tbuckley/cabot-search huggingface dataset:
OC-107 Morphometric analysis of fibrosis and inflammatory activity in recurrent HCV infection post liver transplantation
Authors: S M Noory, R Hajhosseiny, G Noory, D Joshi, A Quaglia
Journal: Gut (2012)

<h3>Introduction</h3> Hepatitis C virus (HCV) recurrence post liver transplantation (LT) is universal. Ishak score (IS) is widely used in the histological assessment of recurrent HCV. Smooth muscle actin (SMA) expression is a marker of hepatic stellate cells (HSC), while Sirius red (SR) staining primarily identifies tissue collagen. We have investigated how morphometric analysis of stellate cell activation, fibrosis and inflammatory activity can contribute to this assessment. <h3>Methods</h3> 78 liver biopsies taken between 6 and 3722 (median 688) days post-transplant were reviewed. Sections from formalin-fixed and paraffin embedded post-tranplant liver biopsy specimens were stained with SR, for SMA and CD3 (T lymphocytes). The SR and SMA stained section were digitalised using the scanning function of a Leica DM6000. We used Image J (Version 1.42q) software and Photoshop CS5 software package for specimen analysis. SR and SMA staining proportionate area were calculated according to Calvaruso <i>et al.</i><sup>1</sup> A cell count of lobular CD3+ve lymphocytes was carried out using a microscope grid. Semi quantitative scoring was also carried out using the Ishak scoring system. Liver collagen was expressed as collagen proportionate area (CPA). <h3>Results</h3> SR CPA, SMA CPA and CD3 count ranged from 0.26% to 29.63% (mean=6.28%), 0.00018–35.62% (mean=4.89%) and 1–63 (median=13) respectively. Mean SMA CPA and mean SR CPA for each IS category were as follows: IS 0=2.34% (0.25–5.37%), IS 1=3.29% (0–13.33%), IS 2=4.44% (0–11.56%), IS 3=6.64% (1.49–13.93%), IS 4=6.37% (6.02–6.83%), IS 5=7.92% (3.21–14.16%), IS 6=28.96% (22.30–35.62%) and IS 0=3.68% (0.59–5.83%), IS 1=4.67% (1.35–19.46%), IS 2=4.43% (0.61–10.00%), IS 3=8.65% (1.20–17.85%), IS 4=6.77% (5.10–8.43%), IS 5=9.79% (0.26–29.63%), IS 6=11.91% (1.60–22.22%) respectively. IS correlated with SMA CPA (r=0.62, p&lt;0.0001) but not SR CPA (r=0.226, p=0.104). CD3 count also correlated with serum AST (r=0.437, p=0.004). <h3>Conclusion</h3> Digitalisation, image analysis and immunohistochemistry for SMA and CD3+ve lymphocytes contribute to the assessment of inflammatory activity and fibrosis in post-liver transplant recurrent HCV infection. <h3>Competing interests</h3> None declared. <h3>Reference</h3> 1. <b>Calvaruso</b>, <i>et al. Hepatology</i> 2009;<b>49</b>:1236–44.
