tbuckley/cabot-search huggingface dataset:
Inhibition of E-cadherin is associated with down-regulation of members of the miR-200 family but not with promoter methylation in human breast cancer cell lines.
Authors: VP Tryndyak, FA Beland, IP Pogribny
Journal: Cancer Research (2009)

Abstract Abstract #6017 Background: Increasing evidence indicates the fundamental role of epithelial to mesenchymal transition (EMT) in breast cancer progression and this is viewed as an essential early step in tumor cell invasion and metastasis. One of the pivotal events of EMT is down-regulation of E-cadherin. Recent findings have demonstrated the importance of the miR-200 microRNA family in the regulation of E-cadherin and EMT. In view of these findings, we examined the relationship between expression of members of the miR-200 family and status of E-cadherin levels in various human breast cancer cell lines.&amp;#x2028; Materials and Methods: Using quantitative real-time PCR analysis, we analyzed the expression of miR-200b, miR-200c, and miR-141 in 15 human breast cancer cell lines. Additionally, we measured the level of ZEB1, ZEB2, and E-cadherin proteins using Western blot analysis and E-cadherin promoter methylation by methylation-specific PCR.&amp;#x2028; Results: We found a substantial down-regulation of miR-200b, miR-200c, and miR-141 in the breast cancer cell lines. The extent of down-regulation was correlated with metastatic potential of cells. The down-regulation of members of the miR-200 family was associated with up-regulation of ZEB1 and ZEB2, transcriptional repressors of E-cadherin, and a subsequent decrease in the E-cadherin levels. More importantly, inhibition of E-cadherin expression was not due to its promoter hypermethylation. Treatment of breast cancer cells with demethylating agent 5-aza-2'-deoxycytidine resulted in over-expression of miR-200b and miR-200c, increase of the level of E-cadherin, and diminished metastatic properties of cancer cells.Discussion: Previous studies have revealed the important role of promoter methylation-related inhibition of E-cadherin in EMT in human breast cancer. However, the transcriptional silencing of E-cadherin is not always related to promoter hypermethylation, which indicates the existence of other mechanisms in E-cadherin down-regulation. In the present study, we demonstrated the crucial role of members of the miR-200 family in up-regulation of ZEB1 and ZEB2 proteins leading to subsequent E-cadherin down-regulation in human breast cancer cell lines. The extent of down-regulation of the miR-200 family was dependent of cancer stage and was associated with metastatic potential of cancer cell lines. This suggests that expression of miR-200 may be a powerful diagnostic marker determining breast cancer stage and cancer invasive phenotype. More importantly, the results indicate the great potential for reversing the invasive phenotype of cancer cells by up-regulation of miR-200 microRNAs. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6017.
Abstract P4-08-10: Systematic expression analysis of the genes related to drug-resistance in isogenic docetaxel- and adriamycin-resistance breast cancer cell lines.
Authors: J Tang, W Li, S Zhong, J Xu, J Zhao
Journal: Cancer Research (2012)

