tbuckley/cabot-search huggingface dataset:
Nuclear Factor-κB Activation Contributes to Vascular Endothelial Dysfunction via Oxidative Stress in Overweight/Obese Middle-Aged and Older Humans
Authors: Gary L. Pierce, Lisa A. Lesniewski, Brooke R. Lawson, Stacy D. Beske, Douglas R. Seals
Journal: Circulation (2009)

We tested the hypothesis that nuclear factor-kappaB (NF-kappaB) activity contributes to vascular endothelial dysfunction with aging and obesity in humans.We conducted a randomized, double-blind, placebo-controlled crossover study in 14 nondiabetic overweight or obese (body mass index > or =25 kg/m(2)) middle-aged and older (age 52 to 68 years) adults. Salsalate (nonacetylated salicylate, 4500 mg/d), a compound that inhibits NF-kappaB activity, or placebo was administered for 4-day periods. Plasma salicylate concentrations reached the midtherapeutic range (21.8+/-1.1 mg/100 mL, P< or =0.0001 versus placebo) by day 4 of salsalate treatment. Salsalate increased expression of the inhibitor of NF-kappaB and reduced total and nuclear expression of NF-kappaB in endothelial cells obtained from the subjects (all P<0.05). Salsalate increased brachial artery flow-mediated dilation by 74% (from 4.0+/-0.4% to 6.6+/-0.5%, P<0.001) but did not affect endothelium-independent dilation (P=0.83). The change in brachial artery flow-mediated dilation with salsalate was inversely related to baseline flow-mediated dilation (r=-0.77, P<0.01). Infusion of vitamin C increased brachial artery flow-mediated dilation during placebo (P<0.001) but not after salsalate (P=0.23). Salsalate reduced nitrotyrosine (P=0.06) and expression of NADPH oxidase p47(phox) (P<0.05) in endothelial cells obtained from the subjects but did not influence circulating or endothelial cell inflammatory proteins.Our findings provide the first direct evidence that NF-kappaB, in part via stimulation of oxidative stress, plays an important role in mediating vascular endothelial dysfunction in overweight and obese middle-aged and older humans.
Multimodal Bacteriochlorophyll Theranostic Agent
Authors: Tracy W.B. Liu, Juan Chen, Laura Burgess, Weiguo Cao, Jiyun Shi, Brian C. Wilson, Gang Zheng
Journal: Theranostics (2011)

The complimentary ability of different noninvasive imaging technologies with therapeutic modalities can be used in tandem providing high-resolution and highly sensitive imaging of events at the molecular and cellular level providing a means for image-guided therapy.There is increasing interest in using porphyrin-based photosensitizers as theranostics to take advantages of their near-infrared fluorescent properties for imaging and their strong singlet oxygen generation abilities for photodynamic therapy.Here we report a targeted multimodal bacteriochlorophyll theranostic probe.This probe consists of a bacteriochlorophyll derivative, a pharmacokinetics modification peptide linker and folate for targeted delivery to folate receptor expressing cancer cells.We demonstrate its multimodal theranostic capability, its folate receptor targeting ability and its utility for both NIR fluorescence imaging and photodynamic therapy purposes both in vitro and in vivo.
Is Renal Living-Donor Transplantation Indicated in Adult Patients with Orthotopic Ileal Neobladder? Lessons Learned from a Clinical Case
Authors: Andrea Airoldi, Alessandro Volpe, Michele Billia, GianSilvio Marchioro, Roberta Fenoglio, Elisa Lazzarich, GianMario Sacchetti, Cinzia Baiocco, Eugenio Inglese, Alberto Menegotto, Carlo Terrone, Piero Stratta
Journal: European Urology (2009)
Vascular angiotensin II receptors and sodium balance in rats. Role of kidneys and vascular renin activity.
Authors: J D Swales, J D Tange, H Thurston
Journal: Circulation Research (1975)

The relationship between the vascular response. to angiotensin II and sodium balance was studied by measuring the volume of specific antiserum needed to block the pressor response to a standard dose of angiotensin II in rats. In normal rats, sodium depletion reduced the volume of antiserum required to prevent a pressor response to 50 ng of angiotensin II from 0.32 to 0.22 ml; sodium loading increased the volume required to 0.65 ml. After bilateral nephrectomy, there was a progressive increase in the antibody requirement to a maximum of 0.63 ml at 6 hours. At this stage, there was no change in the blocking requirement with sodium depletion by either pretreatment with a low-salt diet (0.60 ml) or peritoneal dialysis (0.62 ml). The pressor response to a 50-ng bolus of angiotensin II was closely correlated with the antibody requirement in all experiments (r equals plus 0.93). These observations indicate that sodium-induced changes in the vascular response to angiotensin II require the presence of kidney tissue. We suggest that such changes in response are mediated by alterations in vascular renin which generates angiotensin II at an arteriolar site that is not accessible to antibody molecules. This locally formed angiotensin II reduces the number of receptors free to respond to circulating angiotensin II and raises the threshold of the pressor response
Changes in Integrin and E-Cadherin Expression in Neoplastic Versus Normal Thyroid Tissue
Authors: G Serini, L Trusolino, E Saggiorato, O Cremona, M De Rossi, A Angeli, F Orlandi, P C Marchisio
Journal: JNCI Journal of the National Cancer Institute (1996)