Abstract 1613: BTK as a drug target for cancers that harbor inactivating mutations in the DPC4 gene
Authors: Caroline H. Diep, Michelle Kassner, Yu Zhao, Holly Yin, Daniel D. Von Hoff, Haiyong Han
Journal: Cancer Research (2010)

Abstract The Deleted in Pancreatic Cancer locus 4 (DPC4) is a tumor suppressor gene that is often inactivated in pancreatic and colorectal cancers. In pancreatic adenocarcinomas, the frequency of inactivation of DPC4 is approximately 55%, while in colorectal carcinomas has been reported to be 10% to 35%. The loss of DPC4 has been shown to be associated with the progression and malignancy of pancreatic cancer along with decreased patient survival. We employed a small interfering (siRNA) library based screening strategy to identify potential synthetic lethal partners of the DPC4 gene. We used a kinase focused siRNA library that consisted of two siRNA oligonucleotides for each of the 624 protein kinase genes. A DPC4 isogenic pair, BxPC3-Vector and BxPC3-DPC4 (Wang et al. 2006) were treated by the siRNA oligonucleotides in parallel and the effects of the siRNA oligonucleotides on the growth of the cell lines were then compared. siRNA oligonucleotides that selectively inhibited the cell growth of the BxPC3-Vector cell line were selected as potential positive hits. These genes, once validated, represented potential drug targets that are very specific to cancer cells harboring mutations in the DPC4 gene. One of the top-ranked hits we identified from this screening is the Bruton agammaglobulinemia tyrosine kinase (BTK). With BTK siRNA treatment, BxPC3-Vector cells, which are DPC4 null, showed ∼30% more cell growth inhibition than the BxPC3-DPC4 cells, which are DPC4 wildtype. This selectivity of BTK siRNA against DPC4 null cells was further confirmed in a confirmation screen using two pancreatic cancer cell lines, BxPC3 and PANC-1, which are DPC4 null and DPC4 wildtype, respectively. BTK siRNA also showed significant selectivity against DPC4 deficiency in another pair of DPC4 isogenic colon cancer cell lines, HCT-116 and HCT-116-DPC4-knockout. To validate the BTK siRNA selectivity findings, we evaluated the BTK inhibitor PCI-32765 in our cancer cell line models and observed the same selectively against DPC4 null pancreatic and colon cancer cell lines. These results indicate that BTK is a potential molecular target for pancreas, colon, and other cancers harboring inactivating mutations in the DPC4 gene. (The work was supported by a NCI grant P01CA109552.) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1613.
P229 HCV GENOTYPE 2 AND 1 INTER-GENOTYPE RECOMBINATION VARIANTS ACCOUNT FOR DISCORDANCE BETWEEN LIPA-BASED HCV GENOTYPING AND NS5B SEQUENCING
Authors: C. Hedsko, B. Doehle, K. Chodavarapu, V. Gontcharova, D. Brainard, W.T. Symonds, M.D. Miller, E. Svarovskaia, H. Mo
Journal: Journal of Hepatology (2014)
Risk and revisionism in arsenic cancer risk assessment.
Authors: P Mushak, A F Crocetti
Journal: Environmental Health Perspectives (1995)

Oral exposures of nonoccupational populations to environmental inorganic arsenic are associated with skin and internal cancers as well as various noncarcinogenic effects. Cancer risk assessments have been based largely on epidemiological studies of a large population exposed to inorganic arsenic in well water in Taiwan. Criticisms and skepticism of the use of the Taiwanese data for estimating arsenic cancer risks outside of Taiwan, including potential use by the U.S. Environmental Protection Agency for regulatory purposes, have been expressed on various grounds. The nature and extent of such criticisms have sharpened with recent findings in the exposed Taiwanese of increased incidence of internal cancers (bladder, kidney, liver, and lung), in addition to already-observed skin cancer, coupled with a good likelihood that these findings will produce more stringent arsenic regulation in the United States and elsewhere. These criticisms collectively posit a revisionist view that: 1) cancer incidence among the Taiwanese was amplified by a number of host and environmental factors not applicable elsewhere, 2) the cancer dose-response curve may not be linear at the lower exposures elsewhere, and 3) there is a toxicokinetic and metabolic threshold to cancer risk that was exceeded by the Taiwanese. However, a number of the arguments against wide use of the Taiwanese data are flawed and subject to challenge. We explore some of these arguments and their critical evaluation, particularly as they concern certain exposure, metabolic, and nutritional determinants of the cancer risk of inorganic arsenic in the Taiwanese.
Phase II study of liposomal doxorubicin (Myocet®), docetaxel and trastuzumab combination as first line treatment of patients with her-2/neu positive locally advanced or metastatic breast cancer.
