tbuckley/cabot-search huggingface dataset:
Abstract 207: Caveolin-1 drives oncogenic TGFβ effects in prostate cancer: in vitro mechanistic insights integrated with systems pathology visualization in primary tumor samples
Authors: Teijo Pellinen, Sami Blom, Sara Sanches, Katja Välimäki, John-Patrick Mpindi, Antti Rannikko, Raffaele Strippoli, Maria Montoya, Hind Azegrouz, Tuomas Mirtti, Miguel del Pozo, Olli Kallioniemi
Journal: Cancer Research (2015)

Abstract Caveolin-1 (Cav1) can have both a tumor suppressive or promoting role depending on cancer tissue, and its potential active role in the progression of prostate cancer remains poorly understood. In this study, we found out that Cav1 represses the expression of E-cadherin in prostate cancer cell lines, and that the expressions of these two genes show an inverse correlation both at the mRNA and protein levels in PCa patient samples. We show that the combined loss of E-cadherin and gain of Cav1 expression is an early event in a subgroup of patients (&amp;lt;10%) (n(patients) = 80, n(glands) = 263, r = -0.35, p&amp;lt;0.001). Cav1 positively regulates TGFβ targets with known oncogenic and pro-EMT functions (e.g. Slug, Pai-1), and its absence switches the TGFβ to become inhibitory to PCa cells by inducing p21 (CDKN1A) and STAT1 signaling. These changes were strongly associated with changes in 3D-invasive growth. By using RNAi image-based screening, we found out that Cav1 is positively regulated by beta1-integrins and cell adhesion to ECM. This association together with different alpha-integrins was visualized and quantified in human prostate cancer patient tissues (n = 80) using novel multiplexed fluorescent imaging. Both the integrin beta1 and alpha2 showed high correlation with Cav1 expression (p-values&amp;lt;0.001) in tumor epithelium as well as in stroma. In conclusion, the results suggest that Cav1 could be an important promoter of invasive growth in a subgroup of PCa, where it is upregulated by beta1-integrins, and where it promotes oncogenic TGFβ signaling. Citation Format: Teijo Pellinen, Sami Blom, Sara Sanches, Katja Välimäki, John-Patrick Mpindi, Antti Rannikko, Raffaele Strippoli, Maria Montoya, Hind Azegrouz, Tuomas Mirtti, Miguel del Pozo, Olli Kallioniemi. Caveolin-1 drives oncogenic TGFβ effects in prostate cancer: in vitro mechanistic insights integrated with systems pathology visualization in primary tumor samples. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 207. doi:10.1158/1538-7445.AM2015-207
Allogeneic Bone Marrow Transplantation in a Child with Hemophilia A and Severe Aplastic Anemia.
Authors: Mauricio Ostronoff, Rodrigo Florencio, Fabiana Ostronoff, Gilma Campos, Sandra Arruda, Claudia Vaz, Ana Patricia Souto, Alexandre Sucupira, Mariana Coutinho Domingues, Rodolfo Calixto, Kleber Matias, Tagliari Clemente
Journal: Blood (2005)
Efficacy and tolerability of interferon-free antiviral therapy in kidney transplant recipients with chronic hepatitis C
Authors: Inmaculada Fernández, Raquel Muñoz-Gómez, Juan M. Pascasio, Carme Baliellas, Natalia Polanco, Nuria Esforzado, Ana Arias, Martín Prieto, Lluis Castells, Valentín Cuervas-Mons, Olga Hernández, Javier Crespo, José L. Calleja, Xavier Forns, María-Carlota Londoño
Journal: Journal of Hepatology (2016)
Association of tumor-infiltrating lymphocytes with brain edema and overall survival in brain metastases.
Authors: Matthias Preusser, Anna Sophie Berghoff, Elisabeth Fuchs, Gerda Ricken, Aysegul Ilhan-Mutlu, Manuel Magerle, Thomas Spanberger, Adelheid Woehrer, Monika Hackl, Josef Pichler, Markus Hutterer, Georg Widhalm, Karin Dieckmann, Peter Birner, Daniela Prayer, Johannes A. Hainfellner, Christoph Zielinski, Rupert Bartsch
Journal: Journal of Clinical Oncology (2014)

