tbuckley/cabot-search huggingface dataset:
Expression of miR-17-92 enhances anti-tumor activity of T-cells transduced with the anti-EGFRvIII chimeric antigen receptor in mice bearing human GBM xenografts
Authors: Masasuke Ohno, Takayuki Ohkuri, Akemi Kosaka, Kuniaki Tanahashi, Carl H June, Atsushi Natsume, Hideho Okada
Journal: Journal for ImmunoTherapy of Cancer (2013)

Expression of miR-17-92 enhances T-cell survival and interferon (IFN)-γ production. We previously reported that miR-17-92 is down-regulated in T-cells derived from glioblastoma (GBM) patients. We hypothesized that transgene-derived co-expression of miR17-92 and chimeric antigen receptor (CAR) in T-cells would improve the efficacy of adoptive transfer therapy against GBM.We constructed novel lentiviral vectors for miR-17-92 (FG12-EF1a-miR-17/92) and a CAR consisting of an epidermal growth factor receptor variant III (EGFRvIII)-specific, single-chain variable fragment (scFv) coupled to the T-cell receptor CD3ζ chain signaling module and co-stimulatory motifs of CD137 (4-1BB) and CD28 in tandem (pELNS-3C10-CAR). Human T-cells were transduced with these lentiviral vectors, and their anti-tumor effects were evaluated both in vitro and in vivo.CAR-transduced T-cells (CAR-T-cells) exhibited potent, antigen-specific, cytotoxic activity against U87 GBM cells that stably express EGFRvIII (U87-EGFRvIII) and, when co-transduced with miR-17-92, exhibited improved survival in the presence of temozolomide (TMZ) compared with CAR-T-cells without miR-17-92 co-transduction. In mice bearing intracranial U87-EGFRvIII xenografts, CAR-T-cells with or without transgene-derived miR-17-92 expression demonstrated similar levels of therapeutic effect without demonstrating any uncontrolled growth of CAR-T-cells. However, when these mice were re-challenged with U87-EGFRvIII cells in their brains, mice receiving co-transduced CAR-T-cells exhibited improved protection compared with mice treated with CAR-T-cells without miR-17-92 co-transduction.These results warrant the development of novel CAR-T-cell strategies that incorporate miR-17-92 to improve therapeutic potency, especially in patients with GBM.
Anni 2.0: a multipurpose text-mining tool for the life sciences
Authors: Rob Jelier, Martijn J Schuemie, Antoine Veldhoven, Lambert CJ Dorssers, Guido Jenster, Jan A Kors
Journal: Genome biology (2008)

Anni 2.0 is an online tool ( http://biosemantics.org/anni/ ) to aid the biomedical researcher with a broad range of information needs. Anni provides an ontology-based interface to MEDLINE and retrieves documents and associations for several classes of biomedical concepts, including genes, drugs and diseases, with established text-mining technology. In this article we illustrate Anni's usability by applying the tool to two use cases: interpretation of a set of differentially expressed genes, and literature-based knowledge discovery.
One-year follow-up of ankylosing spondylitis patients responding to rituximab treatment and re-treated in case of a flare
Authors: In-Ho Song, Frank Heldmann, Martin Rudwaleit, Joachim Listing, Heiner Appel, Iris Haug-Rost, Jürgen Braun, Joachim Sieper
Journal: Annals of the Rheumatic Diseases (2012)

Recently we reported on a good clinical response at week 24, especially in tumour necrosis factor (TNF)-blocker-naive patients with ankylosing spondylitis (AS) who were treated with a first course of rituximab (two infusions of each 1000 mg of rituximab with 100 mg methylprednisolone at baseline and week 2).1

Here we report on the follow-up of these patients with a special focus on the good responders.

