tbuckley/cabot-search huggingface dataset:
Abstract 5363: Dual targeting of mTORC1/C2 complexes enhances histone deacetylase inhibitor-mediated antitumor efficacy in primary HCC cancer <i>in vitro</i> and <i>in vivo</i>
Authors: Huanjie Shao, Haikuo Tang, Chun Gao, Hao Zhang, Grace Dy, Chunrong Yu, Alex Adjei, Lewis Roberts
Journal: Cancer Research (2011)

Abstract The mammalian target of rapamycin (mTOR) consists of two distinct complexes, mTORC1 and mTORC2. mTOR plays a pivotal role in Hepatocellular Carcinoma (HCC). Previous studies indicated that inhibition of mTORC1 only moderately enhanced histone deacetylase inhibitors (HDACis)-mediated anti-tumor activity. This limited effect may be attributable to the increase of AKT activation through S6K1-IRS1-PI3K negative feedback loop triggered by selective mTORC1 inhibition. While as AKT is the downstream effector of mTORC2, we hypothesize that dual targeting of mTORC1/C2 would be more efficient in suppressing AKT and in enhancing anti-tumor activity of HDACi. In this study, the interactions between mTOR kinase inhibitors (mTORKis) and HDACis were examined in vitro using established HCC cell lines and in vivo using patient-derived HCC tumor xenografts on SCID mice. Our results demonstrate that inhibition of both mTORC1/2 not only effectively blocked mTORC1 signaling, but also abrogated negative-feedback activation of AKT caused by mTORC1 inhibition. Furthermore, inactivation of mTORC1/C2 by mTORKis substantially enhanced HDACi-induced anti-tumor activity. Either dysfunction of mTORC2 by knockdown of Rictor (a component of mTORC2), or diminution of AKT1 significantly lowered the threshold of HDACi-induced apoptosis. Lastly, in vivo study indicated that the combination of AZD8055 and Vorinostat yielded much greater tumor-growth inhibition compared to either agent alone in primary HCC xenografts without obvious adverse effects. Conclusion: Dual mTORC1/2 inhibition is more efficient than selective mTORC1 inhibition in enhancing anti-tumor activity of HDACi due to abrogation of negative-feedback activation of AKT induced by selective mTORC1 inhibition. Our findings suggest that combining regimen of mTORKi and HDACi may be an effective therapeutic strategy for HCC. 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 5363. doi:10.1158/1538-7445.AM2011-5363
ET-18 * VAL-083 IS A NOVEL N7 ALKYLATING AGENT THAT INHIBITS THE GROWTH OF GLIOMA STEM AND NON-STEM CULTURES, INCLUDING TEMOZOLOMIDE-RESISTANT LINES
Authors: S. Fouse, A. Steino, N. Butowski, J. Bacha, D. Brown, J. Costello
Journal: Neuro-Oncology (2014)

The standard of care for glioblastoma multiforme (GBM) patients is surgical resection followed by temozolomide (TMZ) and radiation (XRT). TMZ is most effective for a minority of patients that exhibit epigenetic inactivation of 0-6-methylguanine DNA methyltransferase (MGMT), a DNA repair enzyme that removes the methyl-group adducts that are caused by TMZ. Thus, adducts that are not subject to the DNA repair mechanism of MGMT might provide additional benefit to GBM patients, the majority of which express MGMT and are TMZ-resistant, or acquire resistance after TMZ administration. The N7 alkylating agent, VAL-083, is not subject to MGMT mediated repair and might therefore be a more potent chemotherapeutic. VAL-083 is a first-in-class alkylating agent that crosses the blood brain barrier and is currently in clinical trials for glioma patients with recurrent disease. We have recently shown that cancer stem cells (CSC) and their paired non-CSC cultures derived from primary GBM tissues exhibit similar responses to TMZ, with this response dependent on the presence or absence of MGMT expression. We sought to investigate how our panel of stem and non-stem cultures responds to VAL-083 alone or in combination with XRT, and how the response would compare to TMZ. Cell cycle and cell viability analysis showed that VAL-083 has a measureable effect at low (1-5) micromolar doses in all cultures tested. Furthermore, the paired CSC and non-CSC cultures have similar responses to VAL-083, indicating that CSCs are not more resistant to VAL-083. At the doses used (5 µm and 2Gy, respectively), the combination of VAL-083 and XRT did not exhibit an additive effect on response in any of the cultures tested, though prior studies demonstrated/suggested VAL-083 has radiation-potentiating effects. Further experiments could elucidate a possible interaction. These results suggest that VAL-083 may provide a greater clinical benefit to glioma patients compared to TMZ.
