tbuckley/cabot-search huggingface dataset:
Clinical Course of Advanced Non–Small-Cell Lung Cancer Patients Experiencing Hypertension During Treatment With Bevacizumab in Combination With Carboplatin and Paclitaxel on ECOG 4599
Authors: Suzanne E. Dahlberg, Alan B. Sandler, Julie R. Brahmer, Joan H. Schiller, David H. Johnson
Journal: Journal of Clinical Oncology (2010)

PURPOSE Bevacizumab is a monoclonal antibody that targets vascular endothelial growth factor (VEGF) with demonstrated efficacy in combination with carboplatin and paclitaxel (PCB) for the treatment of advanced non-small-cell lung cancer (NSCLC). Administration of bevacizumab is postulated to decrease nitric oxide synthesis and lead to hypertension, which may be a physiological sign that the VEGF pathway is more actively being blocked and could result in improved outcomes. PATIENTS AND METHODS Eastern Cooperative Oncology Group (ECOG) 4599 randomly assigned patients with nonsquamous NSCLC to carboplatin and paclitaxel (PC) versus PCB. Hypertensive patients were compared with nonhypertensive patients with respect to overall survival (OS) and progression-free survival (PFS) using blood pressure data and adverse event data separately. High blood pressure (HBP) by the end of cycle 1 was defined as blood pressure > 150/100 at any previous time or at least a 20-mmHg increase in diastolic blood pressure from baseline. Results In a multivariable Cox model adjusting for HBP as a time-varying covariate, comparing those on PCB with HBP with those on PC gave an OS hazard ratio (HR) of 0.60 (95% CI, 0.43 to 0.81; P = .001); comparing those on PCB without HBP with those on PC alone, the OS HR was 0.86 (95% CI, 0.74 to 1.00; P = .05). Comparing the PCB HBP group with PC gave an adjusted PFS HR of 0.54 (95% CI, 0.41 to 0.73; P < .0001) and comparing those on PCB without HBP to those on PC, the HR was 0.72 (95% CI, 0.62 to 0.84; P < .0001). The 6-month cumulative incidence of hypertension was 6.2% (95% CI, 3.9% to 8.6%). CONCLUSION Data from ECOG 4599 suggest that onset of HBP during treatment with PCB may be associated with improved outcomes, and additional studies of the downstream effects of VEGF suppression and hypertension are needed.
Lupus erythematosus profundus associated with neonatal lupus erythematosus
Authors: Y. NITTA
Journal: British Journal of Dermatology (1997)

A female infant with neonatal lupus erythematosus had scanty discoid lesions and concurrent lupus erythematosus profundus on the face. Depression of lupus erythematosus profundus lesions was still evident at 4 years of age.
Letter by Stuehlinger et al Regarding Article, “Metabolic Profiling of Arginine and Nitric Oxide Pathways Predicts Hemodynamic Abnormalities and Mortality in Patients With Cardiogenic Shock After Acute Myocardial Infarction”
Authors: Markus C. Stuehlinger, Bernhard Metzler, John P. Cooke
Journal: Circulation (2008)
Protein kinetic signatures of the remodeling heart following isoproterenol stimulation
Authors: Maggie P.Y. Lam, Ding Wang, Edward Lau, David A. Liem, Allen K. Kim, Dominic C.M. Ng, Xiangbo Liang, Brian J. Bleakley, Chenguang Liu, Jason D. Tabaraki, Martin Cadeiras, Yibin Wang, Mario C. Deng, Peipei Ping
Journal: Journal of Clinical Investigation (2014)

Protein temporal dynamics play a critical role in time-dimensional pathophysiological processes, including the gradual cardiac remodeling that occurs in early-stage heart failure. Methods for quantitative assessments of protein kinetics are lacking, and despite knowledge gained from single-protein studies, integrative views of the coordinated behavior of multiple proteins in cardiac remodeling are scarce. Here, we developed a workflow that integrates deuterium oxide (2H2O) labeling, high-resolution mass spectrometry (MS), and custom computational methods to systematically interrogate in vivo protein turnover. Using this workflow, we characterized the in vivo turnover kinetics of 2,964 proteins in a mouse model of β-adrenergic-induced cardiac remodeling. The data provided a quantitative and longitudinal view of cardiac remodeling at the molecular level, revealing widespread kinetic regulations in calcium signaling, metabolism, proteostasis, and mitochondrial dynamics. We translated the workflow to human studies, creating a reference dataset of 496 plasma protein turnover rates from 4 healthy adults. The approach is applicable to short, minimal label enrichment and can be performed on as little as a single biopsy, thereby overcoming critical obstacles to clinical investigations. The protein turnover quantitation experiments and computational workflow described here should be widely applicable to large-scale biomolecular investigations of human disease mechanisms with a temporal perspective.
Activation and attenuation of transcription factor NF-kB in mouse glomerular mesangial cells in response to tumor necrosis factor-alpha, immunoglobulin G, and adenosine 3':5'-cyclic monophosphate. Evidence for involvement of reactive oxygen species.
Authors: J Satriano, D Schlondorff
Journal: Journal of Clinical Investigation (1994)