At week 24, patients regarded as responders were offered to be followed up and to receive a second course of rituximab in case of flare. A response was defined as reaching 20% improvement in disease activity according to the Assessment of SpondyloArthritis international Society criteria (ASAS20)2 compared with screening on at least two consecutive visits (out of four visits: week 12, week 16, week 20 and week 24). Flare was defined as a 1.5-point worsening of the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) compared to the lowest BASDAI between week 12 and week 24. Flare patients were then followed for another 48 weeks (between the flare visit (=R-baseline) and R-week …
Intrinsic hazard of breech presentation
Authors: M S. C Hopper
Journal: BMJ (1981)

Axons from dorsal/ventral tiers of substantia nigra pars compacta (SNc), ventral tegmental area (VTA), and retrorubral field (RRF) were traced after injecting their cell body with biotinylated dextran amine. Fifty-three single axons were reconstructed from serial sagittal sections with a camera lucida, and μ-opiate receptor immunostaining served to differentiate the striosome/matrix striatal compartments. Most dorsal tier SNc axons terminate within the matrix of the dorsal striatum, but their patterns of arborization vary markedly; some axons innervate one specific matriceal area, whereas others arborize in multiple discontinuous loci. Some dorsal tier SNc axons also project to both striosomes and matrix. Other dorsal tier SNc axons, as well as VTA axons, innervate the ventral striatum and send collaterals to striosomes lying ventrally in the dorsal striatum or to the ventral sector of the subcallosal streak (SS). Ventral tier SNc axons arborize principally in striosomes, but some ramify in both compartments or in striosomes and the SS. Ventral tier neurons that form deep clusters in substantia nigra pars reticulata innervate principally the matrix and the SS. The amygdala and ventral pallidum receive secondary collaterals from striatal axons of dorsal/ventral tier neurons or RRF neurons. The subthalamic nucleus receives collaterals from striatal axons of SNc clustered neurons, whereas the globus pallidus gets collaterals from striatal axons of dorsal/ventral tier SNc neurons. These findings reveal that the nigrostriatal pathway is composed of several neuronal subsystems, each endowed with a widely distributed axonal arborization that allows them to exert a multifaceted influence on striatal and/or extrastriatal structures.
Enhanced Myocardial Angiogenesis by Gene Transfer With Transplanted Cells
Authors: Terrence M. Yau, Karen Fung, Richard D. Weisel, Takeshiro Fujii, Donald A.G. Mickle, Ren-Ke Li
Journal: Circulation (2001)

BACKGROUND The combination of myocardial cell transplantation and angiogenic gene transfer may improve postinfarction left ventricular (LV) perfusion. We evaluated the angiogenic effect of heart cells transfected with vascular endothelial growth factor (VEGF) and transplanted into a myocardial scar.Donor rat heart cells were transfected with plasmids encoding VEGF(165) and green fluorescence protein. Syngeneic adult rats underwent LV cryoinjury to create a transmural scar. Three weeks later, 4x10(6) transfected heart cells (n=14), untransfected heart cells (n=13), or culture medium (n=16) were transplanted into the center of the scar. After 5 weeks, LV function, quantitative histology, and regional blood flow were evaluated. Plates of heart cells transfected with VEGF(165) produced 6.1 times more intracellular VEGF than nontransfected cells. Capillary density (mean+/-SEM) per high-power field in the center of the myocardial scar was 1.1+/-0.02 in control rats, 3.9+/-0.11 in untransfected rats, and 6.3+/-0.11 in transfected rats (P=0.0002). Capillary density in the border zone around the scar was 1.9+/-0.03 in control rats, 6.4+/-0.10 in untransfected rats, and 8.7+/-0.16 in transfected rats (P=0.004). Regional blood flow within the scar was 8.8+/-0.8% of normalized flow in control hearts, 10.4+/-0.7% in hearts transplanted with untransfected cells, but 17.6+/-1.2% in hearts transplanted with transfected cells (P=0.03 versus control, P=0.07 versus nontransfected). There was no difference in LV function attributable to transplantation with transfected cells at the time point studied.Transplantation of heart cells transfected with VEGF induced greater angiogenesis than transplantation of unmodified cells. Combined gene transfer and cell transplantation strategies may improve postinfarction LV perfusion and function.
Is mesalazine really safe for use in breastfeeding mothers?
Authors: D A Silverman
Journal: Gut (2004)

Mesalazine containing preparations are commonly used for the treatment and maintenance of remission of inflammatory bowel disease. The young age of many inflammatory bowel disease sufferers means that the issue of whether to continue therapy in nursing mothers often arises.