Endoscopic vacuum therapy for acute esophageal perforation following pneumatic dilation
Authors: Holger Kronsbein, Markus Etzold, Martin Fein, Juergen Haverkock, Martin Steffen
Journal: Endoscopy (2014)

Esophageal perforation is a feared side effect of pneumatic dilation. Mediastinitis and consecutive sepsis are potentially life-threatening complications. Endoscopic therapy using an endoluminal vacuum-assisted closure system is a new method of treatment for esophageal leakage.
AB0744 Ocular involvement in giant cell arteritis: A cross-sectional study
Authors: C. Stagnaro, R. Talarico, C. Ferrari, A. d’Ascanio, M. Figus, S. Bombardieri
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Giant cell arteritis (GCA) represents the most common primary vasculitis of the elderly, that usually involves large and medium sized arteries. Permanent partial or complete visual loss in one or both eyes is one of the most dreadful manifestations of GCA and has been observed in 15-20% of patients in most series. <h3>Objectives</h3> The primary aim of the study was to evaluate the prevalence of impaired vision as first clinical symptom at the onset of disease, in a cohort of patients with GCA. The secondary aim was to compare the subset of patients characterised by the presence of ocular involvement with the others who didn't experience impaired vision <h3>Methods</h3> The clinical charts of 220 GCA patients (176 females, mean ± SD age at the onset 70±7 years), all fulfilling the 1990 American College of Rheumatology criteria, were analysed. Prevalence of ocular involvement demonstrated by ophthalmological examination and/or visual field and/or fluorescein-angiography and/or optical coherence tomography were retrospectively analysed in all patients (pts). <h3>Results</h3> Forty-three percent (<i>n</i>=95) of pts presented at the onset of disease visual alterations. The most common presenting symptoms among pts who experienced ocular involvement were: visual loss (90%), amaurosis fugax (23%), diplopia (11%) and eye pain (3%). Anterior ischemic optic neuropathy was observed in 70% of the patients, while central retinal artery occlusion was revealed in 17% of cases. In all patients with permanent visual loss (<i>n</i>=11), fundoscopic examination showed signs of ischemic optic neuropathy; moreover, among these, only 4 patients were affected by permanent bilateral visual loss. Any epidemiological or hematochemical difference was noted between patients who experience impaired vision and the others, except for the mean age at disease onset, that was higher in patients with ocular impairment (77±5 years). <h3>Conclusions</h3> The wide spectrum of GCA clinical manifestations can extensively vary, from cranial symptoms, such as headache, jaw claudication or visual alterations, to constitutional symptoms. Impaired vision is often an early manifestation of the disease. Since risk of loss of vision after initiating glucocorticoids is very low, an early recognition and diagnosis is of primary importance. <h3>Disclosure of Interest</h3> None Declared
SP0165 Neuronal Control of TLS in the Intestine
Authors: B. Olivier
Journal: Annals of the Rheumatic Diseases (2013)

