tbuckley/cabot-search huggingface dataset:
Abstract 939: Double mutation of <i>KRAS</i> and <i>PIK3CA</i> affects the efficacy of NVP-BEZ235, a dual PI3K/mTOR inhibitor, in regulating the PI3K/mTOR pathway in colorectal cancer.
Authors: Areumnuri Kim, Seung-Sook Lee, Cherin Kim, Eun Mi Kim, Dong-Yeop Shin, Sun-Joo Lee, Sunhoo Park
Journal: Cancer Research (2013)

Abstract Colorectal cancer (CRC) with mutational activation of KRAS is observed frequently. In addition, PIK3CA mutations commonly coexist with KRAS mutations and lead to additive activation of the PI3K/mTOR signaling pathway. Here, we investigated how CRC cells that harbor KRAS and PIK3CA mutations affect sensitivity to inhibition of PI3K/mTOR with NVP-BEZ235 (BEZ235). We selected CRC patient samples and assessed their mutational status. CRC patients with KRAS or PIK3CA mutations show activation of Akt and mTOR, particularly when KRAS and PIK3CA mutations coexist. Suppression of PI3K/mTOR by BEZ235 results in a growth inhibitory effect and enhanced apoptosis via Bim activation in KRAS mutant cells. Mutational activation of KRAS when accompanied by a PIK3CA mutation converges at PI3K/mTOR pathway activation, resulting in resistance to BEZ235. Bim knockdown blocked the apoptotic response to BEZ235 in KRAS mutant cells, suggesting that PI3K inhibition leads to Bim accumulation. Moreover, BEZ235 treatment resulted in induction of FOXO3a activity and its induced transcription of Bim activation, which sensitized cells to cytotoxic agents leading to apoptosis in double mutant cells in vitro and in vivo. Taken together, our data suggest that targeting PI3K/mTOR sensitizes cells to apoptosis, implying that activation of PI3K/mTOR signaling via KRAS or PIK3CA mutation is an important pathway in CRC cell growth. Based on these results, coexistent KRAS and PIK3CA mutations confer resistance to BEZ235 via suppression of Bim-induced apoptosis, suggesting that combined treatment with conventional chemoagents is a potential strategy in the clinic. Citation Format: Areumnuri Kim, Seung-Sook Lee, Cherin Kim, Eun Mi Kim, Dong-Yeop Shin, Sun-Joo Lee, Sunhoo Park. Double mutation of KRAS and PIK3CA affects the efficacy of NVP-BEZ235, a dual PI3K/mTOR inhibitor, in regulating the PI3K/mTOR pathway in colorectal cancer. [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 939. doi:10.1158/1538-7445.AM2013-939
AB0161 A MMP1-cleavable composite peptide derived from BIG-H3 potently inhibits chronic inflammatory arthritis
Authors: J.H. Kang, E.J. Nam, K.H. Sa, K.H. Kim, J.S. Seo, S.W. Han, Y.M. Kang
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Transforming growth factor β-inducible gene-h3 (βig-h3), an extracellular matrix protein, is composed of four homologous fas-1 domains and an RGD motif. We previously demonstrated that βig-h3 was abundantly expressed in rheumatoid synovium and regulated the adhesion and migration of fibroblast-like synoviocytes (FLS), which was inhibited by the YH18 peptide in the 4th fas-1 domain (4th YH18 peptide). <h3>Objectives</h3> To develop βig-h3 derivative-based peptides that have a therapeutic efficacy in chronic inflammatory arthritis. <h3>Methods</h3> The βig-h3 derivative-based peptides, including the 2nd and 4th YH peptides, 4th fas-1 domain, 4th fas-1 truncated for H1 and H2 (dhfas-1), and a MMP1-cleavable composite peptide (MFK24), were cloned. We tested the MFK24 with different proteases and confirmed the specificity of cleavage by