2012 Background: Density of tumor-infiltrating lymphocytes (TILs) has a prognostic impact in various extracranial solid tumors. We characterized TILs in patients with brain metastases (BM). Methods: We immunostained neurosurgical specimens of patients with newly diagnosed single brain metastasis for CD3, CD8, CD45RO and FOXP3 and used previously published semiquantitative evaluation criteria. Results: 118 BM specimens of patients with lung cancer (62/118; 52%), breast cancer (17/118; 14%), melanoma (6/118; 5%), kidney cancer (10/118; 8%) or another primary tumor (23/118; 19%) were available for this study. Dense infiltration with CD3+ TILs was observed in 64/118 (54%) specimens, with CD8+ TILs in 70/118 (59%), with CD45R0+ TILs in 72/118 (61%) and with FOXP3+ TILs in 26/118 (22%) specimens. Dense CD3+ TILs infiltration was more frequently observed in lung cancer, melanoma and kidney cancer BM than in breast cancer BM (p=0.024; Chi square test). Melanoma BM had more frequently dense infiltration with FOXP3+ TILs (p=0.003; Chi square test) than other BM subtypes. Density of CD3+, CD8+, CD45RO+, or FOXP3+ TILs did not correlate with preoperative steroid application (p>0.05; Chi Square test). Patients with dense infiltration of CD3+ TIL had significantly improved OS (27 vs. 12 months; p=0.002; log rank test). Further, dense infiltration with CD8+ TILs was associated with improved OS (16 vs. 12 months; p=0.048; log rank test) and large peritumoral edema on the preoperative MRI (p=0.03; Chi Square test). Dense infiltration with CD45RO+ TILs was correlated with improved survival prognosis (18 vs. 8 months; p=0.01; log rank test). Patients with dense infiltration of FOXP3+ TILs had an impaired survival prognosis (6 vs. 16 months; p=0.05; log rank test). A composite "immuno score" showed a strong association with median OS (27 months for cases CD8+/CD45RO+/FOXP3- infiltrates and 6 for cases with CD8-/CD45RO-/FOXP3+ infiltrates; p=0.001 log-rank test). Conclusions: Dense TILs infiltrates are common in BM and correlate with the amount of peritumoral brain edema and improved survival prognosis. Further studies should investigate the therapeutic impact of immunomodulatory agents in patients with BM.
Abstract 2692: High allele frequency of KRAS functional mutations predicts resistance to MEK inhibitors: Evidence from cell lines and human tumor xenograft models
Authors: Anupama Reddy, Maria Pinzon-Ortiz, Adnan Derti, Joshua Korn, David Ruddy, Guizhi Yang, John Green, Hui Gao, Joseph Lehar, Giordano Caponigro, Z. Alexander Cao
Journal: Cancer Research (2015)

Abstract Introduction KRAS mutant tumors represent a high unmet need for effective therapy. Even though there is no targeted therapy for KRAS, inhibitors of downstream targets like MEK have shown efficacy in preclinical studies. However, clinical trials of MEK inhibitors in KRAS-mutant tumors have not been successful, although there have been some responders. We sought to understand resistance to MEK inhibition in KRAS-mutant tumors and to develop biomarkers for patient stratification. Results Using DNA and RNA sequencing data from cell lines, we found that high variant allele frequency (&amp;gt;50%) of KRAS functional mutations (G12, G13, Q61) was associated with baseline resistance to MEK inhibitors AZD6244 and MEK162 across multiple tumor types. Low allele frequency of KRAS mutation was found to be necessary but not sufficient for sensitivity to MEK inhibitors, suggesting the existence of additional resistance mechanisms. Comparison of copy number and variant allele frequency of KRAS showed that MEK inhibitor-resistant cell lines have either amplified mutant alleles or lost WT alleles. This prediction of high KRAS mutant allele frequency being associated with MEKi resistance was successfully validated in vivo in 19 primary colorectal tumor xenograft models treated with MEK162. High KRAS mutant allele frequency and high KRAS expression were also associated with acquired resistance to BKM120+MEK162 combination treatment in an in vivo model of HeyA8, an ovarian cell line with a KRAS G12D mutation. This prediction was also supported by the observation in a Phase II clinical trial with MEK inhibitor refametinib + gemcitabine in pancreatic cancer [1]. Patients with disease progression had a significantly higher KRAS mutant allele frequency compared to partial responders and stable disease. Conclusion High allele frequency of KRAS functional mutations is associated with resistance to MEK inhibitors. Excluding patients with high KRAS mutant allele frequency has the potential to improve clinical trial outcomes and benefit patients, with the added benefit that it may not require any additional screening or novel biomarkers. References [1] Reiss et al., J Clin Oncol 32:5s, 2014 (suppl; abstr 4129) Citation Format: Anupama Reddy, Maria Pinzon-Ortiz, Adnan Derti, Joshua Korn, David Ruddy, Guizhi Yang, John Green, Hui Gao, Joseph Lehar, Giordano Caponigro, Z. Alexander Cao. High allele frequency of KRAS functional mutations predicts resistance to MEK inhibitors: Evidence from cell lines and human tumor xenograft models. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2692. doi:10.1158/1538-7445.AM2015-2692
Abstract 3917: PDGF induces cell growth and glycolysis in colon cancer
Authors: Romana Moench, Vinicius Kannen, Tanja Grimmig, Christoph T. Germer, Martin Gasser, Ana Maria Waaga-Gasser
Journal: Cancer Research (2015)

