tbuckley/cabot-search huggingface dataset:
Abstract 905: Design and synthesis of regorafenib analogues against signal transducers and activators of transcription 3 in hepatocellular carcinoma cells.
Authors: Jung-Chen Su, Kuen-Feng Chen, Wen-Tien Tai, Jui-Wen Huang, Chung-Wai Shiau
Journal: Cancer Research (2013)

Abstract Background: Regorafenib has been approved for the treatment of metastatic colorectal cancer (m-RCC) by FDA. The major targets of regorafenib are membrane-bound and intracellular kinases including RET, VEGFR1, VEGFR2, VEGFR3, KIT, PDGFR-alpha, PDGFR-beta, FGFR1, FGFR2, TIE2, DDR2, Trk2A, Eph2A, RAF-1, BRAF, BRAFV600E, SAPK2, PTK5, and Abl pathways. In HCC, signal transducers and activators of transcription 3 (STAT3) is a key transcription factor involving in cell proliferation and survival in hepatocellular carcinoma cells, Targeting STAT3 by small molecule is a promising strategy in HCC therapy. Methods: We have designed and synthesized a series of regorafenib analogues without kinase inhibitory activity. These compounds are treated with and analyzed in terms of STAT3 activity in HCC cell lines. Also, Effects of regorafenib analogues induced cell death are evaluated. Results: We demonstrate that regorafenib and its analogues repress STAT3 phosphorylation, subsequently abrogate STAT3-regulated protein, Mcl-1 and cyclin D1 and further induce apoptosis in HCC cells. Overexpression of STAT3 in PLC-5 cells attenuates apoptotic effect with regorafenib and its analogues treatment, suggesting STAT3, at least, is a major target. Interestingly, the new analugues of regorafenib are devoid of kinase inhibitory activity which implies the involvement of other regulation factors. The activity of negative regulator of STAT3, such as protein tyrosine phosphatases, is under investigation. In summary, the new analogues provide a lead for the design of a new class of agents that inhibit STAT3 along and synergize with clinical drugs in HCC.(Supported by NSC 100-2325-B-010-007) Citation Format: Jung-Chen Su, Kuen-Feng Chen, Wen-Tien Tai, Jui-Wen Huang, Chung-Wai Shiau. Design and synthesis of regorafenib analogues against signal transducers and activators of transcription 3 in hepatocellular carcinoma 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 905. doi:10.1158/1538-7445.AM2013-905
1014 CAN SERIAL CHANGES OF PLASMA OSTEOPONTIN AND GLYPICAN-3 LEVELS PREDICT RECURRENCE OF HEPATOCELLULAR CARCINOMA AFTER TRANSCATHETER ARTERIAL CHEMOEMBOLIZATION? A PROSPECTIVE STUDY
Authors: S.H. Ryu, S.Y. Kim, M.K. Oh, J.N. Kim, Y.S. Kim, J.S. Moon
Journal: Journal of Hepatology (2012)
A3.4 Distinct dysregulation of the small leucine-rich repeat protein (SLRP) family in osteoarthritic labrum compared to articular cartilage
Authors: N Juchtmans, AAM Dhollander, J Coudenys, EA Audenaert, C Pattyn, S Lambrecht, D Elewaut
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Background and objectives</h3> Osteoarthritis, characterised by a gradual progression of extracellular matrix (ECM) degradation, has been traditionally classified as a cartilage disease. However the new paradigm is that in OA the whole joint is involved, the cartilage but also synovium, subchondral bone and supporting structures, such as meniscus and the acetabular labrum. These supporting structures however remain largely unstudied. The acetabular labrum, is a fibrocartilageous horseshoe-shaped structure sealing the hip joint. We had previously proven that labrum cells are active in ECM synthesis and are able the react to pro-inflammatory cytokines. In this study our goal was to investigate hip OA specific gene expression changes in these cells in comparison with chondrocytes. Furthermore we aimed to investigate the functional importance of these gene expression differences. <h3>Material and methods</h3> Labrum cells from 5 OA patients en 3 healthy control patients were isolated and cultured in the 3-Dimensional alginate culture system. A genome wide gene expression analysis was performed using the Affymetrix microarray technology. Differential gene expression levels were confirmed on additional patient samples by quantitative PCR (qPCR), western blot and immunohistochemistry. Functional studies were performed by addition of recombinant protein the 3D-alginate labrum cultures. <h3>Results</h3> Pathway analysis performed on the microarray data indicate a distinct OA gene expression pattern in labrum cells, characterised by an increased cytokine and chemokine signalling as well as a reduced ECM receptor interaction and TGFβ signalling. Several genes were differentially regulated in OA compared to healthy labrum cells. We specifically focused on three proteins members of the short leucine rich repeat protein (SLRP) family: osteomodulin (OMD), osteoglycin (OGN) and asporin (ASPN). These proteins were found to be significantly downregulated in OA labrum but upregulated in OA cartilage. Moreover <i>in vitro</i> stimulation with OMD was able to induce proteoglycan synthesis in labrum cells. <h3>Conclusion</h3> Several features of OA chondrocytes are shared by OA labrum fibrochondrocytes, however SLRP expression seems to be differentially influenced in labrum compared to cartilage by OA degeneration. This suggest a distinct role for this supporting structure in hip OA, in which SLRP may play an important part.