immunoblotting with anti-βig-h3 and anti-His-tag antibodies. Inhibitory effect of adhesion and migration of FLS or mouse fibroblast (NIH3T3) was evaluated in 96-well microtiter and transwell plates coated with βig-h3. A murine collagen-induced arthritis (CIA) model was used for evaluation of therapeutic efficacy of the βig-h3 derivative-based peptides. <h3>Results</h3> The 4th YH18 peptide was weakly effective in suppressing the arthritis severity in CIA mice. The human and murine (MFK00) dhfas-1 was effective in blocking the βig-h3-mediated adhesion and migration of human FLS and murine fibroblasts. Treatment with higher dose (30mg/kg) of dhfas-1 showed a remarkable efficacy, whereas treatment with lower dose (10 mg/kg) revealed only a partial improvement. A composite peptide (MFK24) consisted of dhfas-1 and RGD peptide linked by MMP1 substrate was cleaved by MMP1 specifically. βig-h3-mediated adhesion and migration of NIH3T3 cells were inhibited at low concentration (0.5 and 1 uM respectively) of MFK24. MFK24 suppressed the adhesion of NIH3T cells more efficiently compared to either alone in combination of MFK00 and RGD motif. Therapeutic efficacy of MFK24 in CIA mice was remarkably enhanced with a consistent reduction of expression in inflammatory mediators within joint tissues. <h3>Conclusions</h3> A proof of concept design of the MMP-cleavable composite peptide, based on βig-h3 derivatives, revealed a marked exaltation of therapeutic efficacy for chronic inflammatory arthritis, implicating a new expandable strategy for enhancement of efficacy of two different active molecules in the treatment of RA. <h3>Disclosure of Interest</h3> None Declared
Abstract 2298: MiR-23a regulates TGF-β-induced epithelial-mesenchymal transition by targeting E-cadherin in pulmonary epithelium cells
Authors: Masahiro Seike, Cao Mengru, Chie Soeno, Rintaro Noro, Yuji Minegishi, Akinobu Yoshimura, Akihiko Gemma
Journal: Cancer Research (2012)

Abstract Transforming growth factor-β (TGF-β)-induced epithelial-mesenchymal transition (EMT) has been reported to be related to pathogenesis of various diseases including lung cancer and idiopathic pulmonary fibrosis (IPF). Recently, microRNAs (miRNA) have been recognized as a new class of genes involved in human tumorigenesis. MiR-23a/24/27a is a miRNA cluster located in chromosome 19p13.12, which can function as an oncogene in several human cancers. In this study, we analyzed miR-23a/24/27a expression in 10 non-small cell cancer (NSCLC) cell lines by real-time PCR analysis. Correlation between expression of these miRNAs and TGF-β/Smad signaling was evaluated. We found that miR-23a could be regulated by TGF-β1 in a Smad-dependent manner in A549 lung adenocarcinoma cells originated by type II pneumocyte showing the EMT phenomenon. Knockdown of miR-23a partially restored E-cadherin expression under the condition of TGF-β1 stimulation. In contrast, overexpression of miR-23a could suppress E-cadherin expression and stimulate EMT. Furthermore, A549 cells with overexpressed miR-23a were more resistant to gefitinib than the parental cells. These findings suggested that miR-23a regulates TGF-β-induced EMT by targeting E-cadherin in pulmonary epithelium cells and may be useful as a new therapeutic target in pulmonary diseases including NSCLC and IPF. 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 2298. doi:1538-7445.AM2012-2298
Abstract 1743: SOX10 is required for cell cycle regulation and melanomagenesis.
