tbuckley/cabot-search huggingface dataset:
The anti-erbB3 antibody MM-121/SAR256212 in combination with trastuzumab exerts potent antitumor activity against trastuzumab-resistant breast cancer cells
Authors: Jingcao Huang, Shuiliang Wang, Hui Lyu, Bo Cai, XiaoHe Yang, Jianxiang Wang, Bolin Liu
Journal: Molecular Cancer (2013)

Abstract Background Elevated expression of erbB3 receptor has been reported to induce resistance to therapeutic agents, including trastuzumab in erbB2-overexpressing breast cancer. Our recent studies indicate that erbB3 interacts with both erbB2 and IGF-1 receptor to form a heterotrimeric complex in trastuzumab-resistant breast cancer cells. Herein, we investigate the antitumor activity of MM-121/SAR256212, a fully human anti-erbB3 antibody (Ab), against two erbB2-overexpressing breast cancer cell lines resistant to trastuzumab. Methods MTS-based proliferation assays were used to determine cell viability upon treatment of trastuzumab and/or MM-121/SAR256212. Cell cycle progression was examined by flow cytometric analysis. Western blot analyses were performed to determine the expression and activation of proteins. Tumor xenografts were established by inoculation of the trastuzumab-resistant BT474-HR20 cells into nude mice. The tumor-bearing mice were treated with trastuzumab and/or MM-121/SAR256212 via i.p injection to determine the Abs’ antitumor activity. Immunohistochemical analyses were carried out to study the Abs’ inhibitory effects on tumor cell proliferation and induction of apoptosis in vivo . Results MM-121 significantly enhanced trastuzumab-induced growth inhibition in two sensitive and two resistant breast cancer cell lines. MM-121 in combination with trastuzumab resulted in a dramatic reduction of phosphorylated erbB3 (P-erbB3) and Akt (P-Akt) in the in vitro studies. MM-121 combined with trastuzumab did not induce apoptosis in the trastuzumab-resistant cell lines under our cell culture condition, rather induced cell cycle G1 arrest mainly associated with the upregulation of p27 kip1 . Interestingly, in the tumor xenograft model established from the trastuzumab-resistant cells, MM-121 in combination with trastuzumab as compared to either agent alone dramatically inhibited tumor growth correlated with a significant reduction of Ki67 staining and increase of cleaved caspase-3 in the tumor tissues. Conclusions The combination of MM-121 and trastuzumab not only inhibits erbB2-overexpressing breast cancer cell proliferation, but also promotes the otherwise trastuzumab-resistant cells undergoing apoptosis in an in vivo xenografts model. Thus, MM-121 exhibits potent antitumor activity when combined with trastuzumab under the studied conditions. Our data suggest that further studies regarding the suitability of MM-121 for treatment of breast cancer patients whose tumors overexpress erbB2 and become resistant to trastuzumab may be warranted.
Mapping Fetal Brain Development In Utero Using Magnetic Resonance Imaging: The Big Bang of Brain Mapping
Authors: Colin Studholme
Journal: Annual Review of Biomedical Engineering (2011)

The development of tools to construct and investigate probabilistic maps of the adult human brain from magnetic resonance imaging (MRI) has led to advances in both basic neuroscience and clinical diagnosis. These tools are increasingly being applied to brain development in adolescence and childhood, and even to neonatal and premature neonatal imaging. Even earlier in development, parallel advances in clinical fetal MRI have led to its growing use as a tool in challenging medical conditions. This has motivated new engineering developments encompassing optimal fast MRI scans and techniques derived from computer vision, the combination of which allows full 3D imaging of the moving fetal brain in utero without sedation. These promise to provide a new and unprecedented window into early human brain growth. This article reviews the developments that have led us to this point, examines the current state of the art in the fields of fast fetal imaging and motion correction, and describes the tools to analyze dynamically changing fetal brain structure. New methods to deal with developmental tissue segmentation and the construction of spatiotemporal atlases are examined, together with techniques to map fetal brain growth patterns.
Relationship between serum hyaluronic acid level and disease activity in early rheumatoid arthritis
Authors: M Majeed
Journal: Annals of the Rheumatic Diseases (2004)