Abstract Background: Docetaxel (Doc) and Adriamycin (Adr) are two of the most effective chemotherapeutic agents in the treatment of breast cancer. However, their efficacy is often limited by the emergence of multidrug resistance (MDR). The purpose of this study was to investigate MDR mechanisms through analyzing systematically the expression changes of genes related to MDR in the induction process of isogenic drug resistant MCF-7 cell lines. Material and Methods: Isogenic resistant sublines selected at 100 and 200nM docetaxel (MCF-7/100nM Doc and MCF-7/200nM Doc) or at 500 and 1500 nM adriamycin (MCF-7/500nM Adr and MCF-7/1500nM) were developed from human breast cancer parental cell line MCF-7/S, by exposing MCF-7/S to gradually increasing concentrations of docetaxel or adriamycin in vitro. Flow cytometry, MTT cytotoxicity assay and cell growth curves were preformed to demonstrate the MDR characteristics developed in sublines. Some key genes on the pathways related to drug resistance (including drug-transporters: MDR1, MRP1 and BCRP; drug metabolizing-enzymes: CYP3A4 and GST pi; target gene: Topo IIα and β-tubulin III; apoptosis genes: Bcl-2 and Bax) were analyzed at RNA and protein expression levels by real time RT-qPCR and western blot, respectively. Results: MCF-7/100nM Doc and MCF-7/200nM Doc was 22- and 37-fold resistant to docetaxel, and 18- and 32-fold to adriamycin, respectively. MCF-7/500nM Adr and MCF-7/1500nM Adr was 61- and 274-fold resistant to adriamycin, and 3- and 12-fold to docetaxel, respectively. Meantime, they also showed cross-resistance to the other anticancer drugs in different degree. Compared to sensitive MCF-7/S, RT-qPCR and Western blot results revealed that the expression of MDR1, MRP1, BCRP, Bcl-2 were elevated in both MCF-7/Doc and MCF-7/Adr, and Topo IIα, Bax were down-regulated in both the sublines, while CYP3A4 and β-tubulin III were increased only in MCF-7/Doc and GST pi was increased only in MCF-7/Adr. Furthermore, these changes above were dose-dependent, i.e. acquirement of MDR is dependent on docetaxel or adriamycin concentrations in breast carcer model resistant MCF-7 cells. Conclusions: The established MCF-7/Doc or MCF-7/Adr has the typical MDR characteristics, which can be used as the models for resistance mechanism study. The acquired process of MCF-7/S resistance to docetaxel or adriamycin is gradual, and is also complicated with the various pathways involved in. There are some common mechanisms as well as drug-special mechanisms between MCF-7/Doc and MCF-7/Adr. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-08-10.
AB0614 Prognostic Factors of Functional Outcome in Systemic Sclerosis-Associated Interstitial Lung Disease
Authors: N. Le Gouellec, A. Duhamel, J.-B. Faivre, L. Guillaume, V. Sobanski, T. Perez, E. Hachulla, P.-Y. Hatron, M. Rémy-Jardin, D. Launay
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> Interstitial lung disease (ILD) is a frequent complication of systemic sclerosis (SSc) and is one of the first causes of mortality related to this disease. Screening sclerodermic patients for ILD at diagnosis and during the follow up is recommended. Its evolution is difficult to anticipate because predictive factors are not yet well established in SSc. <h3>Objectives</h3> The aim of this study was to identify prognosis factors associated with the evolution of ILD-SSc. <h3>Methods</h3> Clinical and biological data at the diagnosis of ILD, and serial pulmonary function tests (PFTs) were retrospectively collected in patients with ILD-SSc. We also analyzed the initial chest HRCT using the Wells score and the Goh staging system. The evolution of PFTs was modelled with linear mixed model with random coefficients. <h3>Results</h3> Seventy-five patients (57 women; 23 diffuse scleroderma) with SSc complicated by ILD (18 extensive according to Goh) were included, with a mean follow up of 5 years and a median number of 5 PFTs. Mixed linear model showed that diffusing capacity of lung (DLCO) lowered significantly of 1,45±0,34%/year whereas forced vital capacity (FVC) remained stable. On bivariate analysis, patients with dyspnea class III or IV, baseline DLCO &lt;80%, a greater extent of ILD and of reticular pattern had a lower FVC at baseline. The only parameter associated with a significant decline in FVC was a CRP above 10 mg/L. Patients with a lower baseline FVC and a greater extent of ILD and of reticular pattern had a lower DLCO at baseline. A past history of ulcers, a proportion of ground glass opacities above 70% and a baseline FVC &gt;70% were associated with a decline of DLCO. <h3>Conclusions</h3> Our study shows that modeling PFTs outcome in SSc-associated ILD is interesting to find prognostic factors. Initial CRP, reflecting IL-6 production, appears as an important prognostic factor for FVC evolution overtime. Conversely, SSc and autoantibodies subtypes were not prognostic factors for PFTs evolution in our study. ILD extension is associated with worse PFTs at baseline but is not associated with DLCO of FVC decline. <h3>References</h3> Ohtsuka, J Dermatol 2010; 37(9): 801–6 Liu, Arthritis Care &amp; Res 2013; 65(8):1375-80 Muangchan, Arthritis Care &amp; Res 2012; 64(9): 1405–14 De Lauretis, J Rheumatol 2013;40(4):435-46 Goh, Am J Respir Care Med 2008; 177(11): 1248-54 <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.3866
PM-07 * Bcl-xL DEPENDENCE OF NEURAL PROGENITORS MAY BE EXPLOITED TO IMPROVE MEDULLOBLASTOMA THERAPY
Authors: K. Veleta, A. Crowther, T. Gershon
Journal: Neuro-Oncology (2015)