Authors: Julia C. Cronin, Dawn E. Watkins-Chow, Art Incao, Joanne H. Hasskamp, Nicola Schönewolf, Nicholas K. Hayward, Boris C. Bastian, Reinhard Dummer, Stacie K. Loftus, William J. Pavan
Journal: Cancer Research (2013)

Abstract The transcription factor SOX10 is essential for proper survival and differentiation of neural crest cell lineages, and plays an important role in the establishment and maintenance of melanocytes. SOX10 is also highly expressed in melanoma tumors, however its role in the progression of the disease is not yet understood. Here, we report that melanoma tumor cell lines require wild-type SOX10 expression for proliferation, and detail the rescue of melanoma in the metabotropic glutamate receptor 1 (Grm1Tg) transgenic mouse by Sox10 haploinsufficiency. Stable SOX10 knockdown in human melanoma cells results in arrested growth, altered cellular morphology, and senescence. Cells with a stable loss of SOX10 are arrested in the G1 phase of the cell cycle with elevated cyclin-dependent kinase inhibitor 1A and 1B (p21 and p27) expression. SOX10 loss also results in hypophosphorylation of retinoblastoma protein (RB) and a reduction in the expression of its binding partner E2F1. Previously, the RB-E2F1 pathway has been shown to play a central role in cell cycle regulation, and here we demonstrate that SOX10 expression is required for the maintenance of the RB-E2F1 pathway to promote melanoma cell growth. One of the main events driving cellular transformation is the dysregulation of the cell cycle, therefore the role that SOX10 has in maintaining this process provides great promise for targeted interventions. Citation Format: Julia C. Cronin, Dawn E. Watkins-Chow, Art Incao, Joanne H. Hasskamp, Nicola Schönewolf, Nicholas K. Hayward, Boris C. Bastian, Reinhard Dummer, Stacie K. Loftus, William J. Pavan. SOX10 is required for cell cycle regulation and melanomagenesis. [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 1743. doi:10.1158/1538-7445.AM2013-1743
Abstract 1584: Characterization of 28 patient-derived colorectal cancer xenografts and analysis for predictive response markers to current standard treatment
Authors: Michael Becker, Maria Rivera-Markelova, Johannes Merk, Christine T. Sers, Wassilij Slisow, Andre Rosenthal, Bernd Hinzmann, Peter M. Schlag, Jens Hoffmann, Iduna Fichtner
Journal: Cancer Research (2011)

Abstract Improved methods for the preclinical characterization of anti-cancer drugs in larger panels of primary lung cancer xenograft models have recently described (Fichtner et al. Clin Cancer Res. 2008;14(20):6456-68). These models consider more thoroughly the heterogeneity and genetic instability of tumors in a way ultimately enabeling treatment decisions on an individualized basis. The approach is based on large scale screening for activity in new in vivo models combined with extensive characterization of these models (gene expression and mutations). Bioinformatic methods are then used to further evaluate the mechanism of action of new drugs, to investigate possible resistance mechanisms and provide a rationale for combination therapies. Here we describe the development of a panel of primary patient derived colorectal cancer models. Primary colon carcinoma tissue samples were collected using a standardised procedure. Tumour pieces were transplanted onto immunodeficient mice immediately after surgery. A panel of 28 stably passagable colon cancer xenografts could be established as permanent tumour models. The results obtained so far, show that these patient-derived colon cancer models feature a high coincidence with the original tumour regarding histology and gene expression profiling. Response analysis according to clinical trial criteria revealed that the standard drug Oxaliplatin induce a overall response in 8 of the 28 xenograft models. Gene expression analyses were performed to identify predictive profiles for Oxaliplatin sensitivity. As one example, the effectiveness of Oxaliplatin seems to be related to the differential expression of genes which products are involved in the wnt pathway. The analysis of drug sensitivity in this set of models together with bioinformatics coorelations will provide hypotheses for further studies to identify patients that will more likely benefit from a drug as well as provide a rationale for combinations to be tested in clinical trials. These new approaches may help to better integrate research results in clinical development and may increase the success of new anti-cancer drugs in clinical studies. 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 1584. doi:10.1158/1538-7445.AM2011-1584