Abstract The platelet derived growth factor (PDGF) plays an important role in several solid tumors. Involved in cell migration and proliferation primarily of stromal cells in cancers PDGF represents a key target in cancer therapy. The aim of this study was to analyze the specific role of PDGF on tumor cell proliferation and metabolism in colorectal cancer (CRC). The human colon cancer cell line HT-29 was cultured and stimulated time-dependently with PDGF. Additionally, inhibition of the PI3k/Akt/mTOR-pathway was performed simultaneously to PDGF stimulation. Whole cell and RNA extracts were analyzed by Western Blot and RT-q-PCR for the PI3k/Akt/mTOR-pathway and components of cellular metabolism. To investigate the effects of PDGF on proliferation MTS assays were performed. Additionally, mRNA levels of PDGF and metabolic factors in tumors from patients with CRC were analyzed by RT-qPCR. PDGF stimulation resulted in increased HT29 cell proliferation compared to untreated controls. Blocking of Akt resulted in inhibition of pS6, activation of Retinoblastoma (Rb) and reduced tumor cell growth. Additionally, under stimulation a higher glycolytic rate was observed while oxygen consumption remained unaltered. Investigated tumors from patients with CRC showed a stage-dependent increase in PDGF expression and a boosted glycolytic rate. The cytokine PDGF induced proliferation accompanied with an altered glycolysis in HT-29 colon cancer. An increased glycolysis and tumor cell proliferation support accelerated cell proliferation and tumor growth. The growth reducing effect of Akt inhibition indicates the PI3K/Akt/mTOR-pathway to play a crucial role in CRC progression and therefore could be an important target in cancer therapy. Note: This abstract was not presented at the meeting. Citation Format: Romana Moench, Vinicius Kannen, Tanja Grimmig, Christoph T. Germer, Martin Gasser, Ana Maria Waaga-Gasser. PDGF induces cell growth and glycolysis in colon cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3917. doi:10.1158/1538-7445.AM2015-3917
269. Novel Synthetic AAV Efficiently Transduces Neurosensory Hair Cells in the Cochlea
Authors: Lukas Landegger, Bifeng Pang, Sarah Wassmer, Sarah Gluck, Alice Galvin, Konstantina M. Stankovic, Jeff R. Holt, Luk H. Vandenberghe
Journal: Molecular Therapy (2016)