The transcription factor NF-kB may play an important role in the response to tissue injury and activation of cytokines. We therefore examined the regulation of NF-kB in mesangial cells. Treatment of mesangial cells with TNF-alpha increased nuclear proteins that bound to an NF-kB-specific DNA oligonucleotide. IgG aggregates also increased nuclear NF-kB demonstrating Fc-tau receptor-mediated activation of NF-kB. Treatment of a cytosolic preparation with the detergent deoxycholate also activated NF-kB. The binding characteristics were typical for NF-kB transcription factors as determined by competition experiments with NF-kB-binding wild type kB DNA oligonucleotides or mutated oligonucleotides. Furthermore, a monoclonal antibody against the p65 subunit of NF-kB prevented the binding of NF-kB to the kB oligonucleotide. To evaluate the potential role of reactive oxygen intermediates in the activation of NF-kB, we used PDTC as a scavenger and HMAP as an inhibitor of NADPH-dependent oxidase. Both PDTC and HMAP attenuated the increase in nuclear NF-kB in response to either TNF-alpha or IgG complexes. Finally, generation of superoxide anion by xanthine oxidase activated NF-kB, an effect also mitigated by PDTC. In contrast, exogenous H2O2 did not activate NF-kB. Preincubation of cells with 8 br-cAMP, forskolin, or PGE2 attenuated the increase in nuclear NF-kB in response to TNF-alpha, aggregated IgG, or superoxide anion. Our results provide support for a role of reactive oxygen intermediates as mediators for activation of NF-kB in MC after stimulation with TNF-alpha or IgG aggregates. As an unexpected novel finding we report that cAMP can inhibit activation of NF-kB in MC. These observations may help to explain effects of TNF-alpha, IgG aggregates and cAMP on generation of cytokines by mesangial cells and the resulting glomerular pathophysiology.
Prophylaxis versus Episodic Treatment to Prevent Joint Disease in Boys with Severe Hemophilia
Authors: Marilyn J. Manco-Johnson, Thomas C. Abshire, Amy D. Shapiro, Brenda Riske, Michele R. Hacker, Ray Kilcoyne, J. David Ingram, Michael L. Manco-Johnson, Sharon Funk, Linda Jacobson, Leonard A. Valentino, W. Keith Hoots, George R. Buchanan, Donna DiMichele, Michael Recht, Deborah Brown, Cindy Leissinger, Shirley Bleak, Alan Cohen, Prasad Mathew, Alison Matsunaga, Desiree Medeiros, Diane Nugent, Gregory A. Thomas, Alexis A. Thompson, Kevin McRedmond, J. Michael Soucie, Harlan Austin, Bruce L. Evatt
Journal: New England Journal of Medicine (2007)

Effective ways to prevent arthropathy in severe hemophilia are unknown.We randomly assigned young boys with severe hemophilia A to regular infusions of recombinant factor VIII (prophylaxis) or to an enhanced episodic infusion schedule of at least three doses totaling a minimum of 80 IU of factor VIII per kilogram of body weight at the time of a joint hemorrhage. The primary outcome was the incidence of bone or cartilage damage as detected in index joints (ankles, knees, and elbows) by radiography or magnetic resonance imaging (MRI).Sixty-five boys younger than 30 months of age were randomly assigned to prophylaxis (32 boys) or enhanced episodic therapy (33 boys). When the boys reached 6 years of age, 93% of those in the prophylaxis group and 55% of those in the episodic-therapy group were considered to have normal index-joint structure on MRI (P=0.006). The relative risk of MRI-detected joint damage with episodic therapy as compared with prophylaxis was 6.1 (95% confidence interval, 1.5 to 24.4). The mean annual numbers of joint and total hemorrhages were higher at study exit in the episodic-therapy group than in the prophylaxis group (P<0.001 for both comparisons). High titers of inhibitors of factor VIII developed in two boys who received prophylaxis; three boys in the episodic-therapy group had a life-threatening hemorrhage. Hospitalizations and infections associated with central-catheter placement did not differ significantly between the two groups.Prophylaxis with recombinant factor VIII can prevent joint damage and decrease the frequency of joint and other hemorrhages in young boys with severe hemophilia A. (ClinicalTrials.gov number, NCT00207597 [ClinicalTrials.gov].).
Myeloma cells suppress bone formation by secreting a soluble Wnt inhibitor, sFRP-2
Authors: Takashi Oshima, Masahiro Abe, Jin Asano, Tomoko Hara, Kenichi Kitazoe, Etsuko Sekimoto, Yoichi Tanaka, Hironobu Shibata, Toshihiro Hashimoto, Shuji Ozaki, Shinsuke Kido, Daisuke Inoue, Toshio Matsumoto
Journal: Blood (2005)
Selective Killing of Tumor Neovasculature Paradoxically Improves Chemotherapy Delivery to Tumors
Authors: Freddy E. Escorcia, Erik Henke, Michael R. McDevitt, Carlos H. Villa, Peter Smith-Jones, Ronald G. Blasberg, Robert Benezra, David A. Scheinberg
Journal: Cancer Research (2010)