Accuracy of Magnetic Resonance Imaging Prediction of Pathologic Complete Response in Patients with Breast Cancer Treated with Neoadjuvant Chemotherapy
Authors: L. Garrigos Cubells, M.D. Sabadell Mercadal, A. Rodriguez Arana, J.M. Corominas, M. Martinez-Garcia, I. Gonzalez Maeso, T. Martos Cardenas, J. Albanell, I. Tusquets Trias Bes, S. Servitja Tormo
Journal: Annals of Oncology (2014)
Phase I study of anti-PD-L1 antibody MPDL3280A in patients with advanced solid tumors
Authors: Haruyasu Murakami, Noboru Yamamoto, Hirotsugu Kenmotsu, Toshiaki Takahashi, Yutaka Fujiwara, Hidenori Mizugaki, Yoshimasa Ishida, Tomohisa Kawakami
Journal: Annals of Oncology (2015)
AB0933 Uveitis is associated with increased arterial stiffness and subclinical atherosclerosis in patients with psoriatic arthritis
Authors: I. Gaydukova, A. Rebrov, D. Poddubnyy
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Psoriatic arthritis (PsA) is characterized by increased cardiovascular morbidity and mortality [1]. Data about clinical features related with endothelial dysfunction and atherosclerosis in PsA are limited. Uveitis is an extraarticular feature of PsA that is connected with arterial lesion and considered to be a factor associated with adverse cardiovascular prognosis. <h3>Objectives</h3> The aim of the study was to detect the relationship between presence of uveitis, increase arterial stiffness and atherosclerosis of carotids in patients with PsA. <h3>Methods</h3> In total, 65 patients with PsA without cardiovascular diseases and 20 healthy volunteers were involved in the study (mean age±SD was 41.62±10.2 and 41.33±13.8 years, respectively). 11 patients with PsA had uveitis, confirmed by an ophthalmologist. Arthritis activity assessment was performed by means of the disease activity score (DAS), erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) measurements. Main cardiovascular risk factors (age, gender, smoking, family history, arterial hypertension, body mass index (BMI)) were screened. Patients with and without uveitis were comparable in convectional cardiovascular risk factors and disease activity. Arterial stiffness parameters were performed by the pulse wave analysis: augmentation index (Aix) was calculated. Aix wasseen as optimal; - 30% s normal; -10 10% - increased; Aix &gt;10% of pathological. The ultrasound measuring the thickness of intima-media layer (IMT) in carotid arteries (CA) was performed for atherosclerosis detection. <h3>Results</h3> In patients with uveitis an increase of Aix as compared to PsA patients without uveitis was found. Aix in uveitis patients was 4.6 [-18.3; 4.1] %, in patients without uveitis - 34.5 [-20.1; -43.3] %, p=0.02, in controls Aix =-40.48[-56; -19] %, p IMT of right CA in patients with uveitis exceeded IMT patients without uveitis (0.6 [0.5; 0.7] vs. 0.4 [0.4; 0.6] mm, respectively). Mean IMT in patients with uveitis was 0.68 [0.53; 0.85] mm, n=11, without uveitis – 0.43 [0.4; 0.53] mm, n=54, p=0.03. In healthy controls IMT was 0.51 [0.5; 0.7] mm, n=20, p <h3>Conclusions</h3> Uveitis in psoriatic arthritis patients without cardiovascular diseases was associates with increased arterial stiffness and carotid intima-media layer thickening and could, therefore, serve as a marker of worse cardiovascular prognosis in this population. <h3>References</h3> Gladman D.D. et al. Arthritis Rheum.-1998.-Vol.41.- P.1103-1010. <h3>Disclosure of Interest</h3> None Declared
New ultrasound-guided culdotomy of vaginal ovarian cystectomy for pregnant women incarcerated ovarian dermoid cysts in recto-uterine pouch: case reports
Authors: S Dohi, M Tanaka, R Yamazaki, T Sagawa, M Inoue
Journal: Endoscopy (2012)

Objective of the study: For pregnant women with ovarian cysts, it's important that pregnant uterus is gently treated in laparoscopic cystectomy. Especially the cases incarcerated in recto-uterine pouch are difficult to do laparoscopic ovarian cystectomy. Such cases are suitable for vaginal ovarian cystectomy, but it has severe complication, rectal injury. As a reliable method of transvaginal access, we introduce a new culdotomy procedure and repoted two pregnant cases.