Hearing loss is the most common sensory disorder worldwide. Approximately 15% of American adults report trouble hearing. Prevalence of hearing loss increases from 2% (age 45-54) to 50% (over age 75). Between 2 and 3 per 1000 live births present with hearing loss in one or both ears; 50% of hearing loss at birth is genetic in etiology. While the first cochlear gene therapy for hearing loss is underway, early results, as well as data from preclinical models, indicate a need for improved gene delivery vehicles for safe and efficient targeting of relevant cell types in the cochlea. In particular, outer hair cells (OHC) have been a challenging target for AAV. OHCs are important for auditory sensitivity and frequency selectivity, key parameters for complex and sophisticated hearing function in humans. Here, we evaluated several common AAV serotypes as well as Anc80L65, an in silico designed AAV based on evolutionary modeling, for its ability to target the neurosensory cells in the inner ear, particularly inner (IHC) and outer hair cells. Cochlear explants of both CBA/CaJ and C57Bl/6 mice were exposed to equal doses of iodixonal purified preparations of AAV1,2,6,8,9, and Anc80L65 that encoded eGFP. After 48h, explants were evaluated either immediately or after an additional 5 days of culture. In both animal model explants, Anc80L65 demonstrated highly efficient IHC and OHC transduction (60-100% at 48h, and 100% at 48h+5d). AAV2 in this setting was also efficient, although to a lesser extent. Most serotypes targeted supporting cells and the spiral limbus, to a moderate extent, with AAV8 being least efficient. GFP expression was present from apex to base, with moderately increased targeting for basal hair cells. Next, we tested Anc80L65 in vivo using a clinically relevant round window injection approach. C57Bl/6 mice received 1µl injection of vector at p0-p1 and cochlea were dissected at p6. Results demonstrate transduction from base to apex of IHC, OHC, and supporting cells at rates of close to 100% for IHC, and ranging from approximately 50-100% of OHCs, although at lesser fluorescent intensity. Animals injected at p1 retained similar levels of GFP hair cell positivity at p30 day of sacrifice. Animals in our study were monitored for function of single cells electrophysiogically, hearing function by Auditory Brainstem Response and Distortion Product Otoacoustic Emission measurements, ectopic expression, and immunological parameters. Ongoing studies are evaluating the transduction properties at later times of injection and disease models of hearing loss. In conclusion, Anc80L65's unique ability to target IHC as well as OHC following RW injection is highly desirable to restore higher level hearing function in genetic forms of deafness through gene therapy.
Tissue Factor: Catch Me If You Can!
Authors: Cihan Ay, Nigel Mackman
Journal: Journal of Clinical Oncology (2017)

Article Tools UNDERSTANDING THE PATHWAY Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES Tissue Factor As a Predictor of Recurrent Venous Thromboembolism in Malignancy: Biomarker Analyses of the CATCH Trial. December 27, 2016 ARTICLE CITATION DOI: 10.1200/JCO.2016.70.6788 Journal of Clinical Oncology - published online before print December 27, 2016 PMID: 28029321 Tissue Factor: Catch Me If You Can! Cihan AyxCihan AySearch for articles by this author and Nigel MackmanxNigel MackmanSearch for articles by this author Show More Cihan Ay, University of North Carolina at Chapel Hill, Chapel Hill, NC; Medical University of Vienna, Vienna, Austria; and Nigel Mackman, University of North Carolina at Chapel Hill, Chapel Hill, NC https://doi.org/10.1200/JCO.2016.70.6788 First Page Full Text PDF Figures and Tables © 2016 by American Society of Clinical Oncology Companion Tissue Factor As a Predictor of Recurrent Venous Thromboembolism in Malignancy: Biomarker Analyses of the CATCH Trial
Give heavy drinkers scans to detect liver disease early, says NICE
Authors: Susan Mayor
Journal: BMJ (2016)

GPs and community health services should refer people who drink heavily—including men who drink more than 22 pints of beer and women who drink more than 3.5 bottles of wine a week—for scans to detect liver disease early, the National Institute for Health and Care Excellence (NICE) recommends in a new draft quality standard.1

NICE advises that adults and young people with risk factors for cirrhosis are offered non-invasive testing so that the condition can be detected early and they can …
Abstract 4616: Genome wide association analysis identified 15q24 as a bladder cancer susceptibility locus
Authors: Koichi Matsuda, Atsushi Takahashi, Chizu Tanikawa, Michiaki Kubo, Yusuke Nakamrua
Journal: Cancer Research (2015)

Abstract Bladder cancer is one of the most frequent cancers, which causes ∼150 000 death per year in the world. Both environmental and genetic factors are involved in the development of bladder cancer, and tobacco smoking is known to be the most important factor to increase the risk of bladder cancer; Recent genome-wide association studies (GWASs) in European populations have identified multiple genetic factors associated with bladder cancer. However, no GWAS has yet been conducted in Asian populations. Through genome wide association analysis and an independent replication study using a total of 1,131 bladder cancer cases and 12,558 non-cancer controls of Japanese populations, here we identified a SNP rs11543198 on chromosome 15q24 as a bladder cancer susceptibility locus. Rs1154319 was associated with bladder cancer risk with odds ratio (OR) of 1.41 and P value of 4.03 × 10-9. Subgroup analysis revealed rs11543198 to have a stronger effect in male smokers with OR of 1.66. Imputational analysis in this region suggested CYP1A2, which metabolizes tobacco-derived carcinogen, as a causative gene. We also confirmed the association of previously-reported loci, SLC14A1, APOBEC3A, PSCA, and MYC, with bladder cancer. Our finding implies the crucial roles of genetic variations on the chemically-associated development of bladder cancer. Citation Format: Koichi Matsuda, Atsushi Takahashi, Chizu Tanikawa, Michiaki Kubo, Yusuke Nakamrua. Genome wide association analysis identified 15q24 as a bladder cancer susceptibility locus. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4616. doi:10.1158/1538-7445.AM2015-4616
Abstract 4190: A mouse model of pRb2/p130 in prostate cancer
Authors: Silvia Boffo, Andres J. Klein-Szanto, Flavio Rizzolio, Antonio Giordano
Journal: Cancer Research (2015)

