tbuckley/cabot-search huggingface dataset:
THU0050 Leptin and Neutrophil Activating Protein 2 Promote Mesenchymal Stem Cells Senescence through the Activation of Pi3k/Akt Pathway in Systemic Lupus Erythematosus
Authors: H. Chen, X. Feng, L. Sun
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> Mesenchymal stem cells (MSC) derived from patients with systemic lupus erythematosus (SLE) displays enhanced senescence. <h3>Objectives</h3> The aim is to explore the role and mechanism of SLE inflammatory environment on the regulation of MSC senescence. <h3>Methods</h3> Mesenchymal stem cells were isolated from fresh umbilical cords or human bone marrow. Cellular senescence was measured by senescence-associated b-galactosidase (SA-b-gal) staining, and the mRNA and protein levels of cell cycle inhibitors p53 and p21 were detected by real time PCR and western blot analysis. Proteins involved in senescence related signaling pathways, including Jak/stat, Ras/MEK/Erk, NF-kB and PI3K/Akt, were detected by western blot. Human serum collected from healthy controls and SLE patients were applied for the measurement of 80 human cytokines and chemokines by RayBio® human cytokine antibody arrays. Then differentially expressed factors were replicated by ELISA using independent samples. <h3>Results</h3> SLE serum significantly increased the percentage of SA-b-gal positive MSCs, and upregulated the expression of p53 and p21. Jak/stat1/5, PI3K/Akt and MEK/Erk pathways in MSCs were activated after SLE serum stimulation. Treatment of PI3K/Akt signaling pathway inhibitor, LY294002, could reverse SLE serum induced senescence, while blocking Jak/stat with AG490 or MEK/Erk with PD98059 did not have an effect. As detected by cytokine antibody arrays and independent sample ELISA, leptin and NAP2 were both significantly elevated in SLE serum, and blocking either of them could partially inhibit MSC senescence. Leptin and NAP2 acted synergistically to promote more senescent cells than leptin or NAP2 alone, which were completely blocked by the PI3K/Akt pathway inhibitor. <h3>Conclusions</h3> Elevation of leptin and NAP2 in SLE serum helps to accelerate the cellular senescence of MSCs. PI3K/Akt signaling transduction is important in the senescent effect. <h3>Disclosure of Interest</h3> : None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.2195
227TiP Phase I trial of oxaliplatin/irinotecan/S-1 (OX-IRIS) as first line chemotherapy for unresectable pancreatic cancer (HGCSG1403 study)
Authors: H. Hayashi, S. Yuki, K. Sawada, T. Muranaka, Y. Kawamoto, H. Nakatsumi, Y. Komatsu
Journal: Annals of Oncology (2015)
Abstract 2951: Nicotine induced EMT involves β-arrestin-1 mediated regulation of E2F1 target genes
Authors: Smitha R. Pillai, Michael Damit, Srikumar Chellappan
Journal: Cancer Research (2010)

Abstract Cigarette smoking is strongly correlated with the onset of non-small cell lung cancer. Nicotine, an active component of tobacco smoke has been found to induce proliferation, invasion and epithelial-mesenchymal transition in NSCLC cell lines. While nicotine by itself is not carcinogenic, it can induce cell proliferation utilizing a scaffolding protein, β-arrestin-1 which translocates to nucleus and associates with E2F1 transcription factor. In addition, nicotine induces changes in gene expression consistent with epithelial-mesenchymal transition characterized by increase in the levels of mesenchymal proteins like vimentin and fibronectin. In this study we demonstrate that mesenchymal markers such as vimentin and fibronectin are E2F1 regulated and β-arrestin-1 is involved in regulating their expression in response to nicotine stimulation. Analysis of vimentin and fibronectin promoters revealed the presence of potential E2F binding sites. Transient transfection experiments in A549 cells using vimentin and fibronectin promoter constructs showed that these promoters were induced significantly by E2F1 and repressed by Rb. Depletion of E2F1 using siRNAs resulted in down regulation of vimentin and fibronectin as seen by Real-Time PCR. Chromatin immunoprecipitation assays on quiescent as well as nicotine stimulated A549 cells showed a robust recruitment of E2F1 and β-arrestin-1 to vimentin and fibronectin promoters. In addition, depletion of β-arrestin-1 resulted in down regulation of vimentin and fibronectin expression as revealed by western blot and Real-Time PCR. Nicotine stimulation resulted in the induction of vimentin and fibronectin promoters when A549 cells were transfected with reporter constructs while β-arrestin-1 depleted cells did not show promoter induction with nicotine stimulation. Boyden chamber assays conducted on β-arrestin-1 knocked down cells showed that ablation of β-arrestin-1 resulted in the inhibition of nicotine induced migratory and invasive potential of cells. Taken together, these data suggest that β-arrestin-1 contributes to nicotine induced epithelial-mesenchymal transition by regulating E2F1 mediated vimentin and fibronectin expression. 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 2951.
Abstract 1814: Waldenström macroglobulinemia and lymphoplasmacytic lymphoma: incidence and demographic patterns in the United States, 1988 – 2006
Authors: Mary L. McMaster, Phillip Rosenberg
Journal: Cancer Research (2010)

