tbuckley/cabot-search huggingface dataset:
S75 Do "clinically relevant" tidal volumes really cause ventilator-induced lung injury in mice?
Authors: M. R. Wilson, B. V. Patel, M. Takata
Journal: Thorax (2011)

<h3>Background</h3> Ventilator-induced lung injury (VILI) caused by excessive lung stretch during mechanical ventilation, is an important determinant of intensive care mortality. In recent years the mouse has increasingly become the pre-clinical model of choice, and studies using mice have identified numerous pathways and mediators all apparently vital during VILI. However, findings have not translated into clinical benefit, and it is conceptually extremely difficult to reconcile this plethora of mediators into a single paradigm. We propose that this confused situation has arisen from a somewhat naïve belief that the wide variety of tidal volumes (V<sub>T</sub>) used within such studies all induce over-stretching of the lungs. <h3>Methods</h3> Anaesthetised mice were ventilated (3 cm H<sub>2</sub>O positive end-expiratory pressure, using air ±CO<sub>2</sub> to regulate pH) with a variety of V<sub>T</sub> ranging from “clinically relevant” (10 ml/kg) to “very high” (40 ml/kg) for up to 3 h. <h3>Results</h3> Both 10 ml/kg and 40 ml/kg V<sub>T</sub> evoked deterioration in arterial pO<sub>2</sub> and mean arterial blood pressure (BP), although intermediate V<sub>T</sub> (20–30 ml/kg) did not (see Abstract S75 table 1). Lung wet:dry weight ratio and lavage fluid total protein were both marginally increased by 10–20 ml/kg V<sub>T</sub> compared to non-ventilated controls (NVC). However, raising the V<sub>T</sub> to 30 ml/kg did not further enhance these, suggesting that any increases following 10–20 ml/kg were not due to over-stretching the lungs. Only 40 ml/kg induced substantial increases compared to other groups. Both 40 ml/kg and 30 ml/kg upregulated lavage fluid IL-6, while soluble receptor for advanced glycation end-products (sRAGE) tended to be increased with 10–20 ml/kg but not 30 ml/kg (compared to NVC). Again, only 40 ml/kg V<sub>T</sub> induced significant upregulation. <h3>Conclusions</h3> These data demonstrate that only the highest V<sub>T</sub> used (40 ml/kg) induced major changes in physiological and inflammatory markers consistent with development of VILI. Signs of injury/inflammation using V<sub>T</sub> 10–20 ml/kg are likely to result not from substantial lung over-stretch but from other factors, particularly epithelial shear stress secondary to alveolar derecruitment and atelectasis. While such V<sub>T</sub> may themselves be considered to be “clinically relevant”, whether they induce a “clinically relevant” pathophysiology in healthy mice is questionable.
Abstract 937: Dissection of KRAS-driven survival signaling networks via phosphoproteomics in lung cancer cells.
Authors: Jae-Young Kim, Eric A. Welsh, Bin Fang, Umut Oguz, Jiannong Li, Fumi Kinose, Crystina Bronk, Amer A. Beg, Ann Chen, Steven Eschrich, John Koomen, Eric B. Haura
Journal: Cancer Research (2013)

Abstract KRAS mutation accounts for development of approximately 30% of lung adenocarcinoma yet therapeutic options remain limited. We report our efforts to explore downstream signaling proteins driven by KRAS, including TANK-binding kinase 1 (TBK1), through a mass spectrometry based phosphoproteomics approach. We hypothesized that such a search would identify key survival proteins as well as uncover potential adaptive resistance mechanisms. We identified proteins whose phosphorylation is regulated TBK1 using SILAC and mass spectrometry following RNAi-mediated TBK1 knockdown. A cohesive network view of the underlying results centered major effects on Polo-like Kinase 1 (PLK1) and decreased phosphorylation of its targets implicating TBK1 as involved in mitosis. TBK1 activity was induced especially in late G1 and M phase, and loss of TBK1 sensitized lung cancer cells to a mitotic stressor. Surprisingly, we found that TBK1 knockdown increased phosphorylation of