tbuckley/cabot-search huggingface dataset:
Effects of Dopamine in Man
Authors: David Horwitz, Samuel M. Fox, Leon I. Goldberg
Journal: Circulation Research (1962)

Dopamine, the biochemical precursor of norepinephrine, was infused intravenously into 11 normal subjects and 2 patients. Results of hemodynamic studies in 6 normal subjects indicated that dopamine increased cardiac output and stroke volume in all subjects. Arterial pressure also increased in all subjects with a predominant systolic pressure increment. Calculated vascular resistance decreased in 5 subjects and did not change in the other subject. Changes in heart rate were of small magnitude and were inconstant in direction. Left atrial pressure did not change in 2 patients at a time when substantial increments in cardiac output were produced by dopamine. Comparison of the doses of dopamine and norepinephrine calculated to produce equivalent increments in systolic pressure indicated that dopamine was 1/25 to 1/56 as potent as norepinephrine in this respect. Infusions of dopamine produced relatively small but consistent increments in blood glucose levels. It is concluded that the pharmacological actions of dopamine in man are different from those of epinephrine and norepinephrine. Because of its distinctive properties, dopamine may be useful in the treatment of patients with inadequate cardiac output.
Dissociation, Childhood Interpersonal Trauma, and Family Functioning in Patients With Somatization Disorder
Authors: Richard J Brown, Anette Schrag, Michael R Trimble
Journal: American Journal of Psychiatry (2005)

OBJECTIVE: The goals of this study were to determine 1) the occurrence of various dissociative phenomena in patients with somatization disorder, 2) the occurrence of six different types of childhood interpersonal trauma in these patients, and 3) the nature of these patients' early family environment. METHOD: Twenty-two patients with somatization disorder and 19 medical comparison subjects completed the Structured Clinical Interview for DSM-IV Dissociative Disorders, the Childhood Trauma Interview, and the Family Functioning Scale. RESULTS: The somatization disorder patients reported significantly higher level of dissociative amnesia than the comparison subjects. The two groups reported similar levels of depersonalization, derealization, identity confusion, and identity alteration. Somatization disorder patients reported significantly greater childhood emotional abuse and more severe forms of physical abuse, relative to the comparison subjects, with chronic emotional abuse being the best predictor of unexplained symptoms. Childhood sexual abuse, separation/loss, and witnessing violence were equally common in the two groups. The somatization disorder group reported significantly more family conflict and less family cohesion. CONCLUSIONS: Only some types of dissociation are more severe in patients with somatization disorder, relative to medical comparison subjects. Many patients with somatization disorder are raised in an emotionally cold, distant, and unsupportive family environment characterized by chronic emotional and physical abuse. Sexual abuse is not a necessary prerequisite for the disorder.
Use of Phosphatide Precursors to Promote Synaptogenesis
Authors: Richard J. Wurtman, Mehmet Cansev, Toshimasa Sakamoto, Ismail H. Ulus
Journal: Annual Review of Nutrition (2009)

New brain synapses form when a postsynaptic structure, the dendritic spine, interacts with a presynaptic terminal. Brain synapses and dendritic spines, membrane-rich structures, are depleted in Alzheimer's disease, as are some circulating compounds needed for synthesizing phosphatides, the major constituents of synaptic membranes. Animals given three of these compounds, all nutrients-uridine, the omega-3 polyunsaturated fatty acid docosahexaenoic acid, and choline-develop increased levels of brain phosphatides and of proteins that are concentrated within synaptic membranes (e.g., PSD-95, synapsin-1), improved cognition, and enhanced neurotransmitter release. The nutrients work by increasing the substrate-saturation of low-affinity enzymes that synthesize the phosphatides. Moreover, uridine and its nucleotide metabolites activate brain P2Y receptors, which control neuronal differentiation and synaptic protein synthesis. A preparation containing these compounds is being tested for treating Alzheimer's disease.
Telomerase-Specific T-Cell Immunity in Breast Cancer: Effect of Vaccination on Tumor Immunosurveillance
Authors: Susan M. Domchek, Adri Recio, Rosemarie Mick, Carolyn E. Clark, Erica L. Carpenter, Kevin R. Fox, Angela DeMichele, Lynn M. Schuchter, Michael S. Leibowitz, Michael H. Wexler, Barbara A. Vance, Gregory L. Beatty, Elizabeth Veloso, Michael D. Feldman, Robert H. Vonderheide
Journal: Cancer Research (2007)

