tbuckley/cabot-search huggingface dataset:
Epithelial NEMO/IKKγ limits fibrosis and promotes regeneration during pancreatitis
Authors: Lap Kwan Chan, Melanie Gerstenlauer, Björn Konukiewitz, Katja Steiger, Wilko Weichert, Thomas Wirth, Harald Jakob Maier
Journal: Gut (2016)

Inhibitory κB kinase (IKK)/nuclear factor κB (NF-κB) signalling has been implicated in the pathogenesis of pancreatitis, but its precise function has remained controversial. Here, we analyse the contribution of IKK/NF-κB signalling in epithelial cells to the pathogenesis of pancreatitis by targeting the IKK subunit NF-κB essential modulator (NEMO) (IKKγ), which is essential for canonical NF-κB activation.Mice with a targeted deletion of NEMO in the pancreas were subjected to caerulein pancreatitis. Pancreata were examined at several time points and analysed for inflammation, fibrosis, cell death, cell proliferation, as well as cellular differentiation. Human samples were used to corroborate findings established in mice.In acute pancreatitis, NEMO deletion in the pancreatic parenchyma resulted in minor changes during the early phase but led to the persistence of inflammatory and fibrotic foci in the recovery phase. In chronic pancreatitis, NEMO deletion aggravated inflammation and fibrosis, inhibited compensatory acinar cell proliferation, and enhanced acinar atrophy and acinar-ductal metaplasia. Gene expression analysis revealed sustained activation of profibrogenic genes and the CXCL12/CXCR4 axis in the absence of epithelial NEMO. In human chronic pancreatitis samples, the CXCL12/CXCR4 axis was activated as well, with CXCR4 expression correlating with the degree of fibrosis. The aggravating effects of NEMO deletion were attenuated by the administration of the CXCR4 antagonist AMD3100.Our results suggest that NEMO in epithelial cells exerts a protective effect during pancreatitis by limiting inflammation and fibrosis and improving acinar cell regeneration. The CXCL12/CXCR4 axis is an important mediator of that effect and may also be of importance in human chronic pancreatitis.
Abstract LB-339: Mutation analysis of cell-free DNA captures heterogeneity of individual circulating tumor cells in metastatic breast cancer
Authors: David S. Guttery, Jacqueline A. Shaw, Allison Hills, Daniel Fernandez-Garcia, Karen Page, Brenda Rosales, Kate Goddard, Robert Hastings, Jinli Luo, Olivia Ogle, Laura Woodley, Simak Ali, Justin Stebbing, Charles Coombes
Journal: Cancer Research (2016)

Abstract Circulating tumor cells (CTCs) are more technically challenging to isolate and characterize than circulating cell-free DNA (cfDNA). However, analysis of single CTCs may reveal more actionable information to guide targeted therapies than mutation tracking in cfDNA. Here, we compared CTC count with cfDNA levels in 113 patients with metastatic breast cancer. In 5 patients we compared mutations in 40 individual CTCs and matched cfDNA using targeted amplicon sequencing of 54 genes (∼2800 COSMIC mutations) at &amp;gt;2500x mean read depth. Total cfDNA levels were significantly associated with overall survival (hazard ratio (HR), 2.2; 95% CI, 1.1 to 4.3; P = 0.021) and correlated with CTC counts (P = 0.002). Four patients had mutations detected in cfDNA, the levels of which tracked with levels of circulating tumor DNA (ctDNA). Mutational heterogeneity was seen across individual CTCs (including mutations in PIK3CA, ESR1 and KRAS) and was reflected in matched cfDNA, but cfDNA had other mutations not seen in CTCs (including TP53). Therefore, cfDNA reflects persisting CTCs and enables monitoring of the metastatic burden for clinical decision-making when CTCs cannot be obtained. Moreover, monitoring of total cfDNA levels could provide an inexpensive and simple measure of treatment response. Citation Format: David S. Guttery, Jacqueline A. Shaw, Allison Hills, Daniel Fernandez-Garcia, Karen Page, Brenda Rosales, Kate Goddard, Robert Hastings, Jinli Luo, Olivia Ogle, Laura Woodley, Simak Ali, Justin Stebbing, Charles Coombes. Mutation analysis of cell-free DNA captures heterogeneity of individual circulating tumor cells in metastatic breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-339.
Abstract 234: Mitochondrial morphology as a biomarker of cancer phenotype and drug response
Authors: Randy J. Giedt, Paolo Fumene Fergulio, Divya Pathania, Katherine S. Yang, Aoife Kilcoyne, Claudio Vinegoni, Tim J. Mitchison, Ralph Weissleder
Journal: Cancer Research (2016)