<h3></h3> In chronically inflamed tissue, the formation of tertiary lymphoid structures (TLS) may contribute to the inflammatory process. It is unclear whether TLS are found in the inflamed colon in the context of inflammatory bowel disease, thus we made of an experimental model to establish whether TLS are found in the inflamed intestine. We show that TLS, indeed form in the inflamed colon, and can be distinguished from the other pre-existing lymphoid tissues of the colon. Surprisingly, TLS was found in the inflamed colons of LTα<sup>-/-</sup> mice, indicating a lymphotoxin independent formation of TLS. Remarkably, the formation of TLS required neuronal innervation of the colon, since selective ablation of vagal innervation of the colon lead to a decrease of CXCL13 and CCL20 which was accompanied by absence of TLS. In conclusion, TLS formation is under neuronal control and does not require an intact lymphotoxin signalling pathway. <h3>Disclosure of Interest</h3> None Declared
Phase II Study of Panitumumab + IRI for Metastatic Colorectal Cancer with Wild KRAS, Resistant to IRI (OGSG1001)
Authors: N. Sugimoto, M. Yoshida, K. Taira, Y. Tokunaga, Y. Miyake, T. Hata, T. Shimokawa, D. Sakai, Y. Kurokawa, H. Furukawa
Journal: Annals of Oncology (2013)
A Pain in the Back
Authors: Jon D. Lurie, Paul D. Gerber, Harold C. Sox
Journal: New England Journal of Medicine (2000)

An 80-year-old man with degenerative arthritis of the hip and spine began to have midthoracic back pain and worsening pain in his left hip. The pain began suddenly, was not preceded by trauma, did not radiate, and was not relieved in any position. The back pain persisted for two weeks despite rest and treatment with ibuprofen. The patient took no other medications.In an 80-year-old with back pain, I would worry about osteoporosis, either primary or secondary. The midthoracic area is a common site of compression fractures. Although osteoporosis is more common in women than men, at this . . .
Functions of the cortico-basal ganglia circuits for spoken language may extend beyond emotional-affective modulation in adults
Authors: Takashi Hanakawa, Chihiro Hosoda
Journal: Behavioral and Brain Sciences (2014)

Abstract We support Ackermann et al.'s proposal that the cortico-basal ganglia circuits may play essential roles in the evolution of spoken language. Here we discuss further evidence indicating that the cortico-basal ganglia circuits may contribute to various aspects of spoken language including planning, learning, and controlling of speech in adulthood.
FRI0213 Anti-TNF therapy in refractory uveitis of behcet’s syndrome. A multicenter study of 63 patients:
Authors: C. Bejerano, R. Blanco, M. Mesquida, A. Adán, G. Espinosa, E. Beltrán, L. M-Costa, M. Cordero-Coma, D. Salom, M. D-Llopis, J. G-Serrano, N. Ortego, J. Herreras, A. Rueda, M. H-Garfella, C. F-Espartero, A. G-Aparicio, C. Castillo-Gallego, A. Fonollosa, O. Maíz, A. Blanco, V. Jovani, J. Cruz, C. F-Cid, E. Pato, A. S-Andrade, S. G-Suárez, A. Atanes, M. Caracuel, F. Francisco, C. Montilla, S. Insua, I. Torre, J. Ventosa, J. Cañal, M. G-Gay
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Objectives</h3> To assess the efficacy of Infliximab (IFX) and adalimumab (ADA) in refractory uveitis of Behçet's syndrome. <h3>Methods</h3> Study of 63 patients followed in the Uveitis Clinic of 24 hospitals. All of them were refractory to conventional therapy with systemic steroids and ≥1 immunosuppressive drug. Efficacy was evaluated according to SUN criteria, and macular thickness by optical coherence tomography (OCT). Outcomes and comparisons were made at week 1, week 2, month 1, month 6 and at 1 and 2 years. Statistical analyses were performed using the STATISTICA (Statsoft). Results were expressed: mean±1SD (normally distributed variables) or median [25th-75th interquartile range-IQR] (not normally). Continuous variables were compared with the Wilcoxon test. <h3>Results</h3> We studied 63 patients/110 affected eyes (36M, 27W), mean age 38.9±9.0 years. Prior to anti-TNF, patients had