Antiangiogenic therapies are frequently used with concomitantly administered cancer chemotherapy to improve outcomes, but the mechanism for the benefit of the combination is uncertain. We describe a mechanism by which a specific, cytotoxic antivascular agent causes vascular remodeling and improved chemotherapy results. By selectively killing tumor neovasculature using short-ranged α-particles targeted to vascular endothelial (VE)-cadherin on vascular endothelial cells (by use of 225Ac-labeled E4G10 antibody) we were able both to reduce tumor growth and to increase the efficacy of chemotherapy, an effect seen only when the chemotherapy was administered several days after the vascular targeting agent, but not if the order of administration was reversed. Immunohistochemical and immunofluorescence studies showed that the vasculature of 225Ac-E4G10-treated tumors was substantially depleted; the remaining vessels appeared more mature morphologically and displayed increased pericyte density and coverage. Tumor uptake and microdistribution studies with radioactive and fluorescent small molecule drugs showed better accumulation and more homogenous distribution of the drugs within 225Ac-E4G10-treated tumors. These results show that 225Ac-E4G10 treatment leads to ablation and improvement of the tumor vascular architecture, and also show that the resulting vascular remodeling can increase tumor delivery of small molecules, thus providing a process for the improved outcomes observed after combining antivascular therapy and chemotherapy. This study directly shows evidence for what has long been a speculated mechanism for antiangiogenic therapies. Moreover, targeting the vessel for killing provides an alternative mode of improving chemotherapy delivery and efficacy, potentially avoiding some of the drawbacks of targeting a highly redundant angiogenic pathway.
Different structural constraints for recognition of mouse H-2Kd and -Kk antigens by alloimmune cytolytic T lymphocytes.
Authors: J Schøller, R Shimonkevitz, H R MacDonald, S Kvist
Journal: The Journal of Experimental Medicine (1986)

We have constructed a new series of hybrid genes among the H-2Kd,-Kk, and -Kb. The site of recombination occurs in the third exon, encoding the alpha 2 domain, and divides this domain into two parts, alpha 2A and alpha 2B. The novel genes differ only in the COOH-terminal half of the alpha 2 domain, i.e., the alpha 2B region. This region, comprising residues 142-182, contains a limited number of amino acid differences between the three alleles. The hybrid genes have been introduced into 1T 22-6 cells (H-2q), and cell surface expression of hybrid antigens was verified. Cells expressing different types of hybrid antigens have been examined for their susceptibility to lysis by cytotoxic T lymphocytes directed either against the H-2Kd antigen or the H-2Kk antigen. Our results show that the alpha 1 and alpha 2A domains of the H-2Kk antigen can constitute target molecules for alloimmune anti-Kk T cells, whereas the alpha 2B region, when exchanged for Kd or Kb sequences, plays only a limited role. In contrast, the alpha 1 and alpha 2A domains of Kd are not sufficient to be recognized by alloimmune anti-Kd T cells. In this instance, the alpha 2B domain seems to play an essential role. This region has undergone several amino acid substitutions involving charged residues.
Complete and partial deficiencies of complement factor D in a Dutch family.
Authors: P S Hiemstra, E Langeler, B Compier, Y Keepers, P C Leijh, M T van den Barselaar, D Overbosch, M R Daha
Journal: Journal of Clinical Investigation (1989)