Abstract Mitochondria, critical organelles in quiescent and dividing cells, have been shown to vary in number, mass, and shape. While previous work has focused on understanding molecular mechanisms underlying changes in normal and immortalized cells, less is known about longer-term mitochondrial behavior such as morphological patterns in individual cells and overall populations, the heterogeneity and functional consequences of these patterns, and ultimately how potential mitochondrial heterogeneity can be exploited in the clinic. Indeed, while previous studies have been conducted illustrating mitochondrial dysfunction and morphological alterations in certain tumor types, more comprehensive analyses across tumor and cell types, as well as from cells derived from individual patients, have yet to be conducted. A primary impediment to this work is the technical challenge of consistently assaying mitochondrial morphology in diverse cell types where fixation procedures, collection techniques, and differing optical qualities between samples make potential analyses a challenging application. We have developed an image based analytical technique to phenotype mitochondrial morphology in different cancers, including in vitro cancer cell lines and patient derived cancer cells. Our methodology is based on a combination of novel, clinically relevant collection and fixation techniques, and advanced image processing and computer learning analysis methodologies. Our results demonstrate that i) cancer cells of different origins, including patient-derived xenografts, express highly diverse mitochondrial phenotypes; ii) a given phenotype is characteristic of a cell population and fairly constant over time; iii) mitochondrial patterns correlate with cell metabolomics measurements and iv) therapeutic interventions can alter mitochondrial phenotypes in drug-sensitive cancers as measured in pre- versus post-treatment fine needle aspirates in mice. These observations shed light on the role of mitochondrial dynamics in the biology and drug response of cancer cells. Citation Format: Randy J. Giedt, Paolo Fumene Fergulio, Divya Pathania, Katherine S. Yang, Aoife Kilcoyne, Claudio Vinegoni, Tim J. Mitchison, Ralph Weissleder. Mitochondrial morphology as a biomarker of cancer phenotype and drug response. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 234.
Nonalcoholic fatty liver disease, cardiovascular outcomes, and mortality in patients undergoing a coronary angiogram
Authors: Giovanni Targher, Christopher D. Byrne
Journal: Hepatology (2015)