oncogenic kinases, including EGFR, Met, and ERK1/2. We screened multiple tyrosine kinase inhibitors in combination with TBK1 loss and found the pro-apoptotic effect of TBK1 loss was enhanced by dasatinib, a Src-family kinase inhibitor, providing a mechanistic basis for rational combinatorial therapies involving TBK1. Moving upstream, we analyzed global phosphoproteome change after KRAS knockdown and identified unexpected role of KRAS involved in CDK1 regulation as well as potential adaptive resistant mechanisms that can protect cells against KRAS loss. Finally, we have started exploring changes in the programmed kinome in KRAS mutated lung cancer cells following exposure to MEK inhibitors using activity based protein profiling. Initial experiments have characterized phenotypic effects of two MEK inhibitors in a subset of KRAS mutated lung cancer cells and preliminary studies have identified increased levels of some kinases following MEK inhibition. Collectively, we expect this kinome and phosphoproteomic network based approach will provide better insights into survival signaling mechanism maintaining survival of KRAS mutant lung cancer cell as well as novel therapeutic strategies for this cancer subtype. Updated work will be presented. Supported by the SPORE in Lung Cancer (P50-CA119997) Citation Format: Jae-Young Kim, Eric A. Welsh, Bin Fang, Umut Oguz, Jiannong Li, Fumi Kinose, Crystina Bronk, Amer A. Beg, Ann Chen, Steven Eschrich, John Koomen, Eric B. Haura. Dissection of KRAS-driven survival signaling networks via phosphoproteomics in lung cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 937. doi:10.1158/1538-7445.AM2013-937
Abstract 1301: Involvement of VEGFR-1 signal in solid tumor growth and tumor angiogenesis via recruitment of macrophage-lineage cells
Authors: Masashi Muramatsu, Seiji Yamamoto, Tsuyoshi Osawa, Masabumi Shibuya
Journal: Cancer Research (2010)

Abstract VEGF/VEGFR signaling is essential for pathological angiogenesis. It has been reported that Flt-1 (VEGFR-1) is expressed not only in vascular endothelial cells but also in monocyte/macrophages. Previously, we and others reported that bone marrow derived cells which expressed Flt-1 were involved in the formation of pre-metastatic niche in mouse tumor model. However, the role of Flt-1 signal in tumorigenesis is not fully understood. To clarify the involvement of Flt-1 in solid tumor growth, we used wild type (Wt) mice and Flt-1 tyrosine kinase-deficient (Flt-1 TK-/-) mice which developed basically normal blood vessels and survived. In allograft cancer model, tumor growth was significantly slower in Flt-1 TK-/- mice compared with that in Wt mice. Survival rate of Flt-1 TK-/- mice were also higher than Wt mice under tumor-bearing condition. The degree of tumor angiogenesis and infiltration of macrophage-lineage cells in tumor tissues were remarkably suppressed in Flt-1 TK-/- mice compared with those in Wt mice. Surprisingly, endothelial cells and macrophage-lineage cells at the surrounding tissue of tumors were similar in both mice. The number of pericyte marker-positive cells covered with vascular endothelial cells was reduced in tumor tissue in Flt-1 TK-/- mice compared with that in Wt mice. To distinguish which Flt-1 signal on the vascular endothelial cell or on the macrophage is important, we performed bone marrow transplantation. Tumor volume in Wt mice implanted with bone marrow derived from Flt-1 TK-/- mice was significantly smaller than that in Wt mice implanted with bone marrow derived from Wt mice. In tumor tissue inoculated in Wt mice implanted with Flt-1 TK-/- bone marrow, angiogenesis and infiltration of macrophage-lineage cells were significantly decreased compared with Wt mice implanted with Wt bone marrow. Based on these results, we suggest that, in some tumors, Flt-1 signaling is important for bone marrow-derived macrophage-migration into tumors which promotes tumor angiogenesis and tumor growth. 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 1301.