We report a small study that was instigated after a nursing mother with Crohn’s disease approached us concerned about the safety of continuing to breastfeed while taking mesalazine. She had a cracked bleeding nipple and was worried about the dose of the drug that her baby would be receiving. We agreed to analyse the drug levels in milk from both of her breasts, and given the limited evidence in this area we designed a …
<i>TP53</i> Cancerous Mutations Exhibit Selection for Translation Efficiency
Authors: Yedael Y. Waldman, Tamir Tuller, Roded Sharan, Eytan Ruppin
Journal: Cancer Research (2009)

The tumor suppressor gene TP53 is known to be a key regulator in cancer, and more than half of human cancers exhibit mutations in this gene. Recent evidence shows that point mutations in TP53 not only disrupt its function but also possess gain-of-function and dominant-negative effects on wild-type copies, thus making the mutated gene an oncogene. Hence, this brings about the possibility that TP53 mutations may be under selection for increasing the overall translation efficiency (TE) of defected TP53 in cancerous cells. Here, we perform the first large-scale analysis of TE in human cancer mutated TP53 variants, identifying a significant increase in TE that is correlated with the frequency of TP53 mutations. Furthermore, mutations with a known oncogenic effect significantly increase their TE compared with the other TP53 mutations. Further analysis shows that TE may have influence both on selecting the location of the mutation and on its outcome: codons with lower TE show stronger selection toward nonsynonymous mutations and, for each codon, frequent mutations show stronger increase in TE compared with less frequent mutations. Additionally, we find that TP53 mutations have significantly higher TE increase in progressive versus primary tumors. Finally, an analysis of TP53 NCI-60 cell lines points to a coadaptation between the mutations and the tRNA pool, increasing the overall TP53 TE. Taken together, these results show that TE plays an important role in the selection of TP53 cancerous mutations.
Expression of mitogen activated protein kinases in labial salivary glands of patients with Sjogren's syndrome
Authors: H. Nakamura, A. Kawakami, S. Yamasaki, Y. Kawabe, T. Nakamura, K. Eguchi
Journal: Annals of the Rheumatic Diseases (1999)

<h3>OBJECTIVE</h3> The expression of CD40 and CD40 ligand (CD40L) in mononuclear cells (MNCs) infiltrating the salivary glands of patients with Sjögren's syndrome (SS) has recently been reported. This study determined the expression of mitogen activated protein kinase (MAP kinase) superfamilies, which act as downstream effector molecules of CD40, in MNCs infiltrating labial salivary tissues in SS patients. <h3>METHODS</h3> Six HTLV-I seronegative SS patients and 10 HTLV-I seropositive patients including five HTLV-I associated myelopathy (HAM) patients were examined. The expression of MAP kinase superfamilies in labial salivary glands was examined by immunohistochemistry containing the mirror section technique. <h3>RESULTS</h3> Both active forms of c-Jun N-terminal kinase (JNK) and p38 were found in salivary infiltrating MNCs of SS patients. Only minimal expression of the active form of extracellular signal regulated kinase (ERK) was observed in these tissues, however, co-expression of active JNK and active p38 was confirmed by the mirror section technique. Furthermore, these protein kinases were co-expressed in CD40<sup>+</sup> MNCs. No difference in expression levels of active JNK and p38 was found in patients who were positive or negative for anti-HTLV-I antibody. <h3>CONCLUSION</h3> These results indicate that JNK and p38, but not ERK, function as downstream effector molecules of CD40 in salivary infiltrating MNCs in SS patients, and suggest that these molecules may be involved in the pathological process of chronic sialadenitis in SS.
Is nitric oxide in exhaled air produced at airway or alveolar level?
Authors: CA Byrnes, S Dinarevic, C Busst, A Bush, EA Shinebourne
Journal: European Respiratory Journal (1997)