received ivMprednisolone (n=20), cyclosporine (CyA) (n=53), methotrexate (MTX) (n=31) and azathioprine (AZA) (n=30). IFX was the anti-TNF more commonly used (64%). The remaining patients (36%) were treated with ADA. 14 patients (22%) required switching (12 from IFX→ADA; 2 ADA→IFX). Dosage: IFX 5 mg/kg/iv every 4-8 weeks or ADA 40 mgsc/2weeks. The median[IQR] follow-up from the onset of anti-TNF was 36 [20-60] months. Significant improvement of Visual acuity (VA), Tyndall and vitritis was observed soon (week 1). At 2 years,VA improved from 0.5±0.3 at basal to 0.7±0.3 (p&lt;0.001), Tyndall from a median of 1.07 [0-2] to 0.09 [0-0] (p&lt;0.001) and vitritis, from 1.0 [0-2] to 0.0 [0-0], respectively. Initially,17 patients (24 eyes) had cystoid macular edema (CME). Following anti-TNF OCT decreased from 320.2±120.9 to 260.4±42.8 at 2 years (p&lt;0.001). The most serious side effect was a miliary tuberculosis in 1 patient at month 1 after the onset of IFX. <h3>Conclusions</h3> Monoclonal anti-TNF therapy is effective and relatively safe in uveitis of Behcet's syndrome refractory to conventional therapy. <h3>Disclosure of Interest</h3> None Declared
SP0005 Is it Time to AIM for Remission in PSA and how Should it be Measured?
Authors: P. Helliwell
Journal: Annals of the Rheumatic Diseases (2013)

<h3></h3> Psoriatic arthritis is a multifaceted disease and it provides a challenge to outcome methodologists. A number of measures have been used to define remission in PsA but they have been mostly articular. Composite measures of disease activity and low disease states are now emerging but further work is required to assess the implication of achieving these goals and in developing cost-effective treatment strategies to achieve them. <h3>Disclosure of Interest</h3> None Declared
Early-Stage Prostate Cancer Study Compares Therapy to Watchful Waiting
Authors: J. Randal
Journal: JNCI Journal of the National Cancer Institute (1994)

Journal Article Early-Stage Prostate Cancer Study Compares Therapy to Watchful Waiting Get access Judith Randal Judith Randal Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 86, Issue 18, 21 September 1994, Pages 1376–1377, https://doi.org/10.1093/jnci/86.18.1376 Published: 21 September 1994
P4-09-34: Luminal Infiltrating Lobular Carcinoma of the Breast: Clinical and Prognostic Features.
Authors: NI Valdiviezo, E Vega, C Castañeda, C Flores, CD Mendiola, LM Manso, M Dorta, Velasco GA De, H Cortés-Funés, I Ghanem, EM Ciruelos
Journal: Cancer Research (2011)

Abstract Background Infiltrating lobular carcinoma (ILC) and infiltrating ductal carcinoma (IDC) are the two most common histologic types of invasive breast cancer. Previous studies have demonstrated distinctive clinical and biologic characteristics, however some features of ILC are yet uncertain like the relationship with the particular subtypes according to the gene expression profile. The purpose of our study is to analyze how the patients with ILC differ from IDC regarding of percentage of luminal subtype, the tumor factors, treatment and patterns of recurrence. Patients and Methods We assessed 1190 breast cancer patients treated at the Hospital Universitario 12 de Octubre between 1995 and 2006 categorized as having ILC or IDC pure types. Results: One thousand one hundred ninety tumors were included, being ILC 223 patients (18, 7%), IDC 967 patients (81, 3%) and 200 patients (10%) were luminal HER2+. The current analysis is limited to the 990 patients classified as luminal HER2−. Median age was 59, 2 years for ILC and 58, 8 for IDC, with no significant differences among the groups. Compared to