Abstract Background: Waldenström macroglobulinemia (WM) is a clinicopathological syndrome that typically presents with bone marrow involvement by a lymphoproliferative process that produces monoclonal IgM. WM shares clinicopathological features with lymphoplasmacytic lymphoma (LPL) and has been characterized as a bone marrow-based subset of LPL to define specific patient populations for inclusion in clinical trials. However, previous epidemiologic studies of WM did not include LPL, and the extent to which the two disorders overlap is unknown. Methods: We estimated age-adjusted incidence rates (IRs) of WM and LPL in the population-based Surveillance, Epidemiology and End Results Program in the United States to analyze patterns of WM and LPL separately and jointly by age, gender, and race. We applied generalized linear regression models to test for interaction between the age-specific curves for each disorder. Results: Overall standardized IRs were 3.22 per 1 000 000 person-years for WM (n = 2 230) and 2.21 for extra-medullary LPL (EM-LPL; n = 1 547) during 1988 – 2006. Incidence of WM/LPL combined was 65% higher among males compared to females, and the male: female IR ratio was significantly higher for WM (2.20) than for EM-LPL (1.50). WM/LPL IRs were 40% lower among blacks compared to whites; this difference was due to a black: white IR ratio that was significantly decreased for WM (0.39), but not for EM-LPL (0.94). Racial differences could not be explained solely by covariates reflecting differential access to care. WM and EM-LPL had significantly different age-at-onset curves after adjusting for period effects, and IRs increased with age in both disorders. Conclusions: Epidemiological patterns for WM and EM-LPL appear to suggest disease heterogeneity. Future studies should include assessment of disease classification in reporting to cancer registries; exploration of race, gender, and age effects, with application of additional area-level measures associated with access to care, in epidemiological studies; and clinical and genetic studies to identify unique pathobiological determinants underlying each disease. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1814.
THU0018 The Clinically Quiescent Phase in Early Systemic Lupus Erythematosus (SLE) Diagnosis Patients: Inception Cohort Study
Authors: N. Kasitanon, T. Intaniwet, S. Wangkaew, W. Louthrenoo
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> A majority of systemic lupus erythematosus (SLE) patients have had a relapsing-remitting clinical course. <h3>Objectives</h3> To determine the clinically quiescent survival time and the associated factors of prolong clinically quiescent phase in newly diagnosed SLE patients <h3>Methods</h3> SLE patients in an inception lupus cohort of newly diagnosed SLE patients who were observed for longer than 1 year and seen between May, 2007 and June, 2012 at Rheumatology clinic, Chiang Mai University were included. All patients were assessed for clinically quiescence, modified-SLE disease activity index 2000 (mSLEDAI-2K) was zero with no increase in treatment, no new features of lupus activity compared to the previous assessment. Once they reached the clinically quiescence, they were assessed for the occurrence of flare, mSLEDAI-2K increase more than three (≥4) when compared to the previous visit, increased disease activity in one or more organ systems involving new or worse clinical signs and symptoms and/or laboratory measurements, or consideration of a change or an increase in treatment. <h3>Results</h3> Ninety-five patients (88 females) with mean ± SD age and disease duration at the study entry were 33.22±13.24 years and 2.79±3.19 months were enrolled during the mean observing periods of 3.04±1.38 years. The initial mSLEDAI-2K score was 13.33±5.57. The SLICC damage index was zero in 70 of 95 (73.68%) patients. Eighty-eight patients (92.63%) reached clinically quiescence. Estimated time from cohort entry to reaching clinically quiescence was 11.31±1.10 months. Forty-five (51.14%) patients had a disease flare. The estimated time from reached clinically quiescent criteria to the first flare of disease (the clinically quiescent phase) was 28.30±3.07 months. In uni-variable analysis, age at SLE diagnosis ≥30 years married patients, non-alopecia at presentation, continuing anti-malarial drug therapy after reached clinically quiescent criteria, had longer clinically quiescent phase. Cox-regression analysis revealed age at diagnosis of ≥30 years (Hazard ratio [HR] 2.26, 95% CI 1.06, 4.82), non-alopecia (HR 2.41, 95% CI 1.18, 4.96) and continuing anti-malarial <h3>Conclusions</h3> SLE patients with early diagnosis had a good prognosis. Patients who had age at diagnosis older than 30 years and stay on anti-malarial drug after reaching clinically quiescence may have longer clinically quiescent phase. The confirmed studies are needed. <h3>Disclosure of Interest</h3> : None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.2848
Prevention of Stokes–Adams Seizures with Chlorothiazide
Authors: Louis Tobian
Journal: New England Journal of Medicine (1961)