Medulloblastoma is markedly more sensitive to radiation and chemotherapy than glioblastoma or PNET, but the underlying mechanisms contributing to this sensitivity remain unknown. Identifying the molecular mechanisms that mediate sensitivity of medulloblastoma to radiation and chemotherapy may lead to more targeted, less toxic approaches to therapy. We have previously shown that cerebellar neuronal progenitors (CGNPs), the cells of origin for Shh-driven medulloblastoma, are primed for rapid apoptosis in response to DNA damage, and that this apoptotic mechanism is conserved in medulloblastoma. In CGNPs and medulloblastoma cells, the pro-apoptotic protein Bax is maintained in an active conformation at mitochondria, complexed with its anti-apoptotic homolog, Bcl-xL. In this study we have examined the consequences of disrupting Bcl-xL in CGNPs and medulloblastoma cells in vivo, using conditional genetic deletion. We found that deleting Bcl-xL from CGNPs during development caused cerebellar hypoplasia by dramatically increasing CGNP apoptosis. In medulloblastoma-prone SmoM2 mice, deletion of Bcl-xL markedly decreased tumor growth, leaving large acellular spaces indicative that regions of the tumor had undergone apoptosis. Our findings suggest that therapeutic agents specifically targeting Bcl-xL may directly activate apoptotic pathways in medulloblastoma in the absence of DNA damage, potentially decreasing the toxicity associated with conventional treatments such as radiation therapy.
THU0378 Tocilizumab in the Treatment of Patients with AA Amyloidosis Secondary to Familial Mediterranean Fever: CASE Series: Table 1.
Authors: S. Yilmaz, M. Cinar, I. Simsek, H. Erdem, S. Pay
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> The most frequent underlying diseases responsible for AA amyloidosis worldwide are rheumatoid arthritis, juvenile idiopathic arthritis and ankylosing spondylitis, while familial Mediterranean fever (FMF) is responsible for almost 60% of the cases in Turkey and in countries where the FMF is prevalent. Tocilizumab (TCZ), an IL-6 antagonist, seems to be a promising agent in AA amyloidosis associated with rheumatic disorders, while there is no data regarding its use in amyloidosis due to FMF. <h3>Objectives</h3> We herein describe the short-term results of TCZ treatment in 8 patients with amyloidosis secondary to FMF. <h3>Methods</h3> We described a series of adult FMF patients complicated with amyloidosis and treated with TCZ (8 mg/kg once monthly) in one reference center. Diagnosis of AA amyloidosis was confirmed in the renal and/or rectal biopsy specimens in all patients with Congo red and immunohistochemical staining. <h3>Results</h3> The longest duration on the treatment with TCZ was 16 months in one patient, while 3 months in one patients with the shortest follow-up. At the beginning of TCZ treatment all patients had proteinuria with nephrotic range except case 4. Following treatment with TCZ, proteinuria was normalized in case 1 (Case with the longest duration of treatment), and considerably decreased in 4 cases, and increased in two (case 4 and 5). Serum creatine levels also increased in case 5, and patient refused to receive treatment after 6 cycles. In case 8, TCZ treatment was switched to anakinra due to frequent FMF attacks. The renal function tests were abnormal in 4 patients, and remained almost stable throughout the follow-up (Table 1). Serum albumin levels were normalized in all patients except case 5 and 8. <h3>Conclusions</h3> To our knowledge this is the first report showing the efficacy of TCZ on renal amyloidosis secondary to FMF. While previous reports confirm the efficacy of TCZ in amyloidosis secondary to other rheumatic diseases, our findings suggest that this effect can be extended to other diseases. <h3>Disclosure of Interest</h3> : None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.4058
Acute Hemolytic Anemia with Rigid Red Cells in Hypophosphatemia
Authors: Harry S. Jacob, Thomas Amsden
Journal: New England Journal of Medicine (1971)