A1.23 IFNα mediated deregulation of mitochondrial DNA clearance as an inciting event for the development of SLE autoimmunity
Authors: K Gkirtzimanaki, E Kabrani, A Mplanas, P Sidiropoulos, G Bertsias, D Boumpas, P Verginis
Journal: Annals of the Rheumatic Diseases (2016)

<h3></h3> SLE is a prototypical nucleic acid-triggered autoimmune disease during which pathogenic, IgG anti-dsDNA autoantibodies form glomerular and vascular deposits and cause tissue damage. Recent studies suggest that deregulated lysosomal degradation of cytoplasmic DNA may result in its accumulation and sensing by intracellular receptors culminating in antiDNA autoimmunity. In SLE, circulating IFNαinduces peripheral blood monocytes to differentiate into inflammatory DCs, a process implemented through autophagy and mitophagy. Mitochondrial DNA – a DNA of bacterial origin – is a known cytoplasmic danger signal but it has never been explored as a potential source for the triggering of DNA autoimmunity. We sought to explore this possibility for SLE autoimmunity in humans. Serum and peripheral blood monocytes were isolated from active, newly diagnosed or off-treatment SLE patients and matched healthy donors. IFNα&nbsp;signalling was induced by 10% SLE serum or rIFNα. Autophagy was assessed by QPCR, immunoblotting and confocal microscopy for Atg5, LC3 and P62. Autoreactivity was assayed in MLRs and assessed by ELISA for IL6 and TNFα and flow cytometry for HLADR, CD86 and Tcell CFSE dillution. Autophagolysosomal pH, mtROS production, mitochondrial polarisation and mtDNA accumulation were assessed by confocal microscopy and flow cytometry using specific fluorescent dyes (Lysotracker RedDND99, mitoSOX, JC1, MitotrackerRed CMXRos and picogreen respectively). Freshly isolated SLE monocytes and healthy monocytes exposed to SLE serum or rIFNαdisplay autophagy induction (Atg5 and LC3II increase) but defective autophagolysosomal degradation (increase in autophagosomal P62). Lysosomalalkalinization (decreased Lysotracker intensity P &lt; 0.005) coincided with increased mtROS production (3fold higher mitoSOX intensity P &lt; 0.05) leading to accumulation of damaged, oxidising mitochondria (increase in JC1 aggregates, 4fold higher Mitotracker intensity P &lt; 0.005) and increased survival of mtDNA inside cytoplasmic compartments fused with lysosomes (picogreen-lysotrackercolocalisation). mtROS scavenging (mitoTEMPO) and inversion of autophagy completion (rapamycin) rescued the autoreactive phenotype of IFNαeducated monocytes in all cases. This study unveils a molecular mechanism that leads to the generation of a pool of immunogenic DNA autoantigens in SLE. IFNα mediated mitophagy deregulation leads to accumulation of oxmtDNA, a defect that can be targeted in order to avoid the development of the anti-DNA inflammatory response that drives SLE.
La caecostomie percutanée endoscopique dans la prise en charge de la constipation chronique sévère: résultats fonctionnels et qualité de vie à 1 an
Authors: E Duchalais-Dassonneville, M Le Rhun, S Bruley des Varannes, PA Lehur, G Meurette, E Coron
Journal: Endoscopy (2012)

Le procédé chirurgical de Malone décrit pour l'administration d'irrigations coliques antérogrades (ICA) est proposé dans la constipation chronique sévère afin d'éviter le recours à une chirurgie invasive de type colectomie totale. Récemment, la caecostomie percutanée endoscopique (CPE) a été proposée comme alternative à l'intervention de Malone. L'objectif de notre étude était d'évaluer la faisabilité, la morbidité et les résultats de la CPE à moyen terme.