THIS report describes 8 patients with Stokes—Adams attacks who were seemingly benefited by chlorothiazide. My colleagues and I had been aware of the patient with isolated hypoaldosteronism who had very high levels of serum potassium and recurrent Stokes—Adams seizures.1 When the potassium level in this patient's serum was lowered with desoxycorticosterone, the attacks were relieved. It was reasoned that if the seizures could be relieved in that special situation by lowering of the plasma potassium concentration from above normal levels to normal, it might also be possible to alleviate the attacks associated with ordinary heart block by reduction of . . .
Abstract 4296: STAT3 is required for proliferation and tumor growth of breast cancer stem cells
Authors: Li Lin, Brian Hutzen, Zhengang Peng, Huey-Jen Lin, Pui-Kai Li, Chenglong Li, Max Wicha, Jiayuh Lin
Journal: Cancer Research (2010)

Abstract Breast cancer is the leading type of cancer affecting women. It is estimated that breast cancer accounts for over a quarter of all newly diagnosed cancer cases in women. Despite advances in chemotherapy and hormonal treatment, at the present time, metastatic breast cancer remains an incurable disease. Although a large number of chemotherapeutic agents have been developed that are able to cause the regression of metastatic breast cancers, these tumors almost always recur following chemotherapy treatment. It is possible that breast cancer stem cells or breast cancer initiating cells are responsible for the drug-resistance, metastasis, and recurrence of cancer. Constitutive activation of Signal Transducers and Activators of Transcription 3 (STAT3) signaling is frequently detected in many types of cancers, including breast cancer, and has emerged as an attractive molecular target for cancer treatment. However, whether or not STAT3 is activated in breast cancer stem cells and what role STAT3 signaling plays in cancer stem cells is still unknown. If STAT3 is activated in breast cancer stem cells, targeting STAT3 may offer a promising opportunity to eliminate breast cancer stem cells and prevent the recurrence of cancer. We examined STAT3 activation in breast cancer stem cells, which are characterized by an aldehyde dehydrogenase (ALDH)-positive (ALDH+) and ALDH+/CD44+/CD24− subpopulations. Interestingly, we observed that the ALDH+ and ALDH+/CD44+/CD24− subpopulations of breast cancer cells expressed higher levels of phosphorylated STAT3, an active form of STAT3, as compared to the ALDH− and ALDH−/CD44+/CD24+ subpopulations and un-separated breast cancer cells, suggesting that STAT3 is activated in breast cancer stem cells. We also demonstrated that a novel STAT3 inhibitor, LLL12, inhibited STAT3 phosphorylation, cell viability, STAT3 downstream target gene expression, and induced apoptosis in breast cancer stem cells. In addition, the STAT3 inhibitors Stattic and LLL12 inhibited the tumorsphere forming capacity of breast cancer stem cells. Furthermore, in a mouse tumor model using breast cancer stem cells, we demonstrated that LLL12 can suppress tumor growth in vivo. This is the first report to demonstrate that persistent STAT3 phosphorylation is expressed in breast cancer stem cells and that this subpopulation of breast cancer stem cells is sensitive to STAT3 inhibitors. Our results suggest that STAT3 is a novel therapeutic target in breast cancer stem cells and inhibition of activated STAT3 in cancer stem cells may offer a more effective treatment for breast 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 4296.
Abstract 2401: IGF-IR peptide vaccine inhibits tumor growth via IFN-g-dependent biologic remodeling of the tumor
Authors: Denise L. Cecil, Kyong Hwa Park, Ekram Gad, Mary L. Disis
Journal: Cancer Research (2010)