AB0977 Biomechanical factors and physical examination findings in osteoarthritis of the knee: Associations with tissue abnormalities assessed by conventional radiography and by high resolution magnetic resonance imaging
Authors: J. Knoop, J. Dekker, J.-P. Klein, M. van der Leeden, M. van der Esch, D. Reiding, R.E. Voorneman, M. Gerritsen, L.D. Roorda, M.P. Steultjens, W.F. Lems
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Although biomechanical factors of the knee joint like muscle strength, proprioceptive accuracy and laxity play an important role in knee osteoarthritis (OA), only limited evidence exists on associations with specific tissue abnormalities. Furthermore, findings from physical examination have never been studied in relation to tissue abnormalities of the knee joint. <h3>Objectives</h3> To explore associations between tissue abnormalities assessed by conventional radiography and high resolution MRI, biomechanical factors and physical examination findings in patients with knee OA. <h3>Methods</h3> Explorative cross-sectional study in 105 patients with knee OA. Knees were imaged using radiography and 3.0 Tesla MRI. Multivariable regression analyses were used to explore associations between tissue abnormalities, visualised by radiography or MRI, biomechanical factors (quadriceps and hamstrings muscle strength, proprioceptive accuracy and varus-valgus laxity) and physical examination findings (bony tenderness, crepitus, bony enlargement and palpable warmth). <h3>Results</h3> MRI based synovitis, MRI based cartilage loss and radiographic based joint space narrowing were found to be associated with quadriceps weakness. Radiographic features (joint space narrowing and osteophyte formation) were related to varus-valgus laxity. Multiple tissue abnormalities, but only those detected by MRI, were associated with physical examination findings (crepitus and palpable warmth). Neither MRI features nor radiographic features were found to be associated with hamstrings muscle strength, proprioceptive accuracy, bony tenderness and bony enlargement. <h3>Conclusions</h3> In conclusion, a discordance between tissue abnormalities, biomechanical factors and physical examination findings in knee OA was observed, for both conventional radiography and high resolution MRI. Relevant new findings include a highly significant association between MRI based synovitis and quadriceps weakness and a superiority of MRI over conventional radiography in association with physical examination findings. <h3>Disclosure of Interest</h3> None Declared
Abstract LB-101: A novel role of semaphorin4a (sema4a) in genotoxin-induced DNA damage response in human lung fibroblasts
Authors: Dongsoon Bae, Gina Chun, Steven R. Patierno, Susan M. Ceryak
Journal: Cancer Research (2010)

Abstract Dysregulation of DNA repair signaling after genotoxin exposure contributes to genomic instability and carcinogenesis. Hexavalent chromium [Cr(VI)] is a genotoxin of occupational and environmental concern. Protein tyrosine phosphatase (PTP) inhibitors (i.e., sodium orthovanadate (SOV)) activate key survival pathways. We reported that SOV enhances clonogenic survival after Cr(VI) exposure by overriding Cr-induced growth arrest in human lung fibroblasts (HLFs). PTP inhibition with SOV increased expression of DNA damage/repair genes as determined by microarray analysis. Kinetic analysis of DNA double-strand breaks (DSBs) by comet assay showed equal DSB formation 15 min after Cr(VI) exposure in the absence and presence of SOV. However, PTP inhibition significantly decreased DSBs 0.5-24 hr after Cr(VI) treatment. Aim of the present study was to determine the molecular mechanism(s) by which PTP inhibition affects DNA damage response during genotoxic stress. Gene expression was examined by DNA Damage Signaling Pathway PCR Array after 1 μM Cr(VI) treatment for 24 hr in the absence or presence of SOV. The PTP inhibitor reversed Cr-mediated changes in expression of several unique genes. Interestingly, the sema4a gene, known to be involved in T cell activation and endothelial cell proliferation and migration, was strongly induced by co-treatment of SOV and Cr(VI). Gene expression correlated with increased sema4a protein expression after co-treatment of SOV and Cr(VI). A potential role of sema4a in Cr-induced DNA DSB formation/repair in the absence or presence of SOV was assessed after sema4a siRNA transfection. Silencing of sema4a did not alter the effect of SOV on Cr-induced DSBs. However, sema4a silencing completely blocked Cr-induced DSBs 4 hr after exposure. These results suggest a novel role of sema4a in DNA DSB formation/repair in normal HLFs. Taken together, these data shed light on the emerging role of semaphorins as mediators of cell survival as well as potential therapeutic targets in carcinogenesis. 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 LB-101.