S101 Praziquantel prevents progression and reverses pulmonary hypertension and pulmonary vascular remodelling in a mouse model of Schistosomiasis
Authors: A. Crosby, F. M. Jones, E. Kakolos, M. Southwood, I. Purvis, G. Butrous, D. W. Dunne, N. Morrell
Journal: Thorax (2010)

<h3>Introduction</h3> Schistosomiasis is the most common world-wide cause of pulmonary hypertension. Praziquantel is the drug of choice and has been shown to reverse the liver pathology associated with <i>Schistosomamansoni</i> in mice. We sought to determine whether praziquantel could reverse established pulmonary vascular remodelling and pulmonary hypertension in a mouse model of <i>Schistosomamansoni</i>. <h3>Methods</h3> Mice were infected percutaneously with a low dose of <i>Schistosomamansoni</i>. At 17 weeks post-infection mice were either sacrificed or received praziquantel by oral gavage or a vehicle control. At 17 or 25 weeks post-infection right ventricular systolic pressure (RVSP) and right ventricular (RV) hypertrophy, liver and lung egg counts were measured. Pulmonary vascular remodelling was assessed by morphometry, following immunohistochemistry. A cytokine array was performed and the degree of infectivity was measured by faecal egg counts. <h3>Measurements and main results</h3> At 25 weeks post-infection there was a significant increase in RVSP and RV hypertrophy between infected and control mice, which was reversed by Praziquantel treatment. RVSP was elevated in mice at 25 weeks post-infection but had normalised with praziquantel treatment. There was a significant increase in the muscularisation of small pulmonary arteries following 25 weeks of schistosomal infection, which was prevented by with Praziquantel treatment. Liver, lung and faecal egg counts were elevated following 25 weeks of schistosomal infection and substantially reduced with praziquantel treatment. <h3>Conclusions</h3> This study has shown that severe pulmonary vascular remodelling accompanied by an increase in RVSP and RV hypertrophy occurs 25 weeks post-infection in a mouse model of S mansoni infection. Importantly, this study has shown that progression of disease can be prevented by two oral doses of praziquantel. The mechanism thought to underlie the dramatic pulmonary vascular remodelling, is a local increase in inflammatory cytokines.
Detection of in Vivo Stimulated Cerebrospinal-Fluid Lymphocytes by Flow Cytometry in Patients with Multiple Sclerosis
Authors: Avertano B. C. Noronha, David P. Richman, Barry G. W. Arnason
Journal: New England Journal of Medicine (1980)

To examine the immune response in the central nervous system in patients with multiple sclerosis (MS), we characterized the cell-cycle phase of lymphocytes from cerebrospinal fluid. Cells were stained with acridine orange, and both RNA and DNA content were determined by flow cytometry. Although most cells were in the quiescent phase of the cycle, a significant increase was seen in the percentage of cells in the first stage of the proliferative cycle (G1 phase) when 21 samples of cerebrospinal fluid from 17 patients with MS were compared with samples from 21 controls (P<0.001). Stimulated cells in the first stage of the cycle were seen in all categories of MS: active, progressive, or stable. In addition, increased numbers of cells in the second stage of the cycle (S phase) were seen in six specimens from patients with MS, five of whom had active disease, but no increases were seen in controls (P<0.02). These data indicate that stimulated lymphocytes are present in the cerebrospinal fluid during all phases of MS and that stimulation becomes more intense during an acute exacerbation. (N Engl J Med. 1980; 303:713–7.)