Abstract The insulin-like growth factor (IGF) pathway plays an important role in breast cancer growth and metastasis. The majority of breast tumors overexpress the IGF-I receptor (IGF-IR). Increased IGF-IR signaling in breast cancer is correlated with a poor prognosis and is associated with disease that is resistant to chemotherapy, radiotherapy, and biologic therapy. Thus, therapeutically targeting the IGF-IR signaling pathway is a promising approach to treat breast cancer. We have determined that the IGF-IR is immunogenic in breast cancer. Furthermore, vaccination with MHCII IGF-IR-specific peptides p384-398, p575-589, p951-965, and p1122-1136 induces a CD4+ T cell-dependent anti-tumor immune response in Neu-transgenic mice. Preliminary data suggests that IGF-IR specific immunization results in both decreased proliferation and increased apoptosis of tumor cells. Antigen specific CD4+ T cells secrete IFN-g and we have demonstrated that the inhibition of tumor growth with the IGF-IR vaccine is dependent on IFN-g. We questioned the mechanism whereby IFN-g-secreting CD4+ T cells targeting IGF-IR could inhibit tumor growth. Studies suggest that tumor-associated IGF-IR activation is decreased in tumors from vaccinated mice, with concomitant upregulation in SOCS-3, which has been shown to be modulated by IFN-g. In addition, IFN-g stimulation of the tumor cell line derived from the Neu-transgenic mouse decreased IGF-IR activation and induced SOCS-3 expression. Thus, active immunization targeting IGF-IR may induce both immunologic and biologic effects resulting in inhibition of breast cancer growth. 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 2401.
P3-13-03: Long-Term Symptoms after Radiotherapy of Supraclavicular Lymph Nodes in Breast Cancer Patients.
Authors: D Lundstedt, M Gustafsson, G Steineck, D Alsadius, A Sundberg, U Wilderäng, E Holmberg, K-A Johansson, P Karlsson
Journal: Cancer Research (2011)