The aim of this study was to determine whether the nitric oxide (NO) measured in exhaled air is produced at airway or alveolar level. Exhaled NO was measured using a chemiluminescence analyser, and carbon dioxide (CO2 concentration using a Morgan capnograph in single exhalations in 12 healthy subjects (mean age 32 yrs; 6 males and 6 females). For each subject, five exhalations were made directly into the NO analyser and five were made through a T-piece system, which allowed measurement of expiratory flow rate. The peak NO levels measured via the T-piece system were 41.2 (SEM 10.8) parts per billion (ppb), significantly lower than direct levels 84.8 (14.0) ppb (p<0.001). The levels of NO tended to rise to an early peak and plateau, while the CO2 levels continued to rise to peak late in the exhalation. The mean times to reach peak NO levels were 32.2 s (direct) and 23.1 s (T-piece), which were significantly different from that of peak CO2 levels 50.5 s (direct) and 51.4 s (T-piece) (p<0.001). At peak NO level, the simultaneous CO2 level mean 4.9% (SEM 0.14)%, was significantly lower than the peak CO2 reached, 5.8 (0.21)% (p<0.001). We conclude that peak nitric oxide levels are dependent on measurement conditions. There are significant differences between the time to peak of carbon dioxide and nitric oxide. Therefore, most nitric oxide, unlike carbon dioxide, is produced in airways and not at alveolar level.
Sirukumab, a human anti-interleukin-6 monoclonal antibody: a randomised, 2-part (proof-of-concept and dose-finding), phase II study in patients with active rheumatoid arthritis despite methotrexate therapy
Authors: Josef S Smolen, Michael E Weinblatt, Shihong Sheng, Yanli Zhuang, Benjamin Hsu
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Objectives</h3> The safety and efficacy of sirukumab, an anti-interleukin-6 (IL-6) monoclonal antibody, were evaluated in a 2-part, placebo-controlled phase II study of patients with active rheumatoid arthritis (RA) despite methotrexate therapy. <h3>Methods</h3> In Part A (proof-of-concept), 36 patients were randomised to placebo or sirukumab 100 mg every 2 weeks (q2w) through week 10, with crossover treatment during weeks 12–22. In Part B (dose finding), 151 patients were randomised to sirukumab (100 mg q2w, 100 mg q4w, 50 mg q4w, or 25 mg q4w) through week 24, or placebo through week 10 with crossover to sirukumab 100 mg q2w (weeks 12–24). The proportion of patients with an American College of Rheumatology 50 (ACR50) response and the change from baseline in the 28-joint count disease activity score using C-reactive protein (DAS28-CRP) were determined. Safety was evaluated through week 38 in both parts. <h3>Results</h3> The primary endpoint (ACR50 at week 12 in Part B) was achieved only with sirukumab 100 mg q2w versus placebo (26.7% vs 3.3%; p=0.026). Greater improvements in mean DAS28-CRP at week 12 were observed with sirukumab 100 mg q2w versus placebo in Parts A (2.1 vs 0.6, p&lt;0.001) and B (2.2 vs 1.1; p&lt;0.001). The incidence of adverse events (AEs) was similar for sirukumab-treated and placebo-treated patients through week 12 in Part A (70.6% and 63.2%, respectively) and B (67.8% and 66.7%, respectively). Infections were the most common type of AE; one death occurred (Part B, sirukumab 100 mg q2w, brain aneurysm). <h3>Conclusions</h3> Sirukumab-treated patients experienced improvements in the signs/symptoms of RA. Safety results through 38 weeks were consistent with other IL-6 inhibitors. <h3>Trial registration number</h3> NCT00718718.
Retinoids Induce Fibroblast Growth Factor-2 Production in Endothelial Cells via Retinoic Acid Receptor α Activation and Stimulate Angiogenesis In Vitro and In Vivo
Authors: Carlo Gaetano, Alfonso Catalano, Barbara Illi, Angelina Felici, Saverio Minucci, Roberta Palumbo, Francesco Facchiano, Antonella Mangoni, Salvatore Mancarella, Judith Mühlhauser, Maurizio C. Capogrossi
Journal: Circulation Research (2001)