PROGNOSTIC SIGNIFICANCE OF CLINICAL, HISTOPATHOLOGICAL, AND MOLECULAR CHARACTERISTICS OF MEDULLOBLASTOMAS IN THE PROSPECTIVE HIT2000 MULTICENTER CLINICAL TRIAL COHORT
Authors: T. Pietsch, R. Schmidt, M. Remke, A. Korshunov, V. Hovestadt, D. T. Jones, J. Felsberg, K. Kaulich, T. Goschzik, M. Kool, P. A. Northcott, K. von Hoff, A. O. von Bueren, C. Friedrich, H. Skladny, G. Fleischhack, M. D. Taylor, F. Cremer, P. Lichter, A. Faldum, G. Reifenberger, S. Rutkowski, S. M. Pfister
Journal: Neuro-Oncology (2014)

BACKGROUND: This study aimed to prospectively evaluate clinical, histopathological and molecular variables for outcome prediction in medulloblastoma patients. METHODS: Patients from the HIT2000 cooperative clinical trial were prospectively enrolled based on the availability of sufficient tumor material and complete clinical information. This revealed a cohort of 184 patients (median age 7.6 years), which was randomly split at a 2:1 ratio into a training (n = 127), and a validation (n = 57) dataset. All samples were subjected to thorough histopathological investigation, CTNNB1 mutation analysis, quantitative PCR, MLPA and FISH analyses for cytogenetic variables, and methylome analysis. RESULTS: By univariable analysis, clinical factors (M-stage), histopathological variables (large cell component, endothelial proliferation, synaptophysin pattern), and molecular features (chromosome 6q status, MYC amplification, TOP2A copy-number, subgrouping) were found to be prognostic. Molecular consensus subgrouping (WNT, SHH, Group 3, Group 4) was validated as an independent feature to stratify patients into different risk groups. When comparing methods for the identification of WNT-driven medulloblastoma, this study identified CTNNB1 sequencing and methylation profiling to most reliably identify these patients. After removing patients with particularly favorable (CTNNB1 mutation, extensive nodularity) or unfavorable (MYC amplification) markers, a risk score for the remaining “intermediate molecular risk” population dependent on age, M-stage, pattern of synaptophysin expression, and MYCN copy-number status was identified and validated, with speckled synaptophysin expression indicating worse outcome. CONCLUSIONS: Methylation subgrouping and CTNNB1 mutation status represent robust tools for the risk-stratification of medulloblastoma. A simple clinico-pathological risk score for “intermediate molecular risk” patients was identified, which deserves further validation. SECONDARY CATEGORY: Pediatrics.