Abstract 2226: Intraoperative harvesting of human fallopian tubes for cytodiagnostic and pathobiological studies
Authors: Nicole N. Esposito, Patricia A. Kruk, Mitchell Hoffman, Larry R. Glazerman, Santo V. Nicosia
Journal: Cancer Research (2011)

Abstract Background: Fallopian tube intraepithelial cancer is a potential precursor of high-grade, sporadic and familial, pelvic carcinomas. Materials and Methods: Using a protocol for rapid intraoperative cytology (IC), fallopian tube fimbrial epithelium (FTFE) was harvested from 24 women (age: 40-80) undergoing surgery for non-neoplastic (N = 14, leiomyomas, adenomyosis, ovarian and paraovarian serous cysts, endometriosis) and neoplastic (N = 10, serous and endometrioid carcinomas with tubal involvement) lesions. Under IRB-approved protocol, eight cytological imprints were obtained from each fimbria and stained intraoperatively by Diff-Quik® and Papanicolaou for general morphology, by Trypan blue to assess cell viability and by rapid immunohistochemistry for evaluation of cytokeratin (CAM 5.2), Ki67 (MIB-1) p53 and high motility group protein (HMGA2) expression. Results: Tubal imprints yielded 0.5-1 x106, cytokeratin-positive and &amp;gt; 85% viable cells/patient with a 2:1 distribution of ciliated: mucous cells dispersed within a proteinaceous material of variable density with rare microcalcifications; reactive fibroblasts and mesothelial cells represented &amp;lt; 3% of cell harvests with the highest percentage seen in endometriosis and malignancies. Malignant fimbrial imprints (8 serous and 2 endometrioid carcinomas) exhibited diffuse accumulation of p53 and HMGA2, a Ki67 proliferation index of 50-70% and displayed diagnostic malignant criteria in all cases. Conclusions: Tubal harvest and intraoperative cytology of fallopian tubes allows for: a) rapid evaluation of tubal cancer, currently viewed as the main source of high-grade serous ovarian carcinomas; and b) triaging of cellular material for basic and translational studies including molecular cancer pathobiology and biomarker discovery. The technique will also provide a useful diagnostic adjunct to emerging in vivo high-resolution optical technologies. (Supported by Ovarian Cancer Research Fund). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2226. doi:10.1158/1538-7445.AM2011-2226
Abstract 2415: Phenotypic stabilization of mesenchymal-like cancer cells through mesenchymal-specific DNA hypermethylation
Authors: Ken-ichi Kozaki, Yasuhiro Kurasawa, Tomoki Muramatsu, Hiroaki Ono, Takaya Ishihara, Narikazu Uzawa, Atiphan Pimkhaokham, Issei Imoto, Teruo Amagasa, Johji Inazawa
Journal: Cancer Research (2012)

Abstract The epithelial-mesenchymal transition (EMT) plays a crucial role in normal and disease processes including tumor progression. In this study, we first classified epithelial-like and mesenchymal-like oral squamous cell carcinoma (OSCC) cell lines based on expression profiles of typical EMT-related genes using a panel of 18 OSCC cell lines. Then, we performed methylation-based and expression-based analyses of components of the Wnt signaling pathway, and identified WNT7A and WNT10A as genes silenced by mesenchymal-specific DNA hypermethylation in OSCCs. A significant association was revealed between some clinicopathologic findings and the DNA methylation status of WNT7A (Normal vs Tumor, P = 0.007; T1-2 vs T3-4, P = 0.040; I-III vs IV, P = 0.016) and WNT10A (N0-N1 vs N2-N3, P = 0.046) in the advanced stages of OSCC. Moreover, we found that E-cadherin expression in cancer cells may be positively regulated by WNT7A, whose expression is negatively regulated by mesenchymal-specific DNA hypermethylation or ZEB1 in mesenchymal-like OSCC cells. Our findings indicate that epithelial-specific gene silencing through mesenchymal-specific DNA hypermethylation may stabilize the phenotypic plasticity of cancer cells during EMT/MET. 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 2415. doi:1538-7445.AM2012-2415
Abstract 3725: Combined cytotoxic effects of volasertib and cisplatin in urothelial carcinoma cells
Authors: Chia-Chi Lin, Yu-Mine Lin, Yu-Chieh Tsai, Yeong-Shiau Pu, Ann-Lii Cheng, James C. Yang
Journal: Cancer Research (2012)