Authors: D Amadori, G Gasparini, A Ardizzoni, G Comella, S Saracchini, C Barone, R Bordonaro, K Djazouli, A Barbato
Journal: Cancer Research (2009)

Abstract Abstract #3149 Objective: the aims of the study are to assess activity and safety of liposomal doxorubicin (Myocet®) in combination with Docetaxel and Trastuzumab as first-line treatment of patients with HER-2/neu positive MBC.&amp;#x2028; Methods: forty-six (46) non treated patients with metastatic HER2-overexpressing BC were planned to receive Myocet 50 mg/m2 (d1) and Docetaxel 30 mg/m2 (d2 and d9) plus Trastuzumab (d2, 4 mg/kg followed by 2 mg/kg weekly) for at least 6 cycles (up to a maximum of 8 unless occurrence of unacceptable toxicity or PD). Cycles were repeated every 21 days. Objective response was assessed according to WHO criteria every 3 cycles. To evaluate the tolerability WHO grading toxicity events were assessed at each cycle. Cardiotoxicity was defined as signs and/or symptoms of CHF and/or a decrease in LVEF below normal limit (&amp;lt; 50%) or a decline ≥ 15% from baseline value. To evaluate LVEF an echocardiography was done at baseline and at cycles 3, 6 and 8.&amp;#x2028; Results: we reported preliminary results of 46 patients enrolled. 41 patients completed at least 3 cycles and at first response evaluation Complete Response was seen in 2 pts (CR=4,9%), Partial Response in 22 pts (PR=53,7%), Stable Disease in 15 pts (SD=36,6%) and Progression Disease in 2 pts (PD=4,9%). The Overall Response Rate (ORR) was 58,6%.&amp;#x2028; 36 pts completed the planned chemotherapy (6 cycles): Complete Response was seen in 4 pts (CR=11,1%), Partial Response in 15 pts (PR=41,7%), Stable Disease in 9 (SD=25,0%) and Progression Disease in 8 pts (PD=22,2%). The Overall Response Rate (ORR) was 52,8%. 12 pts were entered in the follow up and for this subgroup median TTP was 13 months.&amp;#x2028; All 46 enrolled patients were included in the safety analysis. Most frequent toxicity events occurred during the study were: granulocytopenia Grade 4 in 16 pts (30.4%), leukocytopenia Grade 3 in 15 pts (32.6%), increase of transaminase levels Grade 1 in 14 pts (30.4%), alopecia Grade 4 in 16 pts (34.8%) and nausea Grade 2 in 13 pts (28.3%). In 2 patients LVEF dropped &amp;lt; 50% and other 2 pts registered a decrease of LVEF &amp;gt;15% with respect to baseline value. In the whole population LVEF mean value changed from 62.6 ± 4.9 at baseline to 61.0 ± 5.5 at cycle 3, to 62.9 ± 6.4 (cycle 6) and to 60.0 ± 8.1 (cycle 8).&amp;#x2028; Conclusion: these preliminary results suggest that the combination of non-pegylated liposomal doxorubicin, docetaxel and trastuzumab has shown a promising activity in first line MBC. The combination is safe with no significant change in LVEF values from baseline to the end of therapy. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3149.
FRI0031 Tyrosine kinase induced fibrosis: implications for systemic sclerosis
Authors: S. O’reilly, J. Van Laar
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Systemic Sclerosis (SSc) is an autoimmune disease characterised by autoimmunity, inflammation, vascular abnormalities and fibrosis. There is a clear link between inflammation and fibrosis however, the mediators and the downstream signalling pathways remain to be elucidated. IL-6 is a pro-fibrotic molecule elevated in SSc serum and is also elevated in the affected tissues. The molecule can signal through both classic signalling and also ‘trans-signalling’ to initiate a signaling cascade that results in activation of pro-fibrotic genes. Upstream of these genes after ligand binding is the inital event of janus kinase activation. The janus kinases are non-receptor tyrosine kinases that activate STATs resulting in target gene expression. JAK2 has previously been implicated in fibrosis and in particular SSc. Ruxolitinib is a tyrosine kinase inhibitor approved for the treatment of myleofibrosis. <h3>Objectives</h3> The aim of this study was to determine the effects of JAK2 inhibition on collagen production after ligand stimulation using Ruxolitinib. <h3>Methods</h3> Primary human dermal fibroblasts were cultured in vitro to confluence and then treated with the cytokines IL-6 and sIL-R either alone or in combination, plus cultures were also treated with a JAK2 pharmacological inhibitor for 24 hours. After 24 hours cells were harvested RNA ioslated and RT performed. Q-RT-PCR was performed with primers specific for collagen 1A1 gene and then normalised to endogenous housekeeper 18s and compared to untreated cultures. 