that about 93% of ABZ was released from BSA-ABZ 10 nm in comparison to 83% from Nab-ABZ 200 nm at pH 7.4 in 8 days. In vitro cell proliferation studies showed that the BSA-ABZ 10 nm exhibited the highest killing efficacy of ovarian cancer cells with surprisingly least toxicity to healthy ovarian epithelial cells. Confocal microscopy and fluorescence activated cell sorting analysis (FACS) revealed more efficient internalization of the BSA-ABZ 10 nm by cancer cells. For in vivo studies, we examined the tumor growth, ascites formation and the expression of VEGF and secreted protein acidic and rich in cysteine (SPARC) in tumor samples and only VEGF in plasma samples. The BSA-ABZ 10 nm reduced the tumor burden significantly (p < 0.02) at a much lower drug dose (10 μg/ml) compare to free drug. Both formulations were capable of suppressing the ascites volume significantly (p < 0.05) and reducing the number of ascites cells. The expression of VEGF and SPARC was also reduced, which indicates the underlying therapeutic mechanism of the ABZ.
Our data suggest that the BSA-ABZ may hold promise for the treatment and control of progression of ovarian cancer with ascites. However further studies are required to examine the efficacy of both the formulations in aggressive models of recurrent ovarian cancer with respect to particle size and dosing parameters.
Electronic supplementary material
The online version of this article (doi:10.1186/s12951-015-0082-8) contains supplementary material, which is available to authorized users.
PMCID: PMC4409778  PMID: 25890381
Angiogenesis; Albendazole; BSA-ABZ 10 nm; Nab-ABZ 200 nm; VEGF; Ascites; Ovarian cancer
21.  Leukotriene B4-mediated sterile inflammation favors susceptibility to sepsis in murine type 1 diabetes 
Science signaling  2015;8(361):ra10.
The chronic systemic inflammation in type I diabetes mellitus (T1DM), which is driven by signaling through the interleukin-1 (IL-1) 1 receptor (IL1R) and the adaptor protein myeloid differentiation factor 88 (MyD88), may be associated with the enhanced susceptibility of diabetics to systemic bacterial infection (sepsis). We hypothesized that low insulin concentrations trigger the enzyme 5-lipoxygenase (5-LO) to produce the lipid mediator leukotriene B4 (LTB4), serving as a trigger of systemic inflammation and increased susceptibility to polymicrobial sepsis in T1DM. In support of this hypothesis, we found that the abundance of MyD88 and its direct transcriptional regulator, STAT-1 were higher in peritoneal macrophages from two mouse models of T1DM compared to nondiabetic mice. Expression of Alox5, synthesis of LTB4, and concentrations of the proinflammatory cytokine IL-1β were also increased in peritoneal macrophages and serum from T1DM mice. Insulin treatment restored LTB4 concentrations and Myd88 and Stat1 expression in T1DM mice. T1DM mice lacking Alox5 or treated with a 5-LO inhibitor showed reduced Myd88 and Il1b mRNA expression and increased IL-1 receptor antagonist concentration. The transcription factor cJun drove LTB4-dependent transcription of Stat1 in macrophages from T1DM mice. Compared to wild-type or untreated diabetic mice, T1DM mice lacking 5-LO or treated with a 5-LO inhibitor survived polymicrobial sepsis and showed reduced production of proinflammatory cytokines and decreased bacterial counts, suggesting that high LTB4 concentrations contribute to enhanced susceptibility to sepsis in T1DM. These results uncover a role for LTB4 in promoting sterile inflammation in diabetes and enhanced susceptibility to sepsis in T1DM.
PMCID: PMC4356178  PMID: 25628460
eicosanoid; SIRS; sepsis; diabetes; leukotriene; 5-LO inhibitor; translational
22.  Heat Sink Effect on Tumor Ablation Characteristics as Observed in Monopolar Radiofrequency, Bipolar Radiofrequency, and Microwave, Using Ex Vivo Calf Liver Model 
Medicine  2015;94(9):e580.
Thermal ablation of liver tumors near large blood vessels is affected by the cooling effect of blood flow, leading to incomplete ablation. Hence, we conducted a comparative investigation of heat sink effect in monopolar (MP) and bipolar (BP) radiofrequency ablation (RFA), and microwave (MW) ablation devices.