IDC, ILC showed a larger tumor size (≥T3: 15, 2% vs. 4, 8%, ***p&amp;lt;0.01), lesser nodal involvement (35% vs 42, 7% p 0.048) and lower Ki67 expression (62, 6% vs. 52, 2% p=0.01). The proportion of luminal A subtype was greater in ILC (56, 3% vs. 46, 7% p=0.01). Mastectomy was more frequently performed for ILC (61, 2 % vs. 47, 7%, p=0.01). Regarding systemic therapy, 127(62,4%) ILC patients and 450 (57, 2%) IDC patients received adjuvant chemotherapy (QT). That was anthracycline-based in most cases (47, 2% for ILC and 46,4% for IDC). Adjuvant hormonal treatment was prescribed equally among both groups (196, 96% ILC and 739, 94% IDC), being the most commonly used drug ***tamoxifen. With a median follow-up of 94 months, 45 ILC patients (22%) and 159(20, 2%) IDC relapsed. No differences were observed in DFS (p=0, 81) or OS (p=0, 47). The most frequent metastatic site was bone (33% for ILC and 40, 8% for IDC), followed by local relapses (17, 7% for ILC vs. 17% for IDC) and liver (15, 5% for ILC vs. 15, 7% for IDC). ILC was associated with an increased incidence of peritoneal/mesenteric metastases (8 pts 17, 7% vs. 1pts 0,6% ***p&amp;lt;0.01) and a lower incidence of lung relapses (8, 8% vs. 19, 4 % pts p&amp;lt;0.05). Conclusion: Luminal HER2− Infiltrating lobular carcinoma carries distinct clinicopathological features. In our study, ILC had similar prognosis as IDC. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-09-34.
DO WOMEN WITH STATIN-RELATED MYALGIAS HAVE LOW VITAMIN D LEVELS?
Authors: Margo Minissian, Kamlesh Kothawade, Megha Agarwal, Greg Lentz, Chrisandra Shufelt, Jo Ann Eastwood, Puja Mehta, C. Noel Bairey Merz
Journal: Journal of the American College of Cardiology (2012)
AB0057 Soluble pd-1 and spd-l2 are unaffected by adalimumab treatment in early ra and associated with presence of anti-ccp and igm-rf
Authors: S. R. Greisen, K. Stengaard-Pedersen, M. L. Hetland, K. Hørslev-Petersen, B. W. Deleuran
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Disturbance of the balance in the immune system plays a major role in rheumatoid arthritis (RA). Programmed Death 1 (PD-1) expressed by activated T cells and its ligand (PD-L2) expressed by antigen presenting cells, are involved in negative regulation of T cell receptor induced activation <sup>1</sup>. Both PD-1 and PD-L2 exist in soluble forms (sPD-1 and sPD-L2). Soluble PD-1 is up-regulated in RA<sup>2</sup>, but sPD-L2 has to our knowledge not been investigated. <h3>Objectives</h3> To investigate sPD-1 and sPD-L2 in early RA patients and their association with disease. <h3>Methods</h3> In a longitudinal set of steroid- and DMARD-naïve RA patients (n=76, &lt;3 months' disease) who initiated treatment with methotrexate (MTX) or MTX and adalimumab, we measured plasma levels of sPD-L2 and sPD-1 by ELISA, at baseline (0 month) and after 3 and 12 months. To remove un-specific binding, plasma samples were saturated with mouse, bovine and human IgG. We examined for correlations (Spearman's rho) with disease parameters (DAS28, doctors VAS, HAQ, CRP), anti-CCP and IgM-RF. Data are expressed as median values (IQR). <h3>Results</h3> Plasma levels of sPD-L2 were 3.88ng/ml (2.8-5.2) at baseline, had increased 78% after 3 months, and stayed high at 12 months (6.44ng/ml (5.5-8.1)), (both p&lt;0.05). In contrast, plasma levels of sPD-1 showed no significant changes. Addition of adalimumab to MTX had no influence on sPD-1 or sPD-L2 plasma levels. Baseline sPD-1 and sPD-L2 plasma levels were associated with the presence of anti-CCP antibodies (rho=0.4 and 0.3, respectively, both p&lt;0.05) and IgM-RF (rho=0.64, p&lt;0.0001 