Abstract INTRODUCTION Prostate Cancer (PCa) is the most commonly diagnosed cancer in men and it is responsible for the second highest number of cancer-related deaths in the United States. There is an urgent need for new treatments and better experimental animal models to study PCa development, progression, and metastasis. Prostate cancer is a heterogeneous and multifocal disease that arises from several genetic and epigenetic aberrations. Among different altered pathways, the Retinoblastoma is inactivated in more than fifty percent of PCa. Despite a plentiful literature, the activity of pRb members (pRb, pRb2/p130 and p107) is not fully elucidated. From a previously published mouse model, we know that the inactivation of all the pRb members induces aberrant proliferation and it is sufficient for tumor initiation. Here, we describe a novel double ko (Rb, pRb2/p130) mouse model, which offers a new opportunity to dissect prostate tumor initiation and development. MATERIALS AND METHODS To study the effect of pRb2/p130 inactivation on prostate tumorigenesis and progression, we knocked out pRb and/or pRb2/p130 in the prostate tissue (Probasin-CRE). The genotypes of each gene were determined by PCR. To analyze the effects of pRb2/p130 loss, we collected prostate tissues at different time points (3, 6, 9, 12 and 18 months). A portion of each prostate sample was fixed in formalin and embedded in paraffin to perform immunohistochemistry analyses and another portion was flash-frozen for molecular studies. The histological classification of each prostate samples was made on H&amp;E-stained sections by A.K.S., a veterinary pathologist with extensive experience in murine prostate pathology. RESULTS As reported in literature, pRb family disruption in the prostate epithelium induces prostatic intraepithelial neoplasia. The prostate of triple ko mice showed extensive abnormal gland architecture beginning as early as 2 months of age with a focal hyperplasia. By 3 months of age, all the triple ko mice displayed characteristic traits of murine prostatic intraepithelial neoplasia (mPIN). Double ko (pRb and pRb2/p130) mice developed hyperplasia after 6 months and focally invasive well-differentiated adenocarcinomas by 12-18 months. CONCLUSIONS Our preliminary findings suggest that the inactivation of pRb and pRb2/p130 leads to the development of a prostate tumor phenotype and highlight the importance of the function of pRb2/p130 in the prostatic epithelium. This model will be useful to clarify the molecular mechanism of pRb2/p130 function and represents a new opportunity for cancer therapy. Citation Format: Silvia Boffo, Andres J. Klein-Szanto, Flavio Rizzolio, Antonio Giordano. A mouse model of pRb2/p130 in prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4190. doi:10.1158/1538-7445.AM2015-4190
Response to: ‘Why CAPS criteria are not diagnostic criteria?’ by Landewé and van der Heijde
Authors: Jasmin B Kuemmerle-Deschner, Susanne M Benseler
Journal: Annals of the Rheumatic Diseases (2016)

It is a great privilege for us to send this response to the letter submitted by Landewe and van der Heijde,1 who are high-profile leaders in the development of classification criteria for the European League Against Rheumatism (EULAR). We thank them for their kind and educational comments.

Cryopyrin-associated periodic syndrome (CAPS) is a rare and clinically heterogeneous disease. As masterfully put together by Toplak et al 2 in 2012, the delay to diagnosis of CAPS—due to lack of recognition and/or lack of access to the gold standard test, the confirmation of disease causing mutations in the NLRP3 gene—result in a tremendous disease burden. …
A functional variant of the neuropeptide S receptor-1 gene modulates clinical outcomes and healthcare utilization in patients with systolic heart failure: results from the Interdisciplinary Network Heart Failure (INH) Study
Authors: Christiane E. Angermann, Mathias Kaspar, Almuth Marx, Sarah Kittel‐Schneider, Dominik Menhofer, Stefan Störk, Georg Ertl, Katharina Domschke, Jürgen Deckert, Andreas Reif
Journal: European Journal of Heart Failure (2016)