The human telomerase reverse transcriptase (hTERT) is nearly universally overexpressed in human cancer, contributes critically to oncogenesis, and is recognized by cytotoxic T cells that lyse tumors. CD8+ T cells specific for hTERT naturally occur in certain populations of cancer patients in remission, but it remains poorly understood whether such T cells could contribute to tumor immunosurveillance. To address this issue, we induced hTERT-specific T cells in vivo via peptide vaccination in 19 patients with metastatic breast cancer who otherwise had no measurable T-cell responses to hTERT at baseline. Tumor-infiltrating lymphocytes (TIL) were evident after, but not before vaccination, with 4% to 13% of postvaccine CD8+ TIL specific for the immunizing hTERT peptide. Induction of TIL manifested clinically with tumor site pain and pruritus and pathologically with alterations in the tumor microenvironment, featuring histiocytic accumulation and widespread tumor necrosis. hTERT-specific CD8+ T cells were also evident after vaccination in the peripheral blood of patients and exhibited effector functions in vitro including proliferation, IFN-gamma production, and tumor lysis. An exploratory landmark analysis revealed that median overall survival was significantly longer in those patients who achieved an immune response to hTERT peptide compared with patients who did not. Immune response to a control cytomegalovirus peptide in the vaccine did not correlate with survival. These results suggest that hTERT-specific T cells could contribute to the immunosurveillance of breast cancer and suggest novel opportunities for both therapeutic and prophylactic vaccine strategies for cancer.
Structural and functional identification of two human, tumor-derived monocyte chemotactic proteins (MCP-2 and MCP-3) belonging to the chemokine family.
Authors: J Van Damme, P Proost, J P Lenaerts, G Opdenakker
Journal: The Journal of Experimental Medicine (1992)

Cytokine-stimulated human osteosarcoma cells (MG-63) secrete several related chemotactic factors, including the neutrophil-activating protein interleukin 8 (IL-8) and the monocyte chemotactic protein (MCP)-1. We describe the isolation and characterization of two novel monocyte chemotactic factors from this tumor cell line. Although these proteins copurified with MCP-1 and IL-8 on heparin-Sepharose, they could be separated by cation-exchange fast protein liquid chromatography and reverse-phase high-performance liquid chromatography. The corresponding 7.5- and 11-kD proteins were NH2-terminally blocked but were identified by sequencing peptide fragments. They showed a primary structure mostly related to that of MCP-1 and were therefore designated MCP-2 and MCP-3, respectively. These molecules can be classified in a subfamily of proinflammatory proteins characterized by the conservation of cysteine residues. MCP-2 and MCP-3 are also functionally related to MCP-1 because they specifically attract monocytes, but not neutrophils, in vitro. The chemotactic potency (specific activity) was comparable for all three MCPs. Intradermal injection of these proteins in rabbits resulted in selective monocyte recruitment in vivo. Since tumor cells are good producers of leukocyte chemotactic factors, it could be questioned whether these molecules can indirectly control tumor growth by attracting leukocytes or whether they rather promote invasion by the secretion of proteases from the attracted cells.
Cigar and pipe smoking, smokeless tobacco use and pancreatic cancer: an analysis from the International Pancreatic Cancer Case-Control Consortium (PanC4)
Authors: P. Bertuccio, C. La Vecchia, D.T. Silverman, G.M. Petersen, P.M. Bracci, E. Negri, D. Li, H.A. Risch, S.H. Olson, S. Gallinger, A.B. Miller, H.B. Bueno-de-Mesquita, R. Talamini, J. Polesel, P. Ghadirian, P.A. Baghurst, W. Zatonski, E.T. Fontham, W.R. Bamlet, E.A. Holly, E. Lucenteforte, M. Hassan, H. Yu, R.C. Kurtz, M. Cotterchio, J. Su, P. Maisonneuve, E.J. Duell, C. Bosetti, P. Boffetta
Journal: Annals of Oncology (2011)
The Accuracy Benefit of Multiple Amperometric Glucose Sensors in People With Type 1 Diabetes
Authors: Jessica R. Castle, Amy Pitts, Kathryn Hanavan, Rhonda Muhly, Joseph El Youssef, Colleen Hughes-Karvetski, Boris Kovatchev, W. Kenneth Ward
Journal: Diabetes Care (2012)