and rho=0.4 p&lt;0.05). Interestingly, sPD-L2 relative to sPD-1 (sPD-L2/sPD-1) showed inverse correlation with anti-CCP and IgM-RF (all rho= -0.40, p&lt;0.05). Changes in plasma levels of sPD-L2 (0-12 months) and sPD-1 correlated with disease parameters. <h3>Conclusions</h3> Plasma levels of sPD-L2 and sPD-1 in RA are unaffected by addition of adalimumab to MTX treatment. The association between plasma levels of sPD-L2 and disease parameters suggests that sPD-L2 plays a vital role in disease progression. Also considering the close correlations with anti-CCP and IgM-RF, sPD-1 and sPD-L2 are possible new indicators of disease activity and progression. Because PD-1 is closely connected to the regulation of follicular T cells, our findings support the involvement of these T cells in the early phase of RA. <h3>References</h3> Messal, N., Serriari, N.-E., Pastor, S., Nunès, J. A. &amp; Olive, D. PD-L2 is expressed on activated human T cells and regulates their function. <i>Molecular Immunology</i><b>48</b>, 2214–2219 (2011). Wan, B. <i>et al.</i> Aberrant regulation of synovial T cell activation by soluble costimulatory molecules in rheumatoid arthritis. <i>J. Immunol.</i><b>177</b>, 8844–8850 (2006). <h3>Disclosure of Interest</h3> None Declared
ET-72 * THE STRATEGY STUDY OF ENHANCED ALA-INDUCED PpIX FLUORESCENT QUALITY IN MALIGNANT GLIOMAS
Authors: S. Zhao, X. Chen, L. Teng
Journal: Neuro-Oncology (2014)

OBJECTIVE: Gliomas are characterized by its local invasiveness and poor prognosis. It has been demonstrated that the survival benefit is associated with the extent of surgical resection. But it is difficult to distinguish tumor margins due to the infiltrative nature, and gliomas often recur within 2-3 cm from the borders of the resection cavity. Recently, fluorescence-guided resection has been demonstrated to improve discrimination of tumor tissue and increase the extent of surgical resection. However, insufficient protoporphyrin IX accumulation may limit the benefits of FGR in low-grade glioma and the marginal area. METHODS: We investigated the expression of the ATP-binding cassette transporter ABCB6 in gliomas, and the correlation between ABCB6 expression and PpIX accumulation. Meanwhile, Glioma cells and astrocytes were preconditioned with calcitriol or arsenic trioxide. Changes in ALA-induced PpIX fluorescence were assessed by flow cytometry and fluorescence microscopy. Furthermore, expression of porphyrin synthetic enzymes in pretreated glioma cells was analyzed. RESULTS: The expression levels of ABCB6 significantly elevated in gliomas, A previously finding was the fact that ABCB6 mRNA expression in solidly fluorescing tumor tissues was significantly higher than that in vaguely fluorescing tumors, Accordingly, ABCB6 overexpression in cell lines increased ALA-induced PpIX accumulation and fluorescent quality. Meanwhile, calcitriol or arsenic trioxide can be administered prior to ALA as a non-toxic preconditioning regimen to significantly enhance ALA- induced PpIX levels and fluorescence. This increase in PpIX level was detected preferentially in glioma versus normal cells. Moreover, mechanistic studies documented that expression of the porphyrin synthesis enzymes coproporphyrinogen oxidase was increased by calcitriol or arsenic trioxide at the mRNA level. CONCLUSIONS: ABCB6 overexpression is a potential approach to enhance accumulation of PpIX for optimising the subjective discrimination of vague fluorescence. We demonstrated for the first time a simple, non-toxic and highly effective preconditioning regimen to selectively enhance PpIX fluorescence in glioma cells.