A young man suffering from recurrent Neisseria infections was shown to lack detectable serum complement factor D hemolytic activity. Addition to the patient's serum of purified factor D to a final concentration of 1 microgram/ml resulted in full restoration of the activity of the alternative pathway. Using an enzyme-linked immunosorbent assay, it was shown that the patient's serum did not contain measurable amounts of factor D antigen either. The sister, the father, as well as the parents of the mother had factor D levels within the normal range, and the factor D level of the mother was decreased. The capacity of the patient's serum, at concentrations up to 5%, to promote phagocytosis of Escherichia coli by normal human granulocytes was low when compared to normal serum. Substitution of the patient's serum with purified factor D resulted in a full restoration of opsonic activity. This study describes the first complete deficiency of factor D, and demonstrates its possible relation to recurrent Neisseria infections.
Lessons from multiple sclerosis: models, concepts, observations
Authors: H Wekerle
Journal: Annals of the Rheumatic Diseases (2008)

Experimental autoimmune encephalomyelitis (EAE) is often termed "the" model of human multiple sclerosis (MS). This is, however, an oversimplification. MS is a multifaceted disorder, with no single experimental model representing the entire complexity of the human disease. On the other hand, EAE comes in numerous, distinct variants, which may reflect individual aspects of MS. This presentation reviews EAE variants and their usability as models for human MS. New transgenic models representing mechanisms determining spontaneous initiation, the course of central nervous system (CNS) autoimmunity, the distribution of lesions within the CNS and the cellular composition of the inflammatory infiltrate are discussed. Aspects of the early, inflammatory phase of MS plaque generation, in particular concerning the dynamics of immune cell invasion into the CNS, are also reviewed. Finally, the usability of EAE models for discovery and validation of MS drugs is discussed.
Ursodeoxycholic acid exerts no beneficial effect in patients with symptomatic gallstones awaiting cholecystectomy
Authors: Niels G. Venneman, Marc G.H. Besselink, Yolande C.A. Keulemans, Gerard P. vanBerge‐Henegouwen, Marja A. Boermeester, Ivo A.M.J. Broeders, Peter M.N.Y.H. Go, Karel J. van Erpecum
Journal: Hepatology (2006)

Ursodeoxycholic acid (UDCA) and impaired gallbladder motility purportedly reduce biliary pain and acute cholecystitis in patients with gallstones. However, the effect of UDCA in this setting has not been studied prospectively. This issue is important, as in several countries (including the Netherlands) scheduling problems result in long waiting periods for elective cholecystectomy. We conducted a randomized, double-blind, placebo-controlled trial on effects of UDCA in 177 highly symptomatic patients with gallstones scheduled for cholecystectomy. Patients were stratified for colic number in the preceding year (<3: 32 patients; > or =3: 145 patients). Baseline postprandial gallbladder motility was measured by ultrasound in 126 consenting patients. Twenty-three patients (26%) receiving UDCA and 29 (33%) receiving placebo remained colic-free during the waiting period (89 +/- 4; median [range]: 75[4-365] days) before cholecystectomy (P = .3). Number of colics, non-severe biliary pain, and analgesics intake were comparable. A low number of prior colics was associated with a higher likelihood of remaining colic-free (59% vs. 23%, P < .001), without effects on the risk of complications. In patients evaluated for gallbladder motility, 57% were weak and 43% were strong contractors (minimal gallbladder volume > respectively < or = 6 mL). Likelihood to remain colic-free was comparable in strong and weak contractors (31% vs. 33%). In weak contractors, UDCA decreased likelihood to remain colic-free (21% vs. 47%, P = .02). In the placebo group, 3 preoperative and 2 post-cholecystectomy complications occurred. In contrast, all 4 complications in the UDCA group occurred after cholecystectomy. In conclusion, UDCA does not reduce biliary symptoms in highly symptomatic patients. Early cholecystectomy is warranted in patients with symptomatic gallstones.
Combination of the mTOR inhibitor Rapamycin and HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17AAG) inhibits proliferation and induces apoptosis in multiple myeloma (MM)
Authors: L. A. Kasdan, G. Lu, U. Singha, S. Lentzsch, G. D. Roodman, I. M. Ghobrial
Journal: Journal of Clinical Oncology (2005)