Abstract LB-82: Basal Cell Carcinoma Nevus Syndrome: Networking for Good
Authors: Kristi Schmitt Burr
Journal: Cancer Research (2011)

Abstract Basal Cell Carcinoma Nevus Syndrome (BCCNS) Life Support Network set out on its journey in 2000 and have since provided support to over 1200 families, stimulated new drug development, and connected with diverse medical specialties – including dermatology, plastic surgery, genetics, cardiology, radiology, oral surgery and dentistry – to increase medical professionals' awareness of the needs of the BCCNS patient community. The organization's success means a better future for everyone vulnerable to this potentially disabling and life-threatening disease. While BCCNS affects a small portion of the American public (1 in 19,000 or about 16,500 American adults and children annually), the disease comes with significant cost and burdens. As there is no cure and few effective treatments, people suffering with this disease face a lifetime challenge in managing the disease. The numerous skin cancers and jaw cysts_the most common symptoms of the disease_generally require numerous surgeries throughout one's life. In addition, patients' experiences are afflicted by brain tumors, cognitive delays, physical disabilities including auditory, vision and speech impairments. Early diagnosis is important in order for children with BCCNS to survive life-threatening brain tumors and to overcome potential future disability. The financial burden for all patients is significant. A major hurdle in coping with BCCNS is finding a doctor knowledgeable about the disorder. Securing a prompt diagnosis and appropriate treatment is complicated by the fact that the disease affects so many different parts of the body, thereby crossing over diverse medical specialties. Working with inadequate knowledge, caregivers may use inappropriate therapies which can cause deformities and increased morbidity and mortality. Common treatments, such as radiation and x-rays, can result in the formation of thousands of basal cell carcinomas (BCCs or skin cancers), which are particularly perilous for undiagnosed children exhibiting brain tumors. To minimize the occurrence of death, widespread networking and education is essential. This is the cornerstone of the organization as it is only through communicating directly with individuals that advocates are made aware of new practices and current concerns. BCCNS is able to connect members with medical professionals in their region, or offer advice on preventative screenings, and serve as a knowledgeable resource. As the only national organization in the United States serving BCCNS patients, the organization has extensive experience in providing educational support to patients and doctors, national credibility and recognition among patients and stakeholders, and well-established communication links with many medical specialties. 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 LB-82. doi:10.1158/1538-7445.AM2011-LB-82
SP0133 Systematic understanding of the quality of pros to improve clinical trials
Authors: J. Dekker
Journal: Annals of the Rheumatic Diseases (2013)

There is an urgent need for standardization of PROs in rheumatology. Only for the evaluation of pain and activity limitations in osteoarthritis, more than 30 PROs are available. Such variation is an obstacle to synthesis of research findings and a threat to scientific progress. In order to standardize PROs in rheumatology, a three-step procedure is proposed. (i) The International Classification of Functioning is available for standardization of concepts and terminology (ICF; WHO, 2001). (ii) Systematic reviews provide information on the clinimetric qualities of PROs (reliability, validity and responsiveness). (iii) As the final step, the international scientific community gathers and reaches consensus on a limited core set of PROs, for use in future clinical trials in rheumatology. The core set includes a generic PRO and a disease specific PRO for each major diagnostic category in rheumatology. Standardization of PROs in rheumatology will contribute strongly to synthesis of knowledge obtained in separate clinical trials, thereby facilitating scientific progress. <h3>Disclosure of Interest</h3> None Declared
Abstract 331: Epithelial-mesenchymal transition confers resistance to complement-dependent cytotoxicity in lung cancer cells
Authors: Moloy T. Goswami, Ajaya K. Reka, Himabindu Kurapati, Viritha Kaza, Venkateshwar G. Keshamouni
Journal: Cancer Research (2012)

Abstract Recent studies have implicated Epithelial-mesenchymal transition (EMT) in conferring several clinically relevant properties to cancer cells, in addition to initiating tumor metastasis. These include stem-cell like properties, resistance to targeted therapies and ability to evade immune surveillance. Pathway analysis of gene expression changes in TGF-β induced EMT identified the complement cascade as one of the significantly enriched pathway. Further analysis of the genes in the complement pathway revealed EMT-induced expression of complement inhibitors and decrease in expression of proteins essential for complement activity, suggesting resistance to complement dependent cytotoxicity (CDC) during EMT. We found lung cancer cells that undergo EMT showed marked decrease in C3 deposition and concomitant resistance to apoptosis by CDC as measured by 7-Aminoactinomycin D staining. Flow cytometric and RT-PCR analysis showed a significant increase in the CD59 expression on the surface of cells undergoing EMT, which is a potent inhibitor of formation of membrane attack complex that mediates complement dependent cell lysis. Furthermore, CD59 inhibition by siRNA mediated knock-down overcame the EMT-induced resistance to anti-EGFR antibody (Cetuximab) mediated CDC. The increase in CD59 was abrogated on disruption of TGF-β signaling as revealed by TGF- β Receptor kinase inhibitor and is dependent on Smad3 signaling. Chromatin immunoprecipitation analysis revealed increased occupancy of Smad3 on CD59 promoter, suggesting a direct regulation by Smad3. These results demonstrate that TGF-β-induced EMT confers another novel immune evasive mechanism to tumor cells that facilitates tumor progression and CD59 as a potential therapeutic target for enhancing the efficacy of anti-EGFR Antibody therapies and against tumor metastasis. 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 331. doi:1538-7445.AM2012-331
A Randomized Trial of Prednisolone in Patients with Severe Alcoholic Hepatitis
Authors: Marie-José Ramond, Thierry Poynard, Bernard Rueff, Philippe Mathurin, Christian Théodore, Jean-Claude Chaput, Jean-Pierre Benhamou
Journal: New England Journal of Medicine (1992)

Controlled trials have yielded inconsistent results with regard to the efficacy of corticosteroids in the treatment of alcoholic hepatitis. Three meta-analyses suggest that they may be effective in patients with encephalopathy who have severe liver disease.
