tbuckley/cabot-search huggingface dataset:
A6.06 P120-Catenin is essential for fibroblast-like synoviocyte function in organising the synovial tissue
Authors: F Kartnig, RA Byrne, T Karonitsch, I Olmos Calvo, L Heinz, J Bigenzahn, B Niederreiter, J Holinka, G Steiner, G Superti-Furga, JS Smolen, HP Kiener
Journal: Annals of the Rheumatic Diseases (2016)

<h3>Background and objectives</h3> Fibroblast like Synoviocytes (FLS) are key for the formation of the synovial lining / sublining architecture via unique cadherin-11 mediated cell-to-cell adherens junctions. Binding to the juxta-membrane domain of the cytoplasmic tail of cadherins, p120 is indispensable for the stabilisation of cadherins on the cell surface. By contrast, unbound p120-catenin interferes with small Rho GTPases, thereby regulating actin cytoskeletal organisation as well as NF-κB pathway activity. Here we probe into the function of p120-catenin for synovial tissue formation. <h3>Methods</h3> Primary FLS were cultured from synovial tissue after synovectomy of RA classified patients. The knock down (KD) of p120-catenin was achieved by the expression of specific shRNA via a lentiviral vector. Immunoblotting was performed to verify decreased p120-catenin expression levels as well as the effects on the expression of cellular cadherin-11. 2D FLS cultures were analysed using phase contrast microscopy as well as confocal immunofluorescence imaging of actin filaments and cadherin-11 mediated cell-to-cell junctions. For the analysis of FLS capacity in forming synovial-like tissue, FLS were cultured in Matrigel® micromasses. Data quantification was done with ImageJ; for statistical analyses Graphpad Prism® was used. <h3>Results</h3> p120-catenin silenced FLS demonstrated an altered cellular phenotype regarding the size, shape and the cytoskeletal organisation when compared to control cells. In conventional 2D cultures, the surface area covered by KD cells was increased threefold (p &lt; 0.0001). Actin staining revealed pronounced stress fibres that were organised in parallel within the cell body. Further, polymerized actin was significantly elevated when compared to control cells, (p &lt; 0.0001). Due to default p120-catenin, reduced quantities of cadherin-11 were observed by immunoblotting. This was consistent with decreased levels of cadherin-11 at cell-to-cell junctions as measured immunofluorescence signal intensity. Strikingly, loss of p120-catenin was associated with the impaired capacity of FLS to establish an organised synovial architecture. <h3>Conclusion</h3> Although the immunological role of p120-catenin for FLS function in synovial inflammation (NF-kB activity) has yet to be shown, our findings strongly suggest the importance of p120-catenin for the formation of the normal synovial tissue.
Affirmative Action in the Balance
Authors: Gregory D. Curfman, Stephen Morrissey, Jeffrey M. Drazen
Journal: New England Journal of Medicine (2013)

To provide good care, physicians must understand the communities and cultures in which they work. An important way to ensure that physicians understand the lives of their patients and to reduce health disparities is to promote racial and ethnic diversity in the physician workforce. However, a crucial tool that has made such diversity possible is currently in danger. Within the next few months, the U.S. Supreme Court will announce its decision in a case destined to chart the future of affirmative action in American higher education. The outcome in Fisher v. University of Texas at Austin 1 will determine whether race . . .
Successful Pregnancies after Human Renal Transplantation
Authors: Joseph E. Murray, Duncan E. Reid, J. Hartwell Harrison, John P. Merrill
Journal: New England Journal of Medicine (1963)

IN May, 1956, one of a pair of twenty-one-year-old identical twin females from Oklahoma was being studied as a potential recipient for a kidney transplant from her twin sister. Both were childless, having been married for less than a year. The ailing twin, with a three-year history of chronic glomerulonephritis, was in a dire preterminal state, with hypertension (blood pressure of 190 systolic, 120 diastolic), congestive heart failure only partially helped by digoxin and severe oral and gastrointestinal hemorrhage. Extra-corporeal hemodialyses were required on three occasions to sustain life until the necessary preliminary studies were completed.At that time there . . .
Case 20-1993
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, William F. McNeely, Betty U. McNeely, R. Bruce Donoff, Andrew E. Rosenberg
Journal: New England Journal of Medicine (1993)