With a perfused calf liver, the ablative performances (volume, mass, density, dimensions), with and without heat sink, were measured. Heat sink was present when the ablative tip of the probes were 8.0 mm close to a major hepatic vein and absent when >30 mm away. Temperatures (T1 and T2) on either side of the hepatic vein near the tip of the probes, heating probe temperature (T3), outlet perfusate temperature (T4), and ablation time were monitored.
With or without heat sink, BP radiofrequency ablated a larger volume and mass, compared with MP RFA or MW ablation, with latter device producing the highest density of tissue ablated. MW ablation produced an ellipsoidal shape while radiofrequency devices produced spheres.
Percentage heat sink effect in Bipolar radiofrequency : Mono-polar radiofrequency : Microwave was (Volume) 33:41:22; (mass) 23:56:34; (density) 9.0:26:18; and (relative elipscity) 5.8:12.9:1.3, indicating that BP and MW devices were less affected.
Percentage heat sink effect on time (minutes) to reach maximum temperature (W) = 13.28:9.2:29.8; time at maximum temperature (X) is 87:66:16.66; temperature difference (Y) between the thermal probes (T3) and the temperature (T1 + T2)/2 on either side of the hepatic vessel was 100:87:20; and temperature difference between the (T1 + T2)/2 and temperature of outlet circulating solution (T4), Z was 20.33:30.23:37.5.
MW and BP radiofrequencies were less affected by heat sink while MP RFA was the most affected. With a single ablation, BP radiofrequency ablated a larger volume and mass regardless of heat sink.
PMCID: PMC4553952  PMID: 25738477
23.  Human Sprouty1 Suppresses Urokinase Receptor-Stimulated Cell Migration and Invasion 
ISRN biochemistry  2013;2013:598251.
The urokinase-type plasminogen activator receptor (uPAR) has been implicated in several processes in tumor progression including cell migration and invasion in addition to initiation of signal transduction. Since uPAR lacks a transmembrane domain, it uses the interaction with other proteins to modulate intracellular signal transduction. We have previously identified hSpry1 as a partner protein of uPAR, suggesting a physiological role for hSpry1 in the regulation of uPAR signal transduction. In this study, hSpry1 was found to colocalize with uPAR upon stimulation with epidermal growth factor (EGF), urokinase (uPA), or its amino terminal fragment (uPA-ATF), implicating a physiological role of hSpry1 in regulation of uPAR signalling pathway. Moreover, hSpry1 was able to inhibit uPAR-stimulated cell migration in HEK293/uPAR, breast carcinoma, and colorectal carcinoma cells. In addition, hSpry1 was found to inhibit uPAR-stimulated cell invasion in breast carcinoma and osteosarcoma cell lines. Increasing our understanding of how hSpry1 negatively regulates uPAR-stimulated cellular functions may determine a distinctive role for hSpry1 in tumour suppression.
PMCID: PMC4393002  PMID: 25937961
24.  Peritonectomy HIPEC—contemporary results, indications 
PMCID: PMC3752351  PMID: 23997522
25.  An MHC Class II Dependent Activation Loop Between Adipose Tissue Macrophages and CD4+ T cells Controls Obesity-Induced Inflammation 
Cell reports  2014;9(2):605-617.
An adaptive immune response triggered by obesity is characterized by the activation of adipose tissue CD4+ T cells by unclear mechanisms. We have examined if interactions between adipose tissue macrophages (ATMs) and CD4+ T cells contribute to adipose tissue metainflammation. Intravital microscopy identifies dynamic antigen dependent interactions between ATMs and T cells in visceral fat. Mice deficient in major histocompatibility complex class II (MHCII) showed protection from diet-induced obesity. Deletion of MHCII expression in macrophages led to an adipose tissue specific decrease in the effector/memory CD4+ T cells, attenuation of CD11c+ ATM accumulation, and improvement in glucose intolerance by increasing adipose tissue insulin sensitivity. Ablation experiments demonstrated that the maintenance of proliferating conventional T cells is dependent on signals from CD11c+ ATMs in obese mice. These studies demonstrate the importance of MHC Class II restricted signals from ATMs that regulate adipose tissue T cell maturation and metainflammation.
PMCID: PMC4252867  PMID: 25310975

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