OBJECTIVE To improve glucose sensor accuracy in subjects with type 1 diabetes by using multiple sensors and to assess whether the benefit of redundancy is affected by intersensor distance. RESEARCH DESIGN AND METHODS Nineteen adults with type 1 diabetes wore four Dexcom SEVEN PLUS subcutaneous glucose sensors during two 9-h studies. One pair of sensors was worn on each side of the abdomen, with each sensor pair placed at a predetermined distance apart and 20 cm away from the opposite pair. Arterialized venous blood glucose levels were measured every 15 min, and sensor glucose values were recorded every 5 min. Sensors were calibrated once at the beginning of the study. RESULTS The use of four sensors significantly reduced very large errors compared with one sensor (0.4 vs. 2.6% of errors ≥50% from reference glucose, P &amp;lt; 0.001) and also improved overall accuracy (mean absolute relative difference, 11.6 vs. 14.8%, P &amp;lt; 0.001). Using only two sensors also significantly improved very large errors and accuracy. Intersensor distance did not affect the function of sensor pairs. CONCLUSIONS Sensor accuracy is significantly improved with the use of multiple sensors compared with the use of a single sensor. The benefit of redundancy is present even when sensors are positioned very closely together (7 mm). These findings are relevant to the design of an artificial pancreas device.
Renal Interstitial Fibrosis Is Reduced in Angiotensin II Type 1a Receptor-Deficient Mice
Authors: MINORU SATOH, NAOKI KASHIHARA, YASUSHI YAMASAKI, KEISUKE MARUYAMA, KAZUNORI OKAMOTO, YOUHEI MAESHIMA, HITOSHI SUGIYAMA, TAKESHI SUGAYA, KAZUO MURAKAMI, HIROFUMI MAKINO
Journal: Journal of the American Society of Nephrology (2001)

Abstract. Unilateral ureteral obstruction (UUO) results in tubulointerstitial fibrosis of the affected kidney by stimulating the renin-angiotensin system. This study established a UUO model in angiotensin type 1a receptor (AT1a) deficient (mutant) mice to elucidate the role of angiotensin II through AT1a on the fibrosis of the obstructed kidney (OBK). The relative volume of the tubulointerstitium was measured by an image analyzer; deposition of collagen types III and IV and monocyte/macrophage infiltration were histologically examined using specific antibodies. Also determined were the mRNA levels of transforming growth factor-β by Northern blot analysis. Nuclear factor-κB activity was assessed by gel shift assay. UUO in wild mice resulted in a marked expansion of relative volume of the tubulointerstitium, together with increased deposition of collagen types III and IV and number of infiltrated monocytes/macrophages in the interstitium, relative to sham-operated mice. In comparison, these changes were significantly lower in mutant mice with UUO. The mRNA level of transforming growth factor-β was significantly higher in the OBK of wild mice with UUO compared with sham-operated mice. In contrast, the increase in mRNA level in the OBK of mutant mice was significantly less than in wild mice. Finally, UUO resulted in activation of nuclear factor-κB in wild mice but was inhibited in the OBK of mutant mice. The results provide direct evidence that angiotensin II acting via the AT1a plays a pivotal role in the development of tubulointerstitial fibrosis in UUO.
Antioxidants Accelerate Lung Cancer Progression in Mice
Authors: Volkan I. Sayin, Mohamed X. Ibrahim, Erik Larsson, Jonas A. Nilsson, Per Lindahl, Martin O. Bergo
Journal: Science Translational Medicine (2014)

The antioxidants acetylcysteine and vitamin E accelerate tumor progression and reduce survival in mouse models of lung cancer by disrupting the ROS-p53 axis.
Nitroxyl-Mediated Disulfide Bond Formation Between Cardiac Myofilament Cysteines Enhances Contractile Function
Authors: Wei Dong Gao, Christopher I. Murray, Ye Tian, Xin Zhong, Jenna F. DuMond, Xiaoxu Shen, Brian A. Stanley, D. Brian Foster, David A. Wink, S. Bruce King, Jennifer E. Van Eyk, Nazareno Paolocci
Journal: Circulation Research (2012)