BACK: The functional organization of polarized epithelia depends mostly on adhesion molecules belonging to the integrin and cadherin families. These molecules either recognize basement membrane components, such as laminins, or form intercellular junctions via homotypic interactions. Such tissue organization is often disrupted upon neoplastic transformation, and the resulting loss of functional polarization and cell cohesion might be a prerequisite for the invasive and metastatic behavior of carcinomas.We studied modifications on thyroid adhesive mechanisms at various stages of neoplastic progression in terms of adhesion molecule expression, topography, and functional regulation by tyrosine kinases. Starting from this working hypothesis, we sought to identify one or more biological markers that would be suggestive of malignant transformation and poorer prognosis and that could be developed as a reliable indicator(s) in early diagnostic steps.The study was carried out on both surgical samples and the corresponding fine-needle aspiration biopsy smears (numbers of specimens collected: 19 adenomas, seven follicular carcinomas, 13 papilary carcinomas, and 39 normal tissues). Immunohistochemistry of tissue sections and smears and immuno-precipitation and western blot analysis of protein extracts were done with a battery of monoclonal and polyclonal antibodies. Northern blotting was performed on RNA extracts from frozen tissue samples and use of an integrin subunit beta4 complementary DNA probe.Our findings can be summarized as follows: 1) In normal thyroid cells, the cooperative role of integrin alpha6beta4 and laminin 5/kalinin in hemidesmosome-mediated adhesion adhesion is missing, and recognition of the basal lamina occurs via integrin alpha3beta1 and laminin 1 and/or 2 (this pattern being maintained in adenomas but altered in carcinomas regardless of their histotype or differentiation grade); 2) only in carcinomas with clinical and/or histologic aggressiveness do neoexpression of integrin subunit beta4 and loss of laminin 2/merosin occur, indicating de novo assembly of integrin alpha6beta4; 3) pericellular redistribution and cytoskeletal disconnection of the E-cadherin-catenin complex occur; and 4) basal E-cadherin tyrosine phosphorylation decreases in carcinomas as compared with that in normal and adenomatous tissue.The malignant progression of thyroid tumors involves marked rearrangement of cell-basement membrane and cell-cell adhesion molecules and changes in their cytoskeleton linkage. These rearrangements are also easily and reproducibly detected on fine-needle aspiration biopsy smears.Immunodetection of adhesion molecules in sections and/or fine-needle smears may complement the toolbox of thyroid surgical pathologists; it may expand the possibilities of achieving a correct early diagnosis of thyroid tumors and of gaining some prognostic information on thyroid tumors.
Psychological morbidity and job satisfaction in hospital consultants and junior house officers: multicentre, cross sectional survey
Authors: N. Kapur, C. Borrill, C. Stride
Journal: BMJ (1998)

Junior house officers have traditionally been the most distressed doctors in the health service. 1 Recently, however, there have been reports of significant psychological morbidity in senior doctors such as hospital consultants. 2Previous studies found that levels of distress decrease with increasing medical seniority. 3uch of the organisational burden of recent hospital reform has fallen on consultants, while junior doctors continue to have their hours of work reduced.We investigated whether these changes had affected the relation between medical seniority, psychological morbidity, and job satisfaction.*Consultants from different specialties considered together as no difference in GHQ scores or job satisfaction.†t test for independent samples.
Evaluation of a rapid immunochromatographic test for the serologic diagnosis of tuberculosis in Italy
Authors: A. Bartoloni, M. Strohmeyer, F. Bartalesi, D. Messeri, E. Tortoli, A. Farese, F. Leoncini, S. Nutini, R. Righi, A. Gabbuti, F. Mazzotta, F. Parodisi
Journal: Clinical Microbiology and Infection (2003)
Angiogenic factors may have a different prognostic role in adult acute lymphoblastic leukemia
Authors: Stefan Faderl, Kim-Anh Do, Marcella M. Johnson, Michael Keating, Susan O'Brien, Iman Jilani, Alessandra Ferrajoli, Farhad Ravandi-Kashani, Christine Aguilar, Amanda Dey, Deborah A. Thomas, Francis J. Giles, Hagop M. Kantarjian, Maher Albitar
Journal: Blood (2005)
Deficiency of Phospholipase A2 Group 7 Decreases Intestinal Polyposis and Colon Tumorigenesis in <i>ApcMin</i>/+ Mice
Authors: Changxin Xu, Ethan C. Reichert, Tomoyuki Nakano, Mariah Lohse, Alison A. Gardner, Mónica P. Revelo, Matthew K. Topham, Diana M. Stafforini
Journal: Cancer Research (2013)