THU0266 Effects of Various Immunosuppressants in the Disease Damage Among Patients with Systemic Lupus Erythematosus (SLE)
Authors: S. S. Shaharir, H. J. Ding, S. Rajalingham, M. S. Mohamed Said, N. CT Kong, H. Hussein
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Various factors have been implicated in the disease damage in SLE. <h3>Objectives</h3> To investigate disease damage among SLE patients and to determine their association with patient exposure to the various immunosuppressive treatment. <h3>Methods</h3> A total of 220 SLE patients from the Universiti Kebangsaan Malaysia Medical Centre and Putrajaya Hospital were recruited. Information on the sociodemographic background, lupus characteristics and treatment were obtained from the medical records. Patients were stratified by the Systemic Lupus International Collaborating Clinics/ American College of Rheumatology cumulative disease damage index (SDI ≥ 1= damage). <h3>Results</h3> Overall, 35% (78/220) patients had disease damage. Those who had ever received hydroxychloroquine (HCQ) were less likely to develop disease damage (37.5% vs 89.3%, p&lt;0.001). Early HCQ treatment (≤3 months from the onset of diagnosis) and receipt of a loading dose of HCQ (6.5mg/kg daily) were less likely to be associated with disease damage [23.2% vs 67.1% and 28 % vs 54%, p&lt;0.001 respectively]. In the HCQ treated group of patients, those with disease damage had a significantly lower cumulative HCQ [189.3 ± 192.2 g vs 314.1 ± 339.4 g, p&lt;0.01]. Those who had a longer duration of corticosteroid treatment tended to develop disease damage (5.1 ± 4.8 years vs 3.8 ± 3.1 years, p=0.057) and more patients who received high dose prednisolone (≥ 1mg/kg daily) developed disease damage (52.2% vs 35.3%, p=0.04). Cyclophosphamide and cyclosporin A use were also associated with disease damage, 78.7% vs 31.7% and 85% vs 41%, p&lt;0.001 respectively. After adjustment of age and major organ involvement of SLE (renal and NPSLE), in the regression analysis, presence of treatment with HCQ (OR 0.12, CI 95% 0.02-0.61, p=0.01) and early treatment with HCQ (≤ 3 months before the onset of SLE) protected against disease damage (OR0.32, CI 95% 0.11-0.91, p=0.03). Cyclophosphamide was an independent risk for disease damage (OR 11.5 CI 95% 3.5-35.6, p=&lt;0.01). These data suggest that the use of cytotoxic agents such as cyclophosphamide and cyclosporine A were probably associated with more severe disease manifestations such as severe lupus nephritis. <h3>Conclusions</h3> Cyclophosphamide use increased the risk of disease damage whilst early treatment with HCQ protected against disease damage. A larger prospective study is needed to further delineate the contribution of the immunosuppressive treatment towards disease damage among SLE. <h3>References</h3> M. Petri et al. Predictors of Organ Damage in SLE: The Hopkins Lupus Cohort Arthritis Rheum. 2012 Dec;64(12):4021-8. <h3>Disclosure of Interest</h3> None Declared