Potential conflict of interest: Nothing to report. To the Editor: We read with interest the prospective study by Wong et al.,1 who analyzed the impact of nonalcoholic fatty liver disease (NAFLD) as diagnosed by ultrasonography on cardiovascular outcomes and mortality in a cohort of 612 adult patients with clinical indications for a coronary angiogram. This study included the same cohort of patients reported by the authors in 2011,2 but the follow‐up period was longer (approximately 5 years versus 2 years). Although the primary outcomes of the 2 studies are related but not identical (and, therefore, not easily compared), the results of the 2 studies differ with the longer follow‐up duration. In the shorter study,2 the presence of NAFLD was independently associated with a greater severity of coronary artery disease at the baseline, but NAFLD did not significantly predict cardiovascular mortality and morbidity among patients with established coronary artery disease (n = 465). In contrast, in the longer study,1 the presence of NAFLD was associated with a significantly lower risk of death from all causes and from cardiovascular diseases both in the whole cohort (n = 612) and in those with established coronary artery disease at the baseline (n = 465). It is important to note that the number of cardiovascular deaths was very small: 9 patients with NAFLD (2.5%) and 18 patients without NAFLD (7.0%).1 However, we think that there are plausible explanations for the authors' findings. First, the modality of cardiac interventions (percutaneous coronary intervention or coronary artery bypass) may have differentially influenced the number of cardiovascular deaths among patients with and without NAFLD (there was a strong trend toward more secondary coronary interventions for recurrent or ongoing myocardial ischemia in the NAFLD group: 15.2% versus 9.4% [adjusted hazard ratio, 1.54; 95% confidence interval, 0.95‐2.50; P = 0.079]). Second, changes in lipid‐lowering drugs or other potentially cardioprotective drugs during the follow‐up period (data not presented) would have remarkably modified the clinical outcomes of patients with NAFLD (most of whom had coronary artery disease of greater severity and a worse cardiovascular risk profile at the baseline). Although the authors report that their results did not change even after adjustments for the mode of cardiac interventions,1 it is extremely important to know whether there were temporal changes in the use and/or dosage of statins and other potentially cardioprotective drugs among these patients. These data might reconcile the apparent discrepancy between the findings of this study and those previously reported, which support a clear association between NAFLD and an increased risk of cardiovascular outcomes and mortality.3
Aging Promotes Sirtuin 3–Dependent Cartilage Superoxide Dismutase 2 Acetylation and Osteoarthritis
Authors: Yao Fu, Michael Kinter, Joanna Hudson, Kenneth M. Humphries, Rachel S. Lane, Jeremy R. White, Michael Hakim, Yong Pan, Eric Verdin, Timothy M. Griffin
Journal: Arthritis & Rheumatology (2016)

Objective To quantify functional age‐related changes in the cartilage antioxidant network in order to discover novel mediators of cartilage oxidative stress and osteoarthritis (OA) pathophysiology. Methods We evaluated histopathologic changes of knee OA in 10‐, 20‐, and 30‐month‐old male F344BN rats and analyzed cartilage oxidation according to the ratio of reduced to oxidized glutathione. Antioxidant gene expression and protein abundance were analyzed by quantitative reverse transcription–polymerase chain reaction and selected reaction–monitoring mass spectrometry, respectively. Superoxide dismutase 2 (SOD2) activity and acetylation were analyzed by colorimetric enzyme assays and Western blotting, respectively. We examined human OA cartilage to evaluate the clinical relevance of SOD2 acetylation, and we tested age‐related changes in the mitochondrial deacetylase sirtuin 3 (SIRT‐3) in rats and mice. Results Cartilage oxidation and OA severity in F344BN rats increased with age and were associated with an increase in SOD2 expression and protein abundance. However, SOD2‐specific activity decreased with age due to elevated posttranslational lysine acetylation. Consistent with these findings, SIRT‐3 levels decreased substantially with age, and treatment with SIRT‐3 increased SOD2 activity in an age‐dependent manner. SOD2 was also acetylated in human OA cartilage, and activity was increased with SIRT‐3 treatment. Moreover, in C57BL/6J mice, cartilage SIRT‐3 expression decreased with age, and whole‐body deletion of SIRT‐3 accelerated the development of knee OA. Conclusion Our results show that SIRT‐3 mediates age‐related changes in cartilage redox regulation and protects against early‐stage OA. These findings suggest that mitochondrial acetylation promotes OA and that restoration of SIRT‐3 in aging cartilage may improve cartilage resistance to oxidative stress by rescuing acetylation‐dependent inhibition of SOD2 activity.
Abstract 5157: Quantitative proteomic analysis identifying Krt17 plays a critical role in areca nut inducing oral carcinogenesis
Authors: Chang Hsu Chiang, Chih-Ching Wu, Ann-Joy Cheng
Journal: Cancer Research (2016)