To measure hyaluronic acid (HA) levels, which are raised in active rheumatoid arthritis (RA), in patients with early RA, and to assess the correlation with clinical and laboratory indices of disease activity and with subsequent radiographic erosive status.Patients fulfilling ACR criteria were recruited into a prospective cohort within 6 months of disease onset and reviewed every 6 months. An HA binding protein based sandwich ELISA was used to measure HA in 240 sera from 82 patients at regular intervals.Patients had higher HA levels than age matched healthy blood donor controls (median 37.4 v 29.1 ng/ml, respectively, p<0.02), which increased with more prolonged disease. Baseline HA level correlated with measures of disease activity, including swollen and tender joint counts, HAQ, global assessments, ESR, and CRP; was higher in men; and increased with age. There was no relationship with HLA-DRB1 shared epitope or rheumatoid factor status. At 6 and 12 month follow up visits, HA levels were higher in patients who later developed erosions. However, a raised HA level was not a good predictor of erosions.Serum HA level correlates with clinical and laboratory measures of disease activity in early RA, but is unlikely to be of practical use in clinical practice.
Control of Lytic Function by Mitogen-activated Protein Kinase/Extracellular Regulatory Kinase 2 (ERK2) in a Human Natural Killer Cell Line: Identification of Perforin and Granzyme B Mobilization by Functional ERK2
Authors: Sheng Wei, Ana M. Gamero, Jin Hong Liu, Angela A. Daulton, Nichola I. Valkov, Joseph A. Trapani, Andrew C. Larner, Michael J. Weber, Julie Y. Djeu
Journal: The Journal of Experimental Medicine (1998)

The signal pathways that control effector function in human natural killer (NK) cells are little known. In this study, we have identified the critical role of the mitogen-activated protein kinase (MAPK) pathway in NK lysis of tumor cells, and this pathway may involve the mobilization of granule components in NK cells upon interaction with sensitive tumor target cells. Evidence was provided by biological, biochemical, and gene transfection methods. NK cell binding to tumor cells for 5 min was sufficient to maximally activate MAPK/extracellular signal–regulatory kinase 2 (ERK2), demonstrated by its tyrosine phosphorylation and by its ability to function as an efficient kinase for myelin basic protein. MAPK activation was achieved in NK cells only after contact with NK-sensitive but not NK-resistant target cells. In immunocytochemical studies, cytoplasmic perforin and granzyme B were both maximally redirected towards the tumor contact zone within 5 min of NK cell contact with tumor cells. A specific MAPK pathway inhibitor, PD098059, could block not only MAPK activation but also redistribution of perforin/granzyme B in NK cells, which occur upon target ligation. PD098059 also interfered with NK lysis of tumor cells in a 5-h 51Cr-release assay, but had no ability to block NK cell proliferation. Transient transfection studies with wild-type and dominant-negative MAPK/ERK2 genes confirmed the importance of MAPK in NK cell lysis. These results document a pivotal role of MAPK in NK effector function, possibly by its control of movement of lytic granules, and clearly define MAPK involvement in a functional pathway unlinked to cell growth or differentiation.
Eicosanoids and control of mesangial cell contraction.
Authors: P Mené, M J Dunn
Journal: Circulation Research (1988)

Contraction of glomerular mesangial cells is stimulated in vitro by the vasoconstrictor metabolite of arachidonic acid, thromboxane A2. To establish the role of mesangial prostaglandin (PG) synthesis in the modulation of contractile responses, we studied the effects of the stable thromboxane A2/endoperoxide analogue U-46619 on cultured rat mesangial cells preincubated with 1) four structurally unrelated, nonsteroidal anti-inflammatory drugs, indomethacin, acetylsalicylic acid, meclofenamate, and piroxicam, to inhibit the synthesis of PGE2, the major mesangial metabolite of arachidonic acid; 2) exogenous PGE2 and the stable analogue of PGI2, iloprost; and 3) indomethacin in the presence of exogenous PGE2. Computer-assisted image analysis microscopy demonstrated enhancement of spontaneous and agonist-induced contraction by nonsteroidal anti-inflammatory drugs in individual cells grown on a glass substrate, from 37.2 +/- 7.3% to a maximum of 75.5 +/- 6.4% of the cells with piroxicam, at 1 microM U-46619. PGE2 and iloprost dose-dependently inhibited U-46619-induced contraction, to 5.0 +/- 2.8% and 12.5 +/- 4.7% of the cells, respectively, at 1 microM U-46619. PGE2 also completely reversed the effects of indomethacin. Both PGE2 and iloprost dose-dependently stimulated intracellular cyclic AMP (cAMP) accumulation during 3-minute incubations, an effect that was blocked by the inhibitor of adenylate cyclase, 2',5'-dideoxyadenosine. The latter reversed the inhibitory action of PGE2, enhancing spontaneous and agonist-induced contractility, thus indicating a modulatory role of cAMP. We conclude that endogenous arachidonate metabolism regulates mesangial cell contraction through elevation of intracellular cAMP.
Dinaciclib is a novel cyclin-dependent kinase inhibitor with significant clinical activity in relapsed and refractory chronic lymphocytic leukemia
Authors: J Flynn, J Jones, A J Johnson, L Andritsos, K Maddocks, S Jaglowski, J Hessler, M R Grever, E Im, H Zhou, Y Zhu, D Zhang, K Small, R Bannerji, J C Byrd
Journal: Leukemia (2015)
The<i>PRSS1</i>c.623G&gt;C (p.G208A) mutation is the most common<i>PRSS1</i>mutation in Korean children with hereditary pancreatitis
Authors: Yeoun Joo Lee, Chong Kun Cheon, KyungMo Kim, Seoak Hee Oh, Jae Hong Park, Han Wook Yoo
Journal: Gut (2014)