9609 Background: The PI3Kinase pathway is constitutively activated in MM. Inhibition of the downstream target mTOR by rapamycin inhibits growth of MM cells. Heat shock protein 90 (HSP90) is a chaperone protein that enhances the proper refolding of proteins and prevents the degradation of AKT in the PI3K pathway upstream of mTOR. The HSP90 inhibitor 17AAG shows potent pro-apoptotic activity in MM. The objectives of this study were to determine the cytotoxic activity of the combination of rapamycin and 17AAG in MM cells to explore targeting multiple levels of the P13K pathway for treatment of MM. Methods: MM cell lines (MM.1S and KAS6/1) were exposed to serial dilutions of rapamycin (10–200 nM) and 17AAG (0.1 to 1.0 μM) alone and in combination for 24 and 48 hrs. Inhibition of proliferation was measured using the MTT proliferation assay. Induction of apoptosis was determined using AnnexinV/PI FACS analysis. Results: Treatment of MM.1S with rapamycin and 17AAG demonstrated dose dependent inhibition of proliferation and induction of apoptosis with a greater than additive effect. At 24 hrs, rapamcyin 20nM demonstrated 35% inhibition, 17AAG 1μM showed 65% inhibition, and the combination revealed 90% inhibition. At 24 hrs, rapamycin 20nM did not demonstrate apoptosis, 17AAG 1μM showed 40% apoptosis, and the combination revealed over 60% apoptosis. KAS6/1 cells were resistant to apoptosis by 17AAG and rapamycin. Conclusions: The combination of rapamycin and 17AAG demonstrates a greater than additive cytotoxic effect on MM cells. The primary activity of rapamycin appears to be anti-proliferative while 17AAG displays potent anti-proliferative and pro-apoptotic effects. These studies provide the framework for in vivo and clinical evaluation of mTOR inhibitors combined with 17AAG in patients with MM. The mechanistic differences in cytotoxicity as well as dually targeting the P13Kinase pathway and the heat shock protein response provides innovative avenues of study in relapsed and drug-resistant disease. Supported in part by MMRF and ASCO Young Investigator Award. No significant financial relationships to disclose.
Decreased Hepcidin-25 Level as a Predictor of Poor Prognosis in Acute Coronary Syndrome Patients
Authors: Tolga Çimen, Ekrem Yeter, Mehmet Doğan, Murat Akçay, Hüseyin Ayhan, Telat Keleş, Tahir Durmaz, Nihal Akar Bayram, Engin Bozkurt
Journal: Journal of the American College of Cardiology (2013)
Enhancement of Spontaneous Hepatic Tumorigenesis in C3H Mice by Dietary Phenobarbital2
Authors: Carl Peraino, R. J. Michael Fry, Everett Staffeldt
Journal: JNCI Journal of the National Cancer Institute (1973)

Male and female C3H mice, housed 1/cage or 5/cage, were fed a control diet or one containing 0.05% phenobarbital. After 12 months the mice were examined for spontaneous liver tumors. In mice fed the control diet, tumor incidence was higher in males than in females, and higher in mice housed 1/cage than in those housed 5/cage. Phenobarbital in the diet increased the incidence of liver tumors, irrespective of population density or sex, but did not decrease the degree of differentiation of the tumors. Phenobarbital apparently accelerated the expression of spontaneous hepatic tumorigenesis in C3H mice.
The Adenylate Cyclase Toxin of <i>Bordetella pertussis</i> Binds to Target Cells via the αMβ2 Integrin (Cd11b/Cd18)
Authors: Pierre Guermonprez, Nadia Khelef, Eric Blouin, Philippe Rieu, Paola Ricciardi-Castagnoli, Nicole Guiso, Daniel Ladant, Claude Leclerc
Journal: The Journal of Experimental Medicine (2001)

The adenylate cyclase toxin (CyaA) of Bordetella pertussis is a major virulence factor required for the early phases of lung colonization. It can invade eukaryotic cells where, upon activation by endogenous calmodulin, it catalyzes the formation of unregulated cAMP levels. CyaA intoxication leads to evident toxic effects on macrophages and neutrophils. Here, we demonstrate that CyaA uses the αMβ2 integrin (CD11b/CD18) as a cell receptor. Indeed, the saturable binding of CyaA to the surface of various hematopoietic cell lines correlated with the presence of the αMβ2 integrin on these cells. Moreover, binding of CyaA to various murine cell lines and human neutrophils was specifically blocked by anti-CD11b monoclonal antibodies. The increase of intracellular cAMP level and cell death triggered by CyaA intoxication was also specifically blocked by anti-CD11b monoclonal antibodies. In addition, CyaA bound efficiently and triggered intracellular cAMP increase and cell death in Chinese hamster ovary cells transfected with αMβ2 (CD11b/CD18) but not in cells transfected with the vector alone or with the αXβ2 (CD11c/CD18) integrin. Thus, the cellular distribution of CD11b, mostly on neutrophils, macrophages, and dendritic and natural killer cells, supports a role for CyaA in disrupting the early, innate antibacterial immune response.