Presentation of CaseA 23-year-old woman was admitted to the hospital because of a rapidly enlarging mass in a tooth-extraction socket and an osteolytic mandibular lesion.The patient had been in excellent health until one month earlier, when a left mandibular third molar tooth was extracted because of pericoronitis, without complications. During the next three weeks the socket failed to heal, and examination showed an exuberant mass within it. A course of penicillin V potassium was ineffective. Radiographs of the teeth and mandible (Figure 1) revealed a multilocular, expansile osteolytic lesion in the left portion of the mandible; the roots . . .
Abstract LB-158: A human xenograft model for developing personalized targeted therapy for pancreatic cancer
Authors: Dustin M. Walters, Sara J. Adair, Jayme B. Stokes, Cheryl Borgman, Bryce Lowrey, Reid B. Adams, Jay W. Fox, Jason A. Papin, J. Thomas Parsons, Todd W. Bauer
Journal: Cancer Research (2010)

Abstract Background: Effective treatment regimens for pancreatic ductal adenocarcinoma (PDAC) are currently lacking. Molecular-targeted therapies, while promising, have been ineffective likely due to the heterogeneity and redundancy of molecular signaling pathways. Identification of predictors of response to defined targeted therapies is critical for the development of effective and personalized therapies. Methods: We have established a human PDAC tumor bank and have orthotopically implanted patient tumors into the pancreas of immunocompromised mice. Clinicopathologic data has been collected for each patient's tumor. Tumors successfully propagated in mice are routinely screened for six genetic mutations commonly found in pancreatic cancer. Gene expression profiling and phospho-receptor tyrosine kinase (pRTK) arrays, cytokine arrays, and reverse phase protein arrays (RPPAs) are used to profile the activated signaling pathways in individual tumors. A unique genetic and molecular profile is then constructed for each human tumor. Ingenuity pathway analysis software (Ingenuity Systems, Inc., Redwood, CA) is being implemented to map the unique signaling network for each tumor using the genetic and molecular data. Results: To date 7 tumors have been analyzed, including 2 metastatic tumors and 5 primary adenocarcinomas. All tumors contained TP53 gene mutation, whereas 5 tumors exhibited mutated KRAS and 3 contained mutations in the SMAD4 gene. Analysis using pRTK arrays revealed universal activation of EGFR and variable activation of ErbB2/Her2, RON, Tie-2, FGF-R1 and 3, and Axl. The profile of pRTKs appeared stable upon tumor passage both in vivo and in culture. RPPAs revealed significant variation among tumors in activation for MAPK, AKT, SAPK, and p38. Additional cytokine/growth factor array analysis and gene expression profiling is currently underway. Conclusion: The establishment of an orthotopic human pancreatic cancer xenograft model allows for the systematic analysis of genetic and molecular characteristics of human tumors propagated within a relevant tumor microenvironment. This model affords the ability to assess tumor growth responses to targeted therapies currently in use for multiple malignancies and to correlate tumor response with genetic perturbations, changes in gene expression and activation of cell signaling networks. This model will be a significant step toward developing personalized targeted therapy for pancreatic cancer. 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-158.
A2.25 Vitamin D induces a TR1-like phenotype in human CCR6<sup>+</sup>T cells and promotes their migration to an inflammatory environment
Authors: W Dankers, JP van Hamburg, N Davelaar, PS Asmawidjaja, K Wen, W Razawy, M Molendijk, JPTM Van Leeuwen, EM Colin, E Lubberts
Journal: Annals of the Rheumatic Diseases (2016)