Rationale: In the myocardium, redox/cysteine modification of proteins regulating Ca 2+ cycling can affect contraction and may have therapeutic value. Nitroxyl (HNO), the one-electron-reduced form of nitric oxide, enhances cardiac function in a manner that suggests reversible cysteine modifications of the contractile machinery. Objective: To determine the effects of HNO modification in cardiac myofilament proteins. Methods and Results: The HNO-donor, 1-nitrosocyclohexyl acetate, was found to act directly on the myofilament proteins, increasing maximum force (F max ) and reducing the concentration of Ca 2+ for 50% activation (Ca 50 ) in intact and skinned cardiac muscles. The effects of 1-nitrosocyclohexyl acetate are reversible by reducing agents and distinct from those of another HNO donor, Angeli salt, which was previously reported to increase F max without affecting Ca50. Using a new mass spectrometry capture technique based on the biotin switch assay, we identified and characterized the formation by HNO of a disulfide-linked actin–tropomyosin and myosin heavy chain–myosin light chain 1. Comparison of the 1-nitrosocyclohexyl acetate and Angeli salt effects with the modifications induced by each donor indicated the actin–tropomyosin and myosin heavy chain–myosin light chain 1 interactions independently correlated with increased Ca 2+ sensitivity and force generation, respectively. Conclusions: HNO exerts a direct effect on cardiac myofilament proteins increasing myofilament Ca 2+ responsiveness by promoting disulfide bond formation between critical cysteine residues. These findings indicate a novel, redox-based modulation of the contractile apparatus, which positively impacts myocardial function, providing further mechanistic insight for HNO as a therapeutic agent.
A DNA microarray survey of gene expression in normal human tissues.
Authors: Radha Shyamsundar, Young H Kim, John P Higgins, Kelli Montgomery, Michelle Jorden, Anand Sethuraman, Matt van de Rijn, David Botstein, Patrick O Brown, Jonathan R Pollack
Journal: Genome biology (2005)

Abstract Background Numerous studies have used DNA microarrays to survey gene expression in cancer and other disease states. Comparatively little is known about the genes expressed across the gamut of normal human tissues. Systematic studies of global gene-expression patterns, by linking variation in the expression of specific genes to phenotypic variation in the cells or tissues in which they are expressed, provide clues to the molecular organization of diverse cells and to the potential roles of the genes. Results Here we describe a systematic survey of gene expression in 115 human tissue samples representing 35 different tissue types, using cDNA microarrays representing approximately 26,000 different human genes. Unsupervised hierarchical cluster analysis of the gene-expression patterns in these tissues identified clusters of genes with related biological functions and grouped the tissue specimens in a pattern that reflected their anatomic locations, cellular compositions or physiologic functions. In unsupervised and supervised analyses, tissue-specific patterns of gene expression were readily discernable. By comparative hybridization to normal genomic DNA, we were also able to estimate transcript abundances for expressed genes. Conclusions Our dataset provides a baseline for comparison to diseased tissues, and will aid in the identification of tissue-specific functions. In addition, our analysis identifies potential molecular markers for detection of injury to specific organs and tissues, and provides a foundation for selection of potential targets for selective anticancer therapy.
The two tempos of nuclear pore complex evolution: highly adapting proteins in an ancient frozen structure.
Authors: Eric Bapteste, Robert L Charlebois, Dave MacLeod, Céline Brochier
Journal: Genome biology (2005)