Abstract 4537: SHLP6: A novel, naturally occurring, mitochondrial peptide has therapeutic and prognostic potential in prostate cancer
Authors: Laura Cobb, Hiromi Nakamura, Pinchas Cohen
Journal: Cancer Research (2010)

Abstract Mitochondrial DNA (mtDNA) mutations have been demonstrated in prostate cancer, particularly at the 16S rRNA region; and abnormal mRNA transcripts from that locus have been described. We and others showed that a novel open reading frame (ORF) within the mitochondrial 16S rRNA region, encoding for a 24 AA peptide called humanin, is a potent cell-survival and metabolic factor (PNAS 2003, PLoS-ONE 2009). Hypothesizing that additional bioactive peptides may be encoded from this region we have identified an additional six ORFs that encode peptides transcribed from within the 16s rRNA gene in the mtDNA, which we have named small humanin-like peptides, or SHLPs. SHLP1-5 are functionally analogous to humanin, and act as potent survival factors. Intriguingly an additional peptide, SHLP6, functions in a completely opposing manner. We demonstrate that endogenous SHLP6 is expressed in serum and in multiple tissues, including the prostate, and that its expression declines with age. In addition, the addition of exogenous SHLP6 promotes apoptosis in prostate cancer cell lines including 22RV1, LNCaP and DU145. Analysis of gene and protein expression of SHLP6 treated cells reveals modulation of cell cycle and apoptosis genes and a dramatic inhibition of VEGF expression. To assess the in vivo potency of SHLP6, we treated 22RV1 xenografts in SCID mice with SHLP6 for 1 week, and observed a potent inhibition of CaP xenograft growth and angiogenesis in vivo. In addition, we show that SHLP6 expression is decreased in preliminary staining of human prostate cancer, compared with normal prostate tissue. Thus, our findings not only introduce the revolutionary concept that a previously unrecognized family of peptides is produced from the mitochondria, challenging existing paradigms about mitochondrial function, but also demonstrate that SHLP6 is altered in prostate cancer, and may serve as a novel therapeutic and diagnostic agent in this disease. 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 4537.
Abstract 4436: Chronic inflammation and gastric carcinogenesis: the role of CD44 variant expression
Authors: Takeyuki Wada, Osamu Nagano, Takatsugu Ishimoto, Toshifumi Yae, Yuko Kitagawa, Hideyuki Saya
Journal: Cancer Research (2012)

Abstract CD44 is a marker of tumor-initiating cells in gastric cancer. Recently, we have reported that a CD44 variant (CD44v) interacts with xCT, a glutamate-cystine transporter, and manifests enhanced protection against reactive oxygen species (ROS), contributing to tumor growth and resistance to chemo- or radiotherapy. Although an inflammation related metaplasia and/or dysplasia of gastric epithelium is considered as key events in gastric carcinogenesis, the cause or process of these phenomena is not known. We investigated the relationship between CD44v expression and gastric carcinogenesis, using three lineages of gastric cancer mouse models, K19-Wnt1, K19-C2mE, and K19-Wnt1/C2mE mice. We also used CD44-/- K19-Wnt1/C2mE mice and Helicobacter. felis-infected C57BL/6 mice. Chronic inflammation triggered by Helicobactor infection played a major role in CD44v related gastric carcinogenesis. CD44v expression and nuclear factor-kappa B (NF-κB) activation were promoted by inflammatory cytokines, IL-1α and TNF-α, in gastric cancer cell lines. Thus, CD44v+ tumor cell expansion induced by inflammation via NF-κB pathway might contribute to tumor development. Finally, an xCT inhibitor sulfasalazine treatment significantly suppressed tumor growth in K19-Wnt1/C2mE mice. These findings suggest a significant role of CD44v in inflammation-mediated gastric carcinogenesis via ROS defense. 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 4436. doi:1538-7445.AM2012-4436