We read the article by Schnur et al 1 and the letter by Atsushi et al 2 reporting the functional aspects and Asian predominance of the p.G208A variant of the serine protease 1 gene ( PRSS1 ) with great interest. Schnur et al found that p.G208A is a rare variant of PRSS1 and suggested that, together with four other PRSS1 mutants, it is a mild pathogenic variant causing a moderate secretion defect and hereditary pancreatitis. Atsushi et al reported a relatively high prevalence of p.G208A variants in alcoholic and idiopathic Japanese patients with chronic pancreatitis (CP). We previously described two Korean children with the p.G208A variant of PRSS1 who presented with CP and necrotising acute …
Subclinical Right Ventricular Dysfunction in Cystic Fibrosis
Authors: ADRIAN A. IONESCU, ALINA-ANDREEA IONESCU, NICOLA PAYNE, IZASKUN OBIETA-FRESNEDO, ALAN G. FRASER, DENNIS J. SHALE
Journal: American Journal of Respiratory and Critical Care Medicine (2001)

Patients with severe cystic fibrosis can develop cor pulmonale, but little is known about the function of the right ventricle (RV) early in the disease. We hypothesized that such patients might have subclinical RV dysfunction, detectable by tissue Doppler echocardiography, and related to the severity of lung disease. We studied 21 clinically stable patients (Group 1), five patients with severe lung disease (Group 2), and 23 age-matched healthy subjects. Patients had impaired RV systolic function. The mean (SD) systolic velocities of the RV free wall were 8.9 (1.7) cm/s in Group 1, 7.7 (1.0) in Group 2, and 10.8 (1.9) in healthy subjects (p < 0.001). The velocities of the tricuspid annulus were less in patients (p < 0.0001). Patients had a greater isovolumic relaxation time (p < 0.001), indicating RV diastolic dysfunction. RV wall thickness was greater in patients (0.4 [0.1] versus 0.3 [0.1] cm/m(2), p < 0.01). RV systolic function was related to C-reactive protein (r = - 0.66, p < 0.001) and FEV(1) (r = 0.62, p = 0.003) and diastolic function to interleukin-6 (r = 0.64, p < 0.005). Patients with cystic fibrosis have subclinical RV dysfunction, which correlates with the severity of lung disease. Tissue Doppler echocardiography provides a quantifiable indicator useful for detection and monitoring of disease progression.
Coaching in Healthy Dietary Practices in At-Risk Older Adults: A Case of Indicated Depression Prevention
Authors: Sarah T. Stahl, Steven M. Albert, Mary Amanda Dew, Michael H. Lockovich, Charles F. Reynolds
Journal: American Journal of Psychiatry (2014)