18s was found to be consistent among treatment groups. In other experiments IL-13 at various concentrations was added to the dermal fibroblast cultures and q-RT-PCR was performed. <h3>Results</h3> Dermal fibroblasts upregulated collagen1A1 transcripts in response to IL-6 and sIL-6R but not either alone, suggesting the primary mechanism was trans signalling. This IL-6-induction collagen transcription cold be abrogated by the pharmacological agent Ruxolitinib. IL-13 also induced collagen expression in dermal fibroblasts and this, to a lesser degree, could also be inhibited by ruxolitinib pre-treatment. <h3>Conclusions</h3> IL-6 trans signalling-stimulated collagen production is mediated by JAKs and selective blockade of JAK2 also reduced the pro-fibrotic molecule IL-13s collagen-inducing effect. Blokade of JAK2 maybe a new therapeutic target in SSc. <h3>Acknowledgements</h3> JGW Patterson. <h3>Disclosure of Interest</h3> None Declared
FRI0113 Coronary athero-protection against high-risk mixed plaque (MP) independently of good disease response in coronary artery disease (CAD)-naÏve patients with rheumatoid arthritis receiving tumor necrosis factor-a (TNFA) inhibitors:
Authors: G.A. Karpouzas, J. Malpeso, T.-Y. Choi, D. Li, S. Munoz, M. Budoff
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> TNFa is a pivotal cytokine in the pathophysiology and progression of both RA and atherosclerosis. Addition of TNFa inhibitors (TNFi) to disease modifying agents (DMARDs) superiorly controls clinical inflammation and radiographic progression in RA. Non-invasive, accurate evaluation of coronary plaque is feasible with computed tomography angiography (CTA); it reliably defines plaque presence, burden, severity and composition as non-calcified (NCP), mixed (MP), or densely calcified (CP). Importantly, MP presence has been correlated with higher risk of future clinical events. <h3>Objectives</h3> To evaluate whether TNFi therapy is associated with lower plaque prevalence, burden, or different plaque composition compared to DMARD-treated patients, and whether good RA response is required for the tentative benefit. <h3>Methods</h3> One hundred and fifty CAD-naïve subjects with RA, 60 on DMARDs alone and 90 on TNFi, underwent CTA. A standard 15-segment American Heart Association (AHA) model was used for plaque evaluation. Involved segments, stenosis severity score (sum of stenosis score of each segment, averaged over all 15 segments/patient) and plaque burden score (sum of the plaque amount per each segment averaged over all 15 segments/patient) were evaluated. Disease activity score (DAS28-3v-CRP) less than 3.2 defined good disease control. Non parametric and Fisher's exact tests compared continuous and categorical variables respectively among groups. <h3>Results</h3> Good responders (R) to either therapy displayed differences in proportions of involved segments, stenosis severity, and plaque burden scores, especially for MP and CP compared to non-responders (NR- table 1). Good responders had similar proportions of involved segments, and quantitative plaque measures for MP and CP regardless of type of therapy. However, TNFi-NR, had significantly lower prevalence of segments involved with MP (p=0.01), lower adjusted stenosis severity (p=0.01) and burden scores (p=0.05) for MP compared to DMARD-NR. Additionally, TNFi-NR, had higher prevalence, stenosis scores (p=0.05), and burden scores (p=0.05) for the lower risk CP. <h3>Conclusions</h3> Treatment with TNFi may have a quantitative atheroprotective effect, particularly against high risk MP, independent of good clinical RA response. <h3>Disclosure of Interest</h3> None Declared
Azygoesophageal fistula successfully treated with endoscopic injection of N-butyl-2-cyanoacrylate
Authors: T.-Y. Shieh, C.-C. Lin, F.-S. Yang, W.-H. Chang, M.-J. Chen
Journal: Endoscopy (2011)

A bedridden 72-year-old man presented with massive hematemesis; esophagogastroduodenoscopy (EGD) at a local clinic revealed esophageal ulcer bleeding. After injection of diluted epinephrine, he was transferred to our hospital and admitted to the intensive care unit for hypovolemic shock (blood pressure, 82/47 mmHg; hemoglobin, 6.9 g/dL).