<h3>Background and objectives</h3> CCR6+ T helper (Th) cells, including Th17 and Th17.1 cells, are thought to play an important role in the pathogenesis of autoimmune diseases such as rheumatoid arthritis (RA). They produce cytokines like IL-17A and TNFα and activate synovial fibroblasts to induce a pro-inflammatory feedback loop. This interaction may underlie the chronic joint inflammation in RA and therefore CCR6+ Th cells are an interesting therapeutic target in this disease. Vitamin D is known to have suppressive effects on autoimmune diseases and its active metabolite directly inhibits the pathogenicity of CCR6+ Th cells. Here we further investigated the effect of 1,25(OH)2D3 on CCR6+ Th cells to understand how 1,25(OH)2D3 suppresses the inflammatory responses in autoimmune diseases. <h3>Materials and methods</h3> We cultured CCR6+ Th cells from treatment-naïve early RA patients with or without 1,25(OH)2D3 and generated gene-expression profiles. These profiles were validated using RT-PCR, ELISA and flow cytometry. Functional effects were evaluated via co-culture with RA synovial fibroblasts (RASF) and Boyden chamber-based migration assays. <h3>Results</h3> The gene-expression profiles confirmed that 1,25(OH)2D3 downregulated pro-inflammatory cytokines like IL-17A, IL-17F and IL-22, but also genes important for the pathogenic Th17 phenotype like RORC and IL23R. In contrast, 1,25(OH)2D3 induced the anti-inflammatory cytokine IL-10, but not the classical Treg transcription factor FoxP3. Instead, upregulation of genes like LAG3, c-MAF, CTLA4, and IRF8 suggests a Tr1-like phenotype. Because of the decreased pathogenicity of these cells, we next investigated whether they migrate towards the site of inflammation. Indeed, the gene-expression profiles indicate a shift in the chemokine receptor profile upon treatment with 1,25(OH)2D3. This altered profile was accompanied by increased migration towards an inflammatory environment as modelled by the CCR6+ Th – RASF co-culture. Interestingly, CCR6+ Th cells that were pre-treated with 1,25(OH)2D3 were less capable of inducing the pro-inflammatory loop upon interaction with RASF. <h3>Conclusions</h3> 1,25(OH)2D3 inhibits the pathogenic Th17 phenotype in CCR6+ Th cells, while inducing a regulatory Tr1-like phenotype. These cells will then migrate towards the site of inflammation, where they are less potent activators of RASF. This effect of 1,25(OH)2D3 on CCR6+ Th cells may underlie the suppression of RA by vitamin D.
Phase II Study of the Novel Epothilone Sagopilone (ZK-EPO) in Patients with Progressive Metastatic Breast Cancer.
Authors: M. Campone, C. Dittrich, T. Cufer, A. Dudov, P. Dao Phan, T. Schmelter, M. Giurescu, M. Martin
Journal: Cancer Research (2009)

Abstract Background: Sagopilone, a microtubule-stabilizing agent, is a novel, fully synthetic epothilone undergoing clinical development in a variety of tumor types. Proof-of-concept has been demonstrated in Phase II trials of platinum-resistant and -sensitive ovarian cancer, prostate cancer, and melanoma. Sagopilone has shown significant preclinical activity in taxane-resistant breast cancer cell lines, and preliminary clinical activity in patients (pts) with taxane-sensitive and -resistant disease in Phase I. This Phase II study assessed the efficacy, safety, and tolerability of sagopilone in metastatic breast cancer (MBC).Methods: Pts with progressive MBC who received a maximum of 2 previous chemotherapies not containing taxanes or vinca alkaloids were randomized to either i.v. sagopilone 12, 16, or 22 mg/m2 over 3 h or 22 mg/m2 over 0.5 h, every 21 days, for up to 6 cycles. The primary endpoint was the proportion of pts with a complete response (CR) or partial response (PR) as best overall response. A Simon's 2-stage design was used: 15 pts were to be initially accrued per arm; a further 12 pts were recruited per arm if ≥5/15 pts showed a response. The study was to be considered successful if an objective response (CR or PR) was observed in ≥10/27 pts.Results: Eighty-two female pts (median age 59 years) were randomized to treatment. The median number of treatment cycles was 3 (range 1-9). Of 77 pts evaluable for best response (per protocol set), 11 (14%) had PR, 32 (42%) stable disease (SD), 30 (39%) progressive disease (PD), and 4 (5%) unknown (Table 1).Table 1. Number of pts (%) with best overall responseSagopilone12 mg/m² 3 h16 mg/m² 3 h22 mg/m² 3 h22 mg/m² 0.5 hTotalNo. of pts14 (100.0)26 (100.0)16 (100.0)21 (100.0)77 (100.0)PR0 (0.0)3 (11.5)3 (18.8)5 (23.8)11 (14.3)SD5 (35.7)10 (38.5)8 (50.0)9 (42.9)32 (41.6)PD9 (64.3)11 (42.3)4 (25.0)6 (28.6)30 (39.0)Unknown0 (0.0)2 (7.7)1 (6.3)1 (4.8)4 (5.2) The study outcome was not considered successful for any of the 4 regimens tested. All 82 pts were evaluable for safety. Thirty-six pts discontinued the study prior to cycle 6: 35 due to adverse events (AEs) and 1 due to consent withdrawal. Treatment-related AEs documented in ≥20% pts were: sensory neuropathy 60% (18% grade 3, 1% grade 4); asthenia 26% (6% grade 3); alopecia 23%, myalgia 20% (2% grade 3); fatigue 20%; and nausea 20% (1% grade 3).Conclusions: Sagopilone did not meet the primary endpoint in this pt population with progressive MBC. Treatment-related AEs appeared to be considerable but manageable at all dose levels. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6107.
Abstract 3149: OncoPredictor: A systematic approach for predicting responsive cancer populations from large scale cell line screening
Authors: Mark Tomilo, Sean F. Eddy, Wendy Lockwood Banka, Seth E. Sadis, Paul D. Williams, Peter J. Wyngaard, Christine O'Day, Yulia Ovechkino, Usha Warrior, Daniel R. Rhodes
Journal: Cancer Research (2011)