Prevention of major depressive disorder is important because current treatments are only partially adequate in reducing symptom burden and promoting health-related quality of life. Lifestyle interventions may be a desirable prevention strategy for reasons of patient preference, particularly among older patients from minority groups. Using evidence from a randomized depression prevention trial for older adults, the authors found that coaching in healthy dietary practices was potentially effective in protecting at-risk older adults from developing incident episodes of major depression. The authors describe the dietary coaching program (highlighted in a case example) as well as the feasibility and potential efficacy of the program within the context of evidence-based interventions for preventing episodes of major depression and mitigating symptoms of depression. Older adults receiving dietary coaching experienced a low incidence of major depressive episodes and exhibited a 40%−50% decrease in depressive symptoms, as well as enhanced well-being, during the initial 6-week intervention; these gains were sustained over 2 years. The authors also describe why lifestyle interventions like coaching in healthy dietary practices may hold promise as effective, practical, nonstigmatizing interventions for preventing episodes of major depressive disorder in older adults with subsyndromal depressive symptoms.
The uncertain reasoner: Bayes, logic, and rationality
Authors: Mike Oaksford, Nick Chater
Journal: Behavioral and Brain Sciences (2009)

Abstract Human cognition requires coping with a complex and uncertain world. This suggests that dealing with uncertainty may be the central challenge for human reasoning. In Bayesian Rationality we argue that probability theory, the calculus of uncertainty, is the right framework in which to understand everyday reasoning. We also argue that probability theory explains behavior, even on experimental tasks that have been designed to probe people's logical reasoning abilities. Most commentators agree on the centrality of uncertainty; some suggest that there is a residual role for logic in understanding reasoning; and others put forward alternative formalisms for uncertain reasoning, or raise specific technical, methodological, or empirical challenges. In responding to these points, we aim to clarify the scope and limits of probability and logic in cognitive science; explore the meaning of the “rational” explanation of cognition; and re-evaluate the empirical case for Bayesian rationality.
Nonunion of Tibial Fracture With Bone Defect
Authors: Otto E. Aufranc
Journal: JAMA (1966)

Dr. Turner: A 19-year-old college student was thrown through the rear door of an automobile following a two-car collision. He was admitted to a hospital in a neighboring state and was found to have the following multiple injuries: bilateral fractured pubic rami; bladder and urethral lacerations; bilateral closed femoral-shaft fractures; closed fracture-dislocation of the right ankle; closed fracture of the right medial tibial plateau; right peroneal nerve palsy; open fractures of the left tibia and fibula with gross contamination and loss of approximately five inches of the middle portion of the tibia. Blood supply and sensation were entirely normal in the left foot. After initial management of shock by transfusion with seven units of whole blood, laparotomy was performed to repair the lacerated bladder. He was placed in bilateral balanced suspension with bilateral proximal tibial wires for traction. The left leg wound was debrided and packed open, but became grossly
Involvement of toll-like receptor 4 in the inflammatory reaction induced by hydroxyapatite particles
Authors: Alexia Grandjean-Laquerriere, Olivier Tabary, Jacky Jacquot, Doriane Richard, Patrick Frayssinet, Moncef Guenounou, Dominique Laurent-Maquin, Patrice Laquerriere, Sophie Gangloff
Journal: Biomaterials (2006)
Improved Insulin Sensitivity despite Increased Visceral Adiposity in Mice Deficient for the Immune Cell Transcription Factor T-bet
Authors: Emilie Stolarczyk, Chi Teng Vong, Esperanza Perucha, Ian Jackson, Michael A. Cawthorne, Edward T. Wargent, Nick Powell, James B. Canavan, Graham M. Lord, Jane K. Howard
Journal: Cell Metabolism (2013)

Low-grade inflammation in fat is associated with insulin resistance, although the mechanisms are unclear. We report that mice deficient in the immune cell transcription factor T-bet have lower energy expenditure and increased visceral fat compared with wild-type mice, yet paradoxically are more insulin sensitive. This striking phenotype, present in young T-bet−/− mice, persisted with high-fat diet and increasing host age and was associated with altered immune cell numbers and cytokine secretion specifically in visceral adipose tissue. However, the favorable metabolic phenotype observed in T-bet-deficient hosts was lost in T-bet−/− mice also lacking adaptive immunity (T-bet−/−xRag2−/−), demonstrating that T-bet expression in the adaptive rather than the innate immune system impacts host glucose homeostasis. Indeed, adoptive transfer of T-bet-deficient, but not wild-type, CD4+ T cells to Rag2−/− mice improved insulin sensitivity. Our results reveal a role for T-bet in metabolic physiology and obesity-associated insulin resistance.
Anti-GPVI–associated ITP: an acquired platelet disorder caused by autoantibody-mediated clearance of the GPVI/FcRγ-chain complex from the human platelet surface
Authors: Brian Boylan, Hong Chen, Vipul Rathore, Cathy Paddock, Michael Salacz, Kenneth D. Friedman, Brian R. Curtis, Michelle Stapleton, Debra K. Newman, Mark L. Kahn, Peter J. Newman
Journal: Blood (2004)
Targeted Radioiodine Therapy of Neuroblastoma Tumors following Systemic Nonviral Delivery of the Sodium Iodide Symporter Gene
Authors: Kathrin Klutz, Verena Russ, Michael J. Willhauck, Nathalie Wunderlich, Christian Zach, Franz Josef Gildehaus, Burkhard Göke, Ernst Wagner, Manfred Ogris, Christine Spitzweg
Journal: Clinical Cancer Research (2009)