Abstract —The effect of retinoic acid (RA) on endothelial cells is still controversial and was examined in the present study. In bovine aortic endothelial cells (BAECs), all-trans RA (ATRA) and 9- cis RA (9CRA), but not 13- cis RA (13CRA), induced fibroblast growth factor-2 (FGF-2) production and exhibited a biphasic dose-dependent effect to enhance BAEC proliferation and differentiation into tubular structures on reconstituted basement membrane proteins (Matrigel); both processes were inhibited by FGF-2–neutralizing antibody. The pan RA receptor (RAR)-selective ligand (E)-4-[2-(5,5,8,8,-tetramethyl-5,6,7,8-tetrahydro-2-naphtalenyl)-1-propenyl] benzoic acid and the RARα-selective ligand 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphtyl)-ethenyl] benzoic acid stimulated the production of FGF-2, whereas the addition of the RARα-antagonist RO 41-5253 inhibited this effect. In BAECs, the forced expression of RARα, but not RARβ or RARγ, enhanced FGF-2 production, whereas the RARα-dominant negative, Δ403, blocked this effect. Furthermore, RARα overexpression directly stimulated BAEC differentiation on Matrigel and potentiated the effects of ATRA in this assay. Finally, ATRA-treated BAECs coinjected with Matrigel subcutaneously in mice induced neovascularization within the Matrigel plug, and ATRA also enhanced angiogenesis in the chicken chorioallantoic membrane assay. In conclusion, RA can stimulate endothelial cell proliferation and differentiation in vitro via enhanced RARα-dependent FGF-2 production, and it can also induce angiogenesis in vivo. The full text of this article is available at http://www.circresaha.org.
Regulation of Fyn Through Translocation of Activated Lck into Lipid Rafts
Authors: Dominik Filipp, Jenny Zhang, Bernadine L. Leung, Andrey Shaw, Steven D. Levin, André Veillette, Michael Julius
Journal: The Journal of Experimental Medicine (2003)

Whether or how the activation of Lck and Fyn during T cell receptor (TCR) signaling is coordinated, and their delivery of function integrated, is unknown. Here we show that lipid rafts function to segregate Lck and Fyn in T cells before activation. Coaggregation of TCR and CD4 leads to Lck activation within seconds outside lipid rafts, followed by its translocation into lipid rafts and the activation of colocalized Fyn. Genetic evidence demonstrates that Fyn activation is strictly dependent on receptor-induced translocation of Lck. These results characterize the interdependence of Lck and Fyn function and establish the spatial and temporal distinctions of their roles in the cellular activation process.
Impaired response of fibroblasts from patients with hyperapobetalipoproteinemia to acylation-stimulating protein.
Authors: K M Cianflone, M H Maslowska, A D Sniderman
Journal: Journal of Clinical Investigation (1990)