Abstract Purpose: Patients with advanced urothelial carcinoma (UC) are treated with cisplatin-based chemotherapy. Polo-like kinase 1 (PLK1) inhibitors (e.g. volasertib) have been shown to be effective in patients with refractory UC (AACR-NCI-EORTC Meeting 2008 abstr 36). We studied the combined cytotoxic effects of volasertib and cisplatin in UC cells in vitro. Materials and methods: The cytotoxicity of the two agents either alone or in combination were studied against UC cell lines with different genetic background: T24 (HRAS mutation), RT4, J82 (FGFR3 mutation), and BFTCC909 (TP53 mutation), using the sulforhodamine B colorimetric assay. Schedule-dependence of the two-drug combination was assayed using 3 different treatment schedules: concurrent and 2 sequential exposures. We examined the effects of volasertib on cell-cycle progression in unsynchronized UC cells by determining the DNA content. Results: The volasertib IC50s of T24, RT4, J82, and BFTCC909 were 13.4±0.13, 54.0±10.6, 14.1±1.3 and 62.4±4.46 nM, respectively and the cisplatin IC50s of the four cells were 2776±361, 8767±1018, 6270±1240 and &amp;gt;10000 nM, respectively. With the median-effect analysis, the combined effects of the two agents when given concurrently were sub-additive in the low fraction affected (Fa) range (0.1-0.3) and additive in the median to high Fa range (0.4-1.0) for the four cells. The combined cytotoxicity was more synergistic if volasertib was given 24 hours earlier than cisplatin. The effects were less synergistic if cisplatin was given prior to volasertib. This phenomenon was seen in all four cells. UC cells in media with 50 nM volasertib arrested in G2/M and showed synchronization 24 hr after release. Conclusions: In our UC cell model, the combined effects may be optimized by sequential use of the two agents, preferably volasertib given 24 hours before cisplatin. Volasertib-treated UC cells arrested in G2/M and showed synchronization which may maximally sensitize UC cells to cisplatin. Our results have clinical implications for the treatment of UC. 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 3725. doi:1538-7445.AM2012-3725
AB0144 Generation of Disease-Specific Induced Pluripotent Stem Cells from Patients with Rheumatoid Arthritis and Osteoarthritis
Authors: S.M. Jung, J.Y. Kang, H.K. Min, J.H. Koh, Y.S. Suh, J.H. Lee, J. Lee, J.Y. Lee, J.-M. Kim, S.-K. Kwok, K.-S. Park, S.-H. Park, H.-Y. Kim, J.H. Ju
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> Since the concept of reprogramming mature somatic cells to generate induced pluripotent stem cells (iPSCs) was demonstrated in 2006, iPSCs have become a potential substitute for embryonic stem cells (ESCs) given their pluripotency and "stemness" characteristics, which resemble those of ESCs. <h3>Objectives</h3> We investigated to reprogram fibroblast-like synoviocytes (FLSs) from patients with rheumatoid arthritis (RA) and osteoarthritis (OA) to generate iPSCs using a 4-in-1 lentiviral vector system. <h3>Methods</h3> A 4-in-1 lentiviral vector containing Oct4, Sox2, Klf4, and c-Myc was transduced into RA and OA FLSs isolated from the synovia of two RA patients and two OA patients. Immunohistochemical staining and real-time PCR studies were performed to demonstrate the pluripotency of iPSCs. Chromosomal abnormalities were determined based on the karyotype. SCID-biege mice were injected with iPSCs and sacrificed to test for teratoma formation. <h3>Results</h3> After 14 days of transduction using the 4-in-1 lentiviral vector, RA FLSs and OA FLSs were transformed into spherical shapes that resembled embryonic stem cell colonies. Colonies were picked and cultivated on matrigel plates to produce iPSC lines. Real-time PCR of RA and OA iPSCs detected positive markers of pluripotency. Immunohistochemical staining tests with Nanog, Oct4, Sox2, Tra-1-80, Tra-1-60, and SSEA-4 were also positive. Teratomas that comprised three compartments of ectoderm, mesoderm, and endoderm were formed at the injection sites of iPSCs. Established iPSCs were shown to be compatible by karyotyping. Finally, we confirmed that the patient-derived iPSCs were able to differentiate into osteoblast, which was shown by an osteoimage mineralization assay. <h3>Conclusions</h3> FLSs derived from RA and OA could be cell resources for iPSC reprogramming. Disease- and patient-specific iPSCs have the potential to be applied in clinical settings as source materials for molecular diagnosis and regenerative therapy. <h3>References</h3> Takahashi K, Yamanaka S: Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 2006, 126:663-76. Tiscornia G, Vivas EL, Izpisúa Belmonte JC: Diseases in a dish: modeling human genetic disorders using induced pluripotent cells. Nat Med 2011, 17:1570-6. Grskovic M, Javaherian A, Strulovici B, Daley GQ: Induced pluripotent stem cells–opportunities for disease modelling and drug discovery. Nat Rev Drug Discov 2011, 10:915-29. <h3>Acknowledgements</h3> This work was supported by a grant from the Korea Healthcare Technology R&amp;D Project, Ministry for Health, Welfare &amp; Family Affairs, Republic of Korea (A092258). <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.4862