Abstract Investigational new drugs for cancer must demonstrate convincing preclinical efficacy and a compelling strategy to translate preclinical observations to the clinical setting. Personalized medicine approaches are gaining wider acceptance, and large scale cell line databases have demonstrated utility in identifying biomarkers of drug response that can inform clinical development strategies. However, the lack of an integrated platform to translate preclinical biomarker profiles to clinical populations limits the power of this approach. To solve this problem we developed, first, a cell line screening and genomic analysis pipeline that associates drug response across 200+ cell lines with mutation, DNA copy number, and gene expression biomarkers; and second, a parallel database of biomarker frequencies in clinical tumor samples, compiled from all available published genomic data. In the present study, we tested 8 targeted anti-cancer agents and identified cell line biomarkers representing each of the genomic data types – mutation, DNA amplification, and gene over-expression – and then assessed the distribution of these biomarkers across tumor samples. In each case the tumor populations predicted to be responsive by this unsupervised approach were validated by results from clinical trials. We also present an example of biomarker results leading to potential new indications for an approved drug. 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 3149. doi:10.1158/1538-7445.AM2011-3149
Case 8-2005
Authors: Mark C. Gebhardt, Daniel I. Rosenthal, Paula M. Arnell
Journal: New England Journal of Medicine (2005)

A 10-year-old boy had pain in the right thigh that interfered with activities, awoke him at night, and was only slightly relieved by acetaminophen. Magnetic resonance imaging and radionuclide bone scans showed a large area of abnormality within the femur. Computed tomography–guided (CT) biopsy was not completed because of the patient's agitation, but CT images showed a small lytic lesion in the cortex surrounded by dense bone. A diagnostic and therapeutic procedure was performed.
A phase II study of enzastaurin as second- or third-line treatment of non-small cell lung cancer (NSCLC)
Authors: G. Bepler, Y. Oh, H. Burris, A. Cleverly, M. Lahn, R. S. Herbst
Journal: Journal of Clinical Oncology (2007)

7543 Background: Enzastaurin, an oral serine/threonine kinase inhibitor, suppresses signaling through PKC and the PI3K/AKT pathway, induces tumor cell apoptosis, reduces proliferation, and suppresses tumor-induced angiogenesis. Over-expression and activity of PKC and PI3K/AKT are associated with poor prognosis and treatment resistance in NSCLC. This multicenter phase II trial of enzastaurin as second- and third-line treatment of NSCLC determined the rate of progression-free survival (PFS) at 6 months (mos). Secondary objectives included safety and the rate of overall survival (OS) at 12 mos. Methods: Eligibility included metastatic (stage IV and wet IIIB) NSCLC and prior platinum-based chemotherapy. Patients (pts) received 500 mg of oral enzastaurin, once daily, until disease progression or unacceptable toxicity occurred. All pts were eligible for 2nd or 3rd line treatment. Results: In the 54 pts enrolled [54% M, 46% F; median age: 63 (range: 43–82); 22.2% stage III, 77.8% stage IV, ECOG PS=2], adenocarcinoma was the most frequent diagnosis (67%). Prior therapies included radiotherapy (74%) and EGFR inhibitors (28%). At the final analysis, the median PFS was 1.9 mos (95% CI: 1.7–1.9), and the PFS rate at 6 mos was 14% (95% CI: 4.4%–23.6%). The median OS was 9.9 mos (95% CI: 6.5–14.6). The OS rate at 12 mos was 46.3% (95% CI: 32.1%–60.5%). Nineteen pts (35%) had stable disease (SD); none had a complete or partial response. Ten (19%) pts were on-study for =6 cycles, 3 of whom continued for &gt;10 months. The most common toxicity, fatigue (grade =2, n=15), occurred within 1 week of enrollment and was not reported in pts with SD. Grade =3 toxicities observed were ataxia (n=1), fatigue (n=2), thrombo-embolism (n=1), and anemia (n=1). Two pts discontinued due to fatigue and dizziness. Five pts died on-study and 4 within 30 days of discontinuation due to PD. Post-study chemotherapy (n=28) included bevacizumab, erlotinib, pemetrexed, gemcitabine, cisplatinum and paclitaxel. Conclusion: Although no objective tumor responses occurred, 14% of the pts were progression-free at 6 months. Based on encouraging survival and tolerability data, further evaluation of enzastaurin as a single agent or in combination, is warranted in NSCLC. No significant financial relationships to disclose.
Résultats préliminaires d'une prothèse biodégradable au cours des sténoses oesophagiennes
Authors: D Heresbach, A Boruchowicz, A Peter, M Delvaux, H Hudziak, M Antonietti, S Lecleire, B Faulques, M Barthet
Journal: Endoscopy (2010)