Severe, but reversible, hemolytic anemia occurred in a patient with profound hypophosphatemia (serum phosphorus less than 0.1 mg per 100 ml). Red-cell ATP and 2,3 DPG were markedly depressed during the hypophosphatemic period (to 11 and 30 per cent of normal, respectively). The striking reduction in red-cell ATP was associated with microspherocytic morphology, increased rigidity and diminished survival of the affected cells. All variables returned to normal after parenteral phosphate supplementation. The more than twofold increase in rigidity of ATP-deficient red cells was corrected by incubation with adenosine for two hours, so as to generate intracellular ATP. In addition to the hemolytic process, tissue oxygenation was probably further curtailed during the hypophosphatemic period because of the lowered red-cell 2,3 DPG and ATP levels. Hypophosphatemia may thus have profound, deleterious effects on the viability of human red cells.
FRI0359 Intravenous cyclophosphamide combined therapy in severe lupus nephritis: Immediate and long-term results
Authors: P. Vachvanichsanong, P. Dissaneewate, E. McNeil
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Intravenous cyclophosphamide (IVCY) has been used to treat severe lupus nephritis (LN) for many years. Because of the wide variety of manifestations of the condition and the long-term nature of the disease, outcomes vary widely. <h3>Objectives</h3> To evaluate and compare the immediate and long-term results of IVCY in pediatric onset severe LN and between patients with normal and abnormal renal function. <h3>Patients and Methods</h3> The records of patients aged &lt;18 years who attended the Department of Pediatrics, Prince of Songkla University, diagnosed with severe LN, and who were given a 36-month IVCY course, were reviewed. <h3>Results</h3> 108 patients were studied with a mean age of 12.6±2.7 years and mean follow up time of 5.7±4.3 years. 48 patients completed the 36-month IVCY course, 29 did not complete the course, and 31 were ongoing at the time of analysis. There were 36 patients with abnormal renal function at the start of therapy and 72 with normal renal function. Abnormal renal function patients had a higher mortality rate than normal renal function patients (13/36 vs 10/72, p-value&lt;0.001). Both groups responded well initially to treatment; proteinuria reduced to normal levels after 1 and 2 courses in the normal and abnormal renal function groups, respectively, while creatinine clearance returned to normal levels after 8 courses in patients with abnormal renal function. <h3>Conclusions</h3> Three years of IVCY treatment reduced proteinuria in both normal and abnormal renal function patients; however the mortality rate was higher in patients with abnormal renal function. <h3>Disclosure of Interest</h3> None Declared
Coverage by the News Media of the Benefits and Risks of Medications
Authors: Ray Moynihan, Lisa Bero, Dennis Ross-Degnan, David Henry, Kirby Lee, Judy Watkins, Connie Mah, Stephen B. Soumerai
Journal: New England Journal of Medicine (2000)

The news media are an important source of information about new medical treatments, but there is concern that some coverage may be inaccurate and overly enthusiastic.
Abstract 4064: Development of ALN-VSP: An RNAi therapeutic for solid tumors
Authors: Iva Toudjarska, Tim Buck, Joshua Brodsky, Akin Akinc, Timothy Racie, Ian MacLachlan, Dinah W. Sah, Jared Gollob, David Bumcrot
Journal: Cancer Research (2010)

Abstract Malignancies of the liver, including primary (hepatocellular carcinoma) and secondary (metastatic) tumors, represent a significant unmet medical need. In most patients with liver metastases, extra-hepatic tumors are also present. We are developing a therapeutic for solid tumors that is comprised of lipid particle (SNALP)-formulated small interfering RNAs (siRNAs) targeting VEGF and the mitotic kinesin, KSP (Eg5). For each target, potent siRNA duplexes were selected following extensive screening in tissue culture cells. A SNALP-formulated combination of the KSP and VEGF siRNAs (referred to as ALN-VSP) was tested in orthotopic liver tumor models, as well as models of extra-hepatic tumors. To generate orthotopic liver tumors, human hepatoma (Hep3B) or colorectal carcinoma (HCT116) cells were implanted directly into the livers of immunocompromised mice. These cell lines were also used to establish tumors at extra-hepatic sites including the lymph nodes and peritoneal cavity. Studies in which tumor-bearing mice were treated with ALN-VSP demonstrated that each siRNA makes a distinct contribution to efficacy. ALN-VSP treatment led to accumulation of aberrant mitotic figures (monoasters), a hallmark of KSP inhibition, in both types of orthotopic liver tumors, as well as in extra-hepatic tumors of different origin. Evidence of therapeutic VEGF inhibition was shown by marked reductions in tumor microvessel density and intratumoral hemorrhage in orthotopic tumors. Similar effects on tumor vasculature were obtained with a SNALP formulation of the VEGF siRNA alone. Finally, we demonstrated that multi-dose administration of ALN-VSP significantly prolongs survival of mice harboring advanced orthotopic liver tumors. A Phase 1 clinical trial of ALN-VSP is ongoing. 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 4064.
Gout Associated with Calcification of Cartilage
Authors: Wylie J. Dodds, Howard L. Steinbach
Journal: New England Journal of Medicine (1966)