Abstract SY27-01: Cutting both ways: Why FADD, FLIP, and Caspase-8 are required for embryonic development
Authors: Douglas R. Green
Journal: Cancer Research (2012)

Abstract Caspase-8 has two opposing biological functions - it promotes cell death by triggering the extrinsic pathway of apoptosis, but also has a survival activity, as it is required for embryonic development, T lymphocyte activation, and resistance to necrosis induced by Tumor Necrosis Factor-α (TNF) and related family ligands. We found that development of caspase-8-deficient mice is completely rescued by ablation of Receptor Interacting Protein Kinase-3 (RIPK3). Adult animals lacking both caspase-8 and RIPK3 display a progressive lymphoaccumulative disease resembling that seen with defects in CD95 or CD95-ligand, and resist the lethal effects of CD95 ligation in vivo. We have found that caspase-8 prevents RIPK3-dependent necrosis without inducing apoptosis by functioning in a proteolytically active complex with FLICE-Like Inhibitory Protein Long (FLIPL), and this complex is required for the protective function. Caspase-8 homodimers and caspase-8-FLIP heterodimers are activated on the oligomerized adapter molecule, FADD. Therefore, while the FADD-caspase-8-FLIP complex protects against RIPK3-dependent necrosis, the FADD-caspase-8 complex does not, and necrosis ensues. In the absence of RIPK3, FADD-caspase-8 instead induces apoptosis. This idea has several ramifications. Knock-outs of FADD, or FLIP show identical embryonic lethality, but while the FADD KO is fully rescued by ablation of RIPK3, the FLIP KO is not. Our in vitro studies suggest that in the FLIP, RIPK3 DKO mouse, sensitive cell populations die by apoptosis rather than necrosis. Indeed, we found that unlike caspase-8 or FADD KO embryos, FLIP RIPK3 DKO embryos at e9.5 show focal regions of apoptosis. Another prediction from the in vitro studies is even more striking_that lethality in the FLIP RIPK3 DKO mouse should be rescued by ablation of FADD. We have now generated the FADD FLIP RIPK3 TKO mouse, and these animals are developmentally normal. In addition to providing strong genetic evidence for a model of FADD-caspase-8-FLIP interaction with RIPK1-RIPK3, these studies involve an effect that has not been previously seen to our knowledge_two lethal genotypes (one KO, one DKO) when combined into a TKO, result in normal development. We think that's pretty cool. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr SY27-01. doi:1538-7445.AM2012-SY27-01
Abstract 3263: Expression of Bim, Noxa, and Puma in non-small cell lung cancer
Authors: Jun Sakakibara-Konishi, Satoshi Oizumi, Junko Kikuchi, Eiki Kikuchi, Hidenori Mizugaki, Ichiro Kinoshita, Hirotoshi Dosaka-Akita, Masaharu Nishimura
Journal: Cancer Research (2012)

Abstract Background: The BH3-only members of the Bcl-2 protein family have been proposed to play a key role in the control of apoptosis and in the initiation of the apoptotic pathways. In this study, we evaluated the expression of Bim, Noxa, and Puma in non-small cell lung cancer (NSCLC). Methods: A total of 135 surgically resected NSCLCs were immunohistochemically assessed for Bim, Noxa, and Puma expression. The immunoscores were determined, and then its correlation with either the clinicopathological variables or the survival outcomes were analyzed. Results: Immunohistochemical reactivity for Bim, Noxa, and Puma was detected in the cytoplasm of the tumor cells. Bim expression was associated with several clinicopathological factors, including sex (p&amp;lt;0.001), smoking habit (p=0.03), pathological histology (p=0.001), pathological T stage (p=0.03), pathological disease stage (p=0.02), and differentiation of tumor (p&amp;lt;0.001). Multivariate logistic regression analysis showed a significant correlation between low Bim expression and squamous cell carcinoma (p=0.04), in addition to a correlation between high Bim expression and well differentiated tumors (p=0.02). Analysis of cellular biological expression demonstrated a link between low Bim expression and high Ki67. While Noxa expression was also shown to be correlated with both smoking habit (p=0.02) and the pathological histology (p=0.03), there was no strong association observed between the expression and the clinical features when they were examined by a multivariate logistic regression analysis. No correlations were noted between Puma expression and any of the variables. Our analyses also indicated that the expression levels of the BH3-only proteins were not pertinent to the survival outcome. Conclusions: The current analyses demonstrated that Bim expression in the NSCLCs was associated with both squamous cell carcinoma histology and tumor proliferation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3263. doi:1538-7445.AM2012-3263