Abstract Areca nut is known a carcinogen for oral cancer in southeast Asia, however, the molecular mechanism leading to the malignancy is still unclear. To mimic the habit of areca nut chewing, our laboratory has established four oral cancer cell sublines (SAS, OECM1, K2, C9), chronically trained by areca nut extract (ANE). To elucidate the molecular basis of areca nut induced oral carcinogenesis, the differential proteomes between oral cancer cells and the ANE sublines were determined using the technique of isobaric mass tag (iTRAQ) labeling and multidimensional liquid chromatography- mass spectrometry (LC-MS/MS). Over thousand proteins were identified in four sublines, in which 194 proteins were found differential expressions in at least two ANE sublines. Bioinforatmic analysis revealed that these proteins participate in several pathways, with the regulation of epithelial to mesenchymal transition (EMT) most prominent. Fourteen proteins were confirmed differential expression in the ANE sublines, including Krt17. To shed more light on the mechanism of ANE induced carcinogenesis, Krt17 was further investigated. Knockdown Krt17 significantly suppressed ANE-induced cell growth, migration, and cell invasion, along with the modulation of EMT process. Furthermore, in a carcinogen-induced oral cancer mice model by 4NQO/arecoline, an active compound of ANE, Krt17 was found significantly up-regulated in all hyperplasia and carcinoma (p&amp;lt;0.001). In conclusion, we have identified proteome associated with chronic areca nut exposure in oral cancer cells. Krt17 was demonstrated contributing to areca nut induced oral malignancy. This study should attribute to risk assessment, disease prevention or other clinical applications of areca nut-induced oral cancer. Citation Format: Chang Hsu Chiang, Chih-Ching Wu, Ann-Joy Cheng. Quantitative proteomic analysis identifying Krt17 plays a critical role in areca nut inducing oral carcinogenesis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5157.
Abstract 421: Non reportable results - maternal neoplasm can alter results from non-invasive prenatal testing (NIPT)
Authors: Daniel Grosu, Nilesh G. Dharajiya, Ron M. McCullough, Youting Sun, Juan-Sebastian Saldivar, Dirk van den Boom, Mathias Ehrich
Journal: Cancer Research (2016)

Abstract Cell free DNA is a powerful new analyte for the detection of chromosomal abnormalities of fetuses from the plasma of pregnant women. In non-invasive prenatal testing (NIPT), cfDNA is contributed into the plasma by the placenta. In rare cases, these results are distorted by additional sources of cfDNA in the maternal bloodstream. For example, organ transplantation can severely affect the cfDNA levels and lead to uninterpretable results. Another source of cfDNA that can lead to similar difficulties and ultimately to a non-reportable NIPT results, can be a maternal neoplasm. In our clinical laboratory, we have processed samples from over 450,000 pregnant patients. In cases of uninterpretable findings due to aberrant genomic profiles, potential reasons for non-reportable results were discussed with the caregiving physician. When feedback about these cases was available, it was collected in a database. In summary, we observed non-reportable NIPT results with aberrant genomic profile for 55 cases. A set of 43 had sufficient information available to allow inclusion in this summary. In 40 cases, a maternal neoplasm was confirmed (18 malignant, 20 benign, and two with imaging but without pathological confirmation). These observational results support further investigation by prospective controlled trials. Citation Format: Daniel Grosu, Nilesh G. Dharajiya, Ron M. McCullough, Youting Sun, Juan-Sebastian Saldivar, Dirk van den Boom, Mathias Ehrich. Non reportable results - maternal neoplasm can alter results from non-invasive prenatal testing (NIPT). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 421.
Abstract 734: Role of TGF-â in myeloid regulation of tumor-induced bone disease
Authors: Denise Buenrostro, Alyssa Merkel, Julie Sterling
Journal: Cancer Research (2016)