Abstract Background and Purpose: Irradiation of the supraclavicular lymph nodes has historically been shown to increase the risk of brachial plexopathy with neurological problems in the upper limb. The purpose of this study was to compare long-term symptoms after modern radiotherapy (based on 3D dose planning) in breast cancer patients with or without irradiation of the supraclavicular lymph nodes. Material and Methods: We collected information from 814 recurrence free women consecutively treated with adjuvant radiotherapy for breast cancer at the Sahlgrenska University Hospital in Gothenburg, Sweden, 1999 to 2004. The women had breast conserving surgery or mastectomy with axillary dissection or sentinel node biopsy. The breast area was irradiated to 50 Gy in 2.0 Gy fractions. Women with more than three lymph node metastases had regional radiotherapy to the supraclavicular lymph nodes delivered in 2.0 Gy fractions up to 50 Gy. Systemic treatments were given according to regional guidelines. In this study the women were classified into three groups depending on if they had axillary dissection and regional radiotherapy. The first group had both axillary dissection and regional radiotherapy, the second group had axillary dissection without regional radiotherapy, and the third group had sentinel node biopsy (i.e. no axillary dissection) without regional radiotherapy. Three to eight years after radiotherapy, the women received a questionnaire asking about paresthesia, pain and strength in the upper limb. Results: Among women with axillary dissection and regional radiotherapy 38/192 (19.8%) reported paresthesia in the hand compared to 68/505 (13.5%) among women with axillary dissection without regional radiotherapy; relative risk (RR) 1.47; 95% confidence interval (95% CI) 1.02 - 2.11, and compared to 9/112 (8.0%) among women with sentinel node biopsy without regional radiotherapy; RR 2.46 (95% CI 1.24−4.90). Type of breast surgery, number of examined axillary lymph nodes, and chemotherapy had no impact on the occurrence of paresthesia. Age was an effect modifier among the women with axillary dissection and regional radiotherapy; up to 49 years of age 26.8% reported paresthesia (RR 2.45; 95% CI 1.05−5.73), between 50 and 59 years of age 19.7% reported paresthesia (RR 1.81; 95% CI 0.73−4.44), and above 59 years of age 10.9% reported paresthesia (RR 1.00 Reference). We found no statistically significant differences between the groups regarding pain or decreased strength. Conclusions: Radiotherapy to the supraclavicular lymph nodes increases the occurrence of paresthesia in the hand. The effect was mainly seen among younger women. Dose/volume-response analysis regarding paresthesia will be presented at the meeting. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-13-03.
Phase III ABMT Studies Under Way
Authors: K. Smigel
Journal: JNCI Journal of the National Cancer Institute (1995)

Journal Article Phase III ABMT Studies Under Way Get access Kara Smigel Kara Smigel Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 87, Issue 13, 5 July 1995, Page 953, https://doi.org/10.1093/jnci/87.13.953 Published: 05 July 1995
SP0026 In Search for Mab Biosimilarity: How to Overcome Obstacles?
Authors: J. Goncalves
Journal: Annals of the Rheumatic Diseases (2014)

<h3></h3> Therapeutic proteins are next-generation drugs in the prevention and treatment of diseases, in particular human critical illness like autoimmune diseases or cancer. The expiration of patents in the originally approved biopharmaceuticals has stimulated a great excitement and the subsequent development of these first-in-line biotherapeutic mAbs, known as mAb Biosimilars. These biologic medicines are a new class of drugs intended to offer comparable safety and efficacy (or clinical equivalence) to their original reference products which are brand name drugs and no longer under patent coverage. However, preparing similar copies of biologicals is much more challenging than replicating small molecules due to their structural complexity, intricate manufacturing processes and their potential risks for increased immunogenicity. Therefore, specific regulatory approval pathways and guidelines must be followed when creating Biosimilars. Biosimilars require more rigorous assessments than traditional chemical generics. This is because of the molecular complexity of recombinant proteins, and the complexity of biological manufacturing processes. Small differences can arise in a recombinant protein product which are hard to detect with state-of-the-art analytical techniques. Yet, these differences can have significant impact on the safety and efficacy of the drug. Thus, the European Medicines Agency (EMEA) has taken the lead in issuing guidelines that use the totality of data with orthogonal methodologies to assess the comparability of two biologic medicines in all their scientifically proven characteristics and mechanisms of action. This talk will describe the task to evaluate the drug in the context of the disease but not the opposite. With this concept it is possible to concentrate on assessing similarity of two mAbs but not their benefit to the patient, which was evaluated before by the original biologic. The guidelines advocate pre-clinical and clinical testing of biosimilars prior to market authorization, complemented by tailored pharmacovigilance plans. These guidelines provide a valuable base from which to develop in this evolving regulatory environment. <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.6351
Giant Syphilitic Aortic Aneurysm
Authors: Taufiek Konrad Rajab, Robert P Gallegos
Journal: New England Journal of Medicine (2011)

A 76-year-old man with a history of syphilis presented with progressive dyspnea and leg swelling. Auscultation of the precordium was notable for a diastolic blowing murmur of aortic regurgitation, and there was ECG evidence of left ventricular hypertrophy.