THE association of gout and demonstrable calcification of cartilage has received scanty mention in the medical literature. The present study demonstrates that in a high percentage of patients with gout, cartilage, especially of the knees, is calcified. This association suggests that more than a coincidental factor is involved.Review of the LiteratureFor the past forty years an increasing number of case reports have described cartilage calcification.The first report of the roentgenographic appearance of calcified meniscuses was that of Fründ1 in 1926. Two years later Werwath2 described calcification of the articular cartilage of the knee as well as of . . .
Gastric Neuroendocrine Carcinoma Staged and Followed With 18F-FDG PET/CT—A Report of 3 Cases
Authors: William Makis, Anthony Ciarallo, Marc Hickeson, Vilma Derbekyan, Javier-A. Novales-Diaz, Robert Lisbona
Journal: Clinical Nuclear Medicine (2013)

Gastric neuroendocrine carcinomas (NEC) are very rare, aggressive tumors of the stomach that are distinct from the more benign neuroendocrine tumors, sometimes referred to as "gastric carcinoids." We present 3 cases of gastric NEC representing various histological subtypes that were successfully staged and followed with F-FDG PET/CT, impacting therapeutic management in each case.
Narrow-band imaging of interdigitating dendritic cell sarcoma originating in the duodenum
Authors: K. Nonaka, Y. Honda, R. Gushima, Y. Maki, K. Sakurai, K. Iyama, Y. Sasaki
Journal: Endoscopy (2011)

Interdigitating dendritic cell sarcoma (IDCS) is an exceedingly rare neoplasm arising from the antigen-presenting cells of the immune system [1] [2]. In general, IDCS is an aggressive tumor. The median overall duration of survival is 10 months [2] [3]. This is the first report of magnifying endoscopic observation of IDCS using narrow-band imaging.
PWE-081 Thioguanine Remains an Acceptable Alternative Immunosuppressant in IBD
Authors: K V Patel, R M Goel, V C Kariyawasam, P A Blaker, M G Ward, S Mashari, A Clark, M Sastrillo, J Duncan, S H Anderson, P M Irving, J D Sanderson
Journal: Gut (2013)

<h3>Introduction</h3> A significant proportion of inflammatory bowel disease (IBD) patients do not tolerate conventional thiopurines (azathioprine (AZA) and mercaptopurine (MP)). Thioguanine (TG) remains an alternative immunomodulator (IM) and has been in regular use in the IBD clinic at Guy’s &amp; St. Thomas’ for more than 10 years. Concerns remain regarding nodular regenerative hyperplasia (NRH) in long-term use. <h3>Methods</h3> We aimed to describe the indications, efficacy, monitoring and sequelae of TG use in IBD patients. Patients prescribed TG for IBD from 2008–2012, subsequent to a previously published series, were reviewed. <h3>Results</h3> 37 patients were identified (15 male, mean age 43 years). 29 patients had Crohn’s disease with 2 having co-existing orofacial granulomatosis, 6 had ulcerative colitis and 1 had IBD-unclassified. All had previous exposure to AZA and/or MP. The indications for TG were thiopurine intolerance in 23 and thiopurine induced pancreatitis in 13 patients. Median duration of exposure was 11 months (IQR: 3–30). Maintenance doses were 20mg or 40mg. 20 patients (54%) were in clinical remission at the end of follow-up period, and 16 (41%) of these were steroid free. Mean TGN levels were 1177 pmol/8 × 10<sup>8</sup> RBC (range 70–3182 pmol/8x10<sup>8</sup>). Differences in TGN concentrations in clinical responders and non-responders were not statistically significant. Treatment was withdrawn in 7 patients. Withdrawal was for adverse events in 3 patients, which resolved on TG withdrawal (neutropenic sepsis, pancytopenia and AST rise) and treatment failure in further 3 patients. TG was ceased in another after the diagnosis of metastatic breast cancer whilst receiving Adalimumab and concomitant TG for 12 months. 7 patients discontinued TG because of side effects occurring within 2 months of initiation. 11 patients had long-term exposure (&gt; 18 months). Screening with liver biopsy and/or MRI-Liver was performed in 9 patients. All patients were screened with regular platelet counts and liver profile. None were diagnosed with NRH during follow-up. <h3>Conclusion</h3> TG is a viable second-line IM and appears to be effective with an acceptable safety profile. Side effects are uncommon, occur early and cease upon TG withdrawal. Chief indications are previous failure of immunosuppressant therapy or thiopurine-associated pancreatitis. There were no cases of TG-associated pancreatitis. Concerns regarding hepatotoxicity and NRH were not manifest in this small series of patients in concordance with results from similar recent European series. Dedicated liver MRI screening along with quarterly liver profile and platelet counts to monitor for NRH should be offered to patients on long term therapy. <h3>Disclosure of Interest</h3> None Declared.