Abstract Bone is one of the most common metastatic sites for breast cancer, where nearly 70% of patients that die from disease have reported skeletal metastases upon autopsy. Specifically in the bone microenvironment, TGF-â has a complex role in the regulation of tumor growth and is critical for the initiation and continuation of bone destruction, an important parameter of tumor-induced disease. Previous publications have demonstrated that TGF-â can affect myeloid cells by increasing their expansion in the tumor microenvironment and modulating host immune surveillance, thus supporting a tumor promoting environment. Therefore, we hypothesize that inhibition of TGF-â will decrease tumor-induced bone disease by reducing myeloid expansion and tumor growth in bone. To address this we injected mice with the TGF-â inhibitory antibody, 1D11, one week prior to tumor inoculation and continuously treated until sacrifice where myeloid expansion and parameters of tumor-induced bone disease were measured. Two mouse models were used to assess the importance of the immune system, an immunodeficient model inoculated with human breast cancer cells (MDA-MB-231) and a syngeneic model using murine breast cancer cells (4T1). Flow cytometry analysis revealed that TGF-â inhibition decreased a triple positive myeloid population (CD11b+F4/80+Gr-1+) in mice sacrificed at day 28 by five percent. This triple positive myeloid cell population has been associated with supporting tumor progression. Surprisingly our flow cytometry analysis demonstrated that myeloid-derived suppressor cells (MDSCs: CD11b+GR-1+) remained unchanged when TGF-â was inhibited. Micro-CT analysis demonstrated that 1D11 treated mice had a 2-fold increase in bone volume and connective density compared to control mice. X-ray analysis demonstrated that control mice had greater than 2-fold osteolytic bone destruction compared to mice treated with the TGF-â inhibitory antibody. Histomorphometric analyses suggests that TGF-â inhibition reduces tumor burden, increases osteoclast cell numbers and modulates macrophage cell populations. Together these results suggest that inhibiting TGF-â prior to tumor inoculation and subsequently after may prevent expansion of a tumor-promoting myeloid population and promote a bone-phenotype that does not support tumor growth in bone. Future studies will focus on investigating specific myeloid factors and assessing whether TGF-â inhibition decreases expression of these pro-tumorigenic factors. Citation Format: Denise Buenrostro, Alyssa Merkel, Julie Sterling. Role of TGF-â in myeloid regulation of tumor-induced bone disease. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 734.
CTAS: a CT score to quantify disease activity in pulmonary sarcoidosis
Authors: Rachel Benamore, Yvonne R Kendrick, Emmanouela Repapi, Emma Helm, Suzanne L Cole, Stephen Taylor, Ling-Pei Ho
Journal: Thorax (2016)

<h3>Background</h3> A major gap in the management of sarcoidosis is the lack of accessible and objective methods to measure disease activity. Since 90% of patients have pulmonary involvement, we explored if a disease activity score based on thoracic CT scans could address this clinical issue. <h3>Methods</h3> High-resolution CT scans from 100 consecutive patients with sarcoidosis at a regional sarcoidosis service were scored for extent of CT abnormalities known to relate to granuloma or lymphocytic infiltration from published CT-pathological studies. These individual abnormality scores were then correlated against serum ACE, sIL-2R and change in FVC to identify CT abnormalities that reflect contemporaneous disease activity. The sum of these scores, or <i>CT A</i>ctivity <i>S</i>core (CTAS), was then validated against FVC response to treatment. <h3>Findings</h3> CT extent scores for nodularity, ground-glass opacification, interlobular septal thickening and consolidation correlated significantly with at least one of the disease activity parameters and were used to form CTAS. CTAS was found to predict FVC response to treatment at 1 year and was highly reproducible between radiologists. An abbreviated CTAS (aCTAS), constructed from presence or absence of the four CT abnormalities, also showed significant correlation with FVC response to treatment. CTAS and aCTAS also correlated with response to treatment in the fibrotic subgroup. <h3>Interpretation</h3> CTAS provides a concept for an objective and reproducible CT scoring method to quantify disease activity in sarcoidosis. The score can potentially be used to stratify patients according to disease activity, determine response to treatment and establish if fibrotic sarcoidosis is active.