Introduction: Les sténoses oesophagiennes (SO) malignes sont traitées par prothèse métallique partiellement couverte de façon palliative ou pour les SO bénignes par prothèse totalement couverte ou plastique. Les matériaux biodégradables utilisés comme prothèses vasculaires deviennent disponibles pour les SO. Le but de notre étude était de colliger les résultats préliminaires de l'utilisation de la prothèse oesophagienne biodégradable (BD-Stent, ABS, Bolton) au cours de SO.
AB0008 Reduced phosphoinositide 3-kinase Δ expression in synovial membrane is associated with the response to anti-tnf response in rheumatoid arthritis.
Authors: A. Julià, R. Celis, G. Ávila, R. Sanmartí, S. Marsal, J. Cañete
Journal: Annals of the Rheumatic Diseases (2013)

Background Tumor necrosis alpha (TNF) blockade has been a highly successful therapeutical approach in the management of Rheumatoid Arthritis (RA). However, ∼33% of RA patients do not respond adequately to this treatment. To date, there is insufficient knowledge on the biological mechanisms that prevent an adequate clinical response when using anti-TNF agents.

Objectives We have performed a microarray gene expression analysis on synovial biopsies to identify key genes and pathways associated with the lack of response to anti-TNF therapies. We also performed immunohistochemistry in order to confirm mRNA expression data.

Methods Synovial biopsies from n=11 RA patients were obtained during active inflammation, before the initiation of an anti-TNF therapy. Samples from pathological tissue were obtained by guided arthroscopy and preserved for RNA and histological examination. RNA was extracted from all samples and analyzed using Illumina WG-6 v3.0 expression BeadChip, containing probes for the analysis of 48,000 transcripts. Gene expression data normalization and statistical analysis was performed using the Bioconductor statistical software tools. EULAR response was measured after 5 months of anti-TNF treatment. Quantification of PIK3-delta ( PIK3CD ) in synovial biopsies was performed using Digital Image Analysis.

Results After 5 months of therapy, 8 patients achieved an EULAR moderate or good response and 3 patients were categorized as none responders. [Table 1][1] shows the main clinical features of the patient cohort. Differential gene expression between both groups revealed several genes significantly associated with anti-TNF response. Pathway analysis revealed an elevated expression of genes associated with CD14+ monocyte profiles in the synovial tissue of non-responder patients (P 1.5 fold change difference between the two groups was PIK3CD (P < 1x10-12), a gene recently identified as a key regulator of synoviocyte function in RA. The differential expression of PIK3CD and other highly significant genes was confirmed by RealTime-PCR. Histological analysis of synovial samples demonstrated a significant reduction in PIK3CD expression in responders (P=0.036 PIK3CD/mm2) as well as a significant reduction in CD68 expressing cells in the synovial lining (P=0.027) after 5 months of anti-TNF therapy.

![Figure][2] 

Conclusions This study is in line with previous investigations that PIK3CD is crucial for RA pathophysiology. We have found, for the first time, an association of this gene with the response to anti-TNF therapy in RA.

Acknowledgements Patent pending.

Disclosure of Interest None Declared

 [1]: #F1
 [2]: pending:yes
Double-tunnel endoscopic submucosal tunnel dissection for circumferential superficial esophageal neoplasms
Authors: Yaqi Zhai, Enqiang Linghu, Huikai Li
Journal: Endoscopy (2014)

Endoscopic submucosal tunnel dissection (ESTD) was first introduced by us as a new strategy for rapid resection of large esophageal neoplasms [1]. However, for circumferential superficial esophageal neoplasms (CSENs), an obscured view and poor submucosal lifting have been experienced during lateral resection of the final one-third of the circumference. In our early experience using single-tunnel ESTD to treat four patients with CSENs, the mean operation time was 382.5 minutes and one patient experienced a perforation. To counteract the problems with this technique, we have now successfully performed a double-tunnel ESTD procedure on a patient with an 8-cm CSEN.