Acylation-stimulating protein (ASP) is a small, basic, human plasma protein that markedly stimulates triglyceride synthesis in human adipocytes and cultured human skin fibroblasts. The present studies examine the response to ASP of cultured skin fibroblasts from normal subjects patients with hyperapobetalipoproteinemia, patients with familial hypercholesterolemia, and patients with hypertriglyceridemia without hyperapobetalipoproteinemia. Triglyceride synthesis induced by ASP did not differ significantly among the normals, the patients with familial hypercholesterolemia, and the patients with hypertriglyceridemia with normal low density lipoprotein (LDL) apolipoprotein B levels; however, on average, it was markedly reduced in the patients with hyperapobetalipoproteinemia. In all groups studied, evidence of specific saturable binding of radioiodinated ASP was present. Binding, however, was significantly reduced in the groups with hyperapobetalipoproteinemia whereas the other three groups were indistinguishable. By contrast, LDL-specific binding was reduced only in the patients with familial hypercholesterolemia. There was a significant direct relation between the degree of ASP binding and the triglyceride synthesis inducible by ASP. In addition, with the exception of the patients with familial hypercholesterolemia, there was an inverse relation between both ASP-specific binding and ASP-induced triglyceride synthesis in fibroblasts to LDL levels in plasma whereas no relation was evident to plasma high density lipoprotein and very low density lipoprotein.
Phase III Randomized Trial of FOLFIRI Versus FOLFOX4 in the Treatment of Advanced Colorectal Cancer: A Multicenter Study of the Gruppo Oncologico Dell’Italia Meridionale
Authors: Giuseppe Colucci, Vittorio Gebbia, Giancarlo Paoletti, Francesco Giuliani, Michele Caruso, Nicola Gebbia, Giacomo Cartenì, Biagio Agostara, Giuseppe Pezzella, Luigi Manzione, Nicola Borsellino, Andrea Misino, Sante Romito, Ernesto Durini, Stefano Cordio, Marisa Di Seri, Massimo Lopez, Evaristo Maiello
Journal: Journal of Clinical Oncology (2005)

We performed this phase III study to compare the irinotecan, leucovorin (LV), and fluorouracil (FU) regimen (FOLFIRI) versus the oxaliplatin, LV, and FU regimen (FOLFOX4) in previously untreated patients with advanced colorectal cancer.A total of 360 chemotherapy-naive patients were randomly assigned to receive, every 2 weeks, either arm A (FOLFIRI: irinotecan 180 mg/m(2) on day 1 with LV 100 mg/m(2) administered as a 2-hour infusion before FU 400 mg/m(2) administered as an intravenous bolus injection, and FU 600 mg/m(2) as a 22-hour infusion immediately after FU bolus injection on days 1 and 2 [LV5FU2]) or arm B (FOLFOX4: oxaliplatin 85 mg/m(2) on day 1 with LV5FU2 regimen).One hundred sixty-four and 172 patients were assessable in arm A and B, respectively. Overall response rates (ORR) were 31% in arm A (95% CI, 24.6% to 38.3%) and 34% in arm B (95% CI, 27.2% to 41.5%; P = .60). In both arms A and B, median time to progression (TTP; 7 v 7 months, respectively), duration of response (9 v 10 months, respectively), and overall survival (OS; 14 v 15 months, respectively) were similar, without any statistically significant difference. Toxicity was mild in both groups: alopecia and gastrointestinal disturbances were the most common toxicities in arm A; thrombocytopenia and neurosensorial were the most common toxicities in arm B. Grade 3 to 4 toxicities were uncommon in both arms, and no statistical significant difference was observed.There is no difference in ORR, TTP, and OS for patients treated with the FOLFIRI or FOLFOX4 regimen. Both therapies seemed effective as first-line treatment in these patients. The difference between these two combination therapies is mainly in the toxicity profile.
ARID1B is a specific vulnerability in ARID1A-mutant cancers
Authors: Katherine C Helming, Xiaofeng Wang, Boris G Wilson, Francisca Vazquez, Jeffrey R Haswell, Haley E Manchester, Youngha Kim, Gregory V Kryukov, Mahmoud Ghandi, Andrew J Aguirre, Zainab Jagani, Zhong Wang, Levi A Garraway, William C Hahn, Charles W M Roberts
Journal: Nature Medicine (2014)