Abstract Purpose: We recently reported the significant therapeutic efficacy of radioiodine therapy in various tumor mouse models following transcriptionally targeted sodium iodide symporter (NIS) gene transfer. These studies showed the high potential of NIS as a novel diagnostic and therapeutic gene for the treatment of extrathyroidal tumors. As a next crucial step towards clinical application of NIS-mediated radionuclide therapy we aim at systemic delivery of the NIS gene to target extrathyroidal tumors even in the metastatic stage. Experimental Design: In the current study, we used synthetic polymeric vectors based on pseudodendritic oligoamines with high intrinsic tumor affinity (G2-HD-OEI) to target a NIS-expressing plasmid (CMV-NIS-pcDNA3) to neuroblastoma (Neuro2A) cells. Results: Incubation with NIS-containing polyplexes (G2-HD-OEI/NIS) resulted in a 51-fold increase in perchlorate-sensitive iodide uptake activity in Neuro2A cells in vitro. Through 123I-scintigraphy and ex vivo gamma counting Neuro2A tumors in syngeneic A/J mice were shown to accumulate 8% to 13% ID/g 123I with a biological half-life of 13 hours, resulting in a tumor-absorbed dose of 247 mGy/MBq 131I after i.v. application of G2-HD-OEI/NIS. Nontarget organs, including liver, lung, kidneys, and spleen revealed no significant iodide uptake. Moreover, two cycles of systemic NIS gene transfer followed by 131I application (55.5 MBq) resulted in a significant delay in tumor growth associated with markedly improved survival. Conclusions: In conclusion, our data clearly show the high potential of novel pseudodendritic polymers for tumor-specific NIS gene delivery after systemic application, opening the prospect of targeted NIS-mediated radionuclide therapy of nonthyroidal tumors even in metastatic disease. (Clin Cancer Res 2009;15(19):6079–86)
Loss of enterocyte mass is accompanied by diminished turnover of enterocytes after myeloablative therapy in haematopoietic stem-cell transplant recipients
Authors: J.P.M. Derikx, N.M.A. Blijlevens, J.P. Donnelly, H. Fujii, T. Kanda, A.A. van Bijnen, E. Heineman, W.A. Buurman
Journal: Annals of Oncology (2008)
Protamine-mediated transport of albumin into brain and other organs of the rat. Binding and endocytosis of protamine-albumin complex by microvascular endothelium.
Authors: W M Pardridge, J L Buciak, Y S Kang, R J Boado
Journal: Journal of Clinical Investigation (1993)

High doses of intravenous protamine cause generalized vascular permeability changes in brain and other organs, and concomitant hypoproteinemia. The present investigations test the hypothesis that protamine has a dual action of both binding serum proteins and of undergoing absorptive-mediated transcytosis through microvascular endothelial barriers. Binding of albumin to protamine was demonstrated using equilibrium dialysis, and protamine was shown to selectively augment the uptake of albumin, but not sucrose, in isolated bovine or human brain capillaries. In contrast, the anionic macromolecule, dextran sulfate, resulted in an increased capillary uptake of both albumin and sucrose in vitro. The selective effects of protamine on albumin transport were also documented in vivo using an external organ technique; the intravenous injection of 1.5 mg/kg protamine resulted in a marked and selective influx of albumin into brain, heart, kidney, lung, and liver, and the increased albumin transport exceeded the increased sucrose uptake in some organs by an order of magnitude. The transcytosis of protamine through the cerebral microvascular barrier was documented with an internal carotid artery perfusion technique. In summary, these studies provide evidence for protamine-mediated vectorial transport of albumin through microvascular barriers in brain and other organs.