Abstract Background The origin of the nuclear compartment has been extensively debated, leading to several alternative views on the evolution of the eukaryotic nucleus. Until recently, too little phylogenetic information was available to address this issue by using multiple characters for many lineages. Results We analyzed 65 proteins integral to or associated with the nuclear pore complex (NPC), including all the identified nucleoporins, the components of their anchoring system and some of their main partners. We used reconstruction of ancestral sequences of these proteins to expand the detection of homologs, and showed that the majority of them, present all over the nuclear pore structure, share homologs in all extant eukaryotic lineages. The anchoring system, by contrast, is analogous between the different eukaryotic lineages and is thus a relatively recent innovation. We also showed the existence of high heterogeneity of evolutionary rates between these proteins, as well as between and within lineages. We show that the ubiquitous genes of the nuclear pore structure are not strongly conserved at the sequence level, and that only their domains are relatively well preserved. Conclusion We propose that an NPC very similar to the extant one was already present in at least the last common ancestor of all extant eukaryotes and it would not have undergone major changes since its early origin. Importantly, we observe that sequences and structures obey two very different tempos of evolution. We suggest that, despite strong constraints that froze the structural evolution of the nuclear pore, the NPC is still highly adaptive, modern, and flexible at the sequence level.
Pemetrexed Versus Pemetrexed and Carboplatin As Second-Line Chemotherapy in Advanced Non–Small-Cell Lung Cancer: Results of the GOIRC 02-2006 Randomized Phase II Study and Pooled Analysis With the NVALT7 Trial
Authors: Andrea Ardizzoni, Marcello Tiseo, Luca Boni, Andrew D. Vincent, Rodolfo Passalacqua, Sebastiano Buti, Domenico Amoroso, Andrea Camerini, Roberto Labianca, Giovenzio Genestreti, Corrado Boni, Libero Ciuffreda, Francesco Di Costanzo, Filippo de Marinis, Lucio Crinò, Antonio Santo, Antonio Pazzola, Fausto Barbieri, Nicoletta Zilembo, Ida Colantonio, Carmelo Tibaldi, Rodolfo Mattioli, Mara A. Cafferata, Roberta Camisa, Egbert F. Smit
Journal: Journal of Clinical Oncology (2012)

Purpose To compare efficacy of pemetrexed versus pemetrexed plus carboplatin in pretreated patients with advanced non–small-cell lung cancer (NSCLC). Patients and Methods Patients with advanced NSCLC, in progression during or after first-line platinum-based chemotherapy, were randomly assigned to receive pemetrexed (arm A) or pemetrexed plus carboplatin (arm B). Primary end point was progression-free survival (PFS). A preplanned pooled analysis of the results of this study with those of the NVALT7 study was carried out to assess the impact of carboplatin added to pemetrexed in terms of overall survival (OS). Results From July 2007 to October 2009, 239 patients (arm A, n = 120; arm B, n = 119) were enrolled. Median PFS was 3.6 months for arm A versus 3.5 months for arm B (hazard ratio [HR], 1.05; 95% CI, 0.81 to 1.36; P = .706). No statistically significant differences in response rate, OS, or toxicity were observed. A total of 479 patients were included in the pooled analysis. OS was not improved by the addition of carboplatin to pemetrexed (HR, 90; 95% CI, 0.74 to 1.10; P = .316; P heterogeneity = .495). In the subgroup analyses, the addition of carboplatin to pemetrexed in patients with squamous tumors led to a statistically significant improvement in OS from 5.4 to 9 months (adjusted HR, 0.58; 95% CI, 0.37 to 0.91; P interaction test = .039). Conclusion Second-line treatment of advanced NSCLC with pemetrexed plus carboplatin does not improve survival outcomes as compared with single-agent pemetrexed. The benefit observed with carboplatin addition in squamous tumors may warrant further investigation.
Bone resorption by cells isolated from rheumatoid synovium.
Authors: J S Chang, J M Quinn, A Demaziere, C J Bulstrode, M J Francis, R B Duthie, N A Athanasou
Journal: Annals of the Rheumatic Diseases (1992)

Cellular mechanisms accounting for the osteolysis of rheumatoid erosions are poorly understood. Cells were isolated and characterised from the synovium of 16 patients with rheumatoid arthritis (RA) and four patients with osteoarthritis and their ability to resorb bone was assessed using a scanning electron microscope bone resorption assay. Macrophages were the major cell type isolated from the synovium of patients with RA. These produced extensive roughening of the bone surface without resorption pit formation. This low grade type of bone resorption was not affected by systemic (calcitonin, parathyroid hormone, 1,25-dihydroxyvitamin D3) or local (interleukin 1, prostaglandin E2) factors influencing bone resorption. Macrophage mediated bone resorption differs qualitatively and quantitatively from that of osteoclasts but is likely to play an important part in the development of marginal erosions in RA.