Platelet-activating factor (PAF) is a naturally occurring phospholipid that mediates diverse effects such as physiological and pathological inflammation, immunosuppression, and cancer. Several lines of evidence support both positive and negative roles for PAF in carcinogenesis. PAF stimulates cell growth, oncogenic transformation, and metastasis, but can also limit proliferation and induce apoptosis. The biological context and microenvironment seem to define whether PAF has pro- or anticarcinogenic effects. To investigate the role of exacerbated PAF signaling in colon cancer, we conducted cell-based and in vivo studies using genetically engineered mice lacking expression of phospholipase A2 group 7 (PLA2G7), an enzyme that specifically metabolizes PAF and structurally related glycerophospholipids. Absence of Pla2g7 robustly decreased intestinal polyposis and colon tumor formation in Apc(Min)(/+) mice, suggesting an antitumorigenic role for PAF in settings characterized by aberrant function of the tumor suppressor Adenomatous polyposis coli (Apc). In colonic epithelial cells, exposure to a PAF analog led to dephosphorylation of Akt at serine-473 and induction of apoptosis. The mechanism of this response involved formation of a complex between β-arrestin 1 and the Akt phosphatase PHLPP2, and activation of the intrinsic pathway of apoptosis. Our results suggest that strategies based on inhibiting PLA2G7 activity or increasing PAF-mediated signaling hold promise for the treatment of intestinal malignancies that harbor mutations in APC.
Gene Expression and Benefit of Chemotherapy in Women With Node-Negative, Estrogen Receptor–Positive Breast Cancer
Authors: Soonmyung Paik, Gong Tang, Steven Shak, Chungyeul Kim, Joffre Baker, Wanseop Kim, Maureen Cronin, Frederick L. Baehner, Drew Watson, John Bryant, Joseph P. Costantino, Charles E. Geyer, D. Lawrence Wickerham, Norman Wolmark
Journal: Journal of Clinical Oncology (2006)

Purpose The 21-gene recurrence score (RS) assay quantifies the likelihood of distant recurrence in women with estrogen receptor–positive, lymph node–negative breast cancer treated with adjuvant tamoxifen. The relationship between the RS and chemotherapy benefit is not known. Methods The RS was measured in tumors from the tamoxifen-treated and tamoxifen plus chemotherapy–treated patients in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B20 trial. Cox proportional hazards models were utilized to test for interaction between chemotherapy treatment and the RS. Results A total of 651 patients were assessable (227 randomly assigned to tamoxifen and 424 randomly assigned to tamoxifen plus chemotherapy). The test for interaction between chemotherapy treatment and RS was statistically significant (P = .038). Patients with high-RS (≥ 31) tumors (ie, high risk of recurrence) had a large benefit from chemotherapy (relative risk, 0.26; 95% CI, 0.13 to 0.53; absolute decrease in 10-year distant recurrence rate: mean, 27.6%; SE, 8.0%). Patients with low-RS (&lt; 18) tumors derived minimal, if any, benefit from chemotherapy treatment (relative risk, 1.31; 95% CI, 0.46 to 3.78; absolute decrease in distant recurrence rate at 10 years: mean, −1.1%; SE, 2.2%). Patients with intermediate-RS tumors did not appear to have a large benefit, but the uncertainty in the estimate can not exclude a clinically important benefit. Conclusion The RS assay not only quantifies the likelihood of breast cancer recurrence in women with node-negative, estrogen receptor–positive breast cancer, but also predicts the magnitude of chemotherapy benefit.
MAFFT Multiple Sequence Alignment Software Version 7: Improvements in Performance and Usability
Authors: K. Katoh, D. M. Standley
Journal: Molecular Biology and Evolution (2013)

We report a major update of the MAFFT multiple sequence alignment program. This version has several new features, including options for adding unaligned sequences into an existing alignment, adjustment of direction in nucleotide alignment, constrained alignment and parallel processing, which were implemented after the previous major update. This report shows actual examples to explain how these features work, alone and in combination. Some examples incorrectly aligned by MAFFT are also shown to clarify its limitations. We discuss how to avoid misalignments, and our ongoing efforts to overcome such limitations.
Hyperinflation of the lungs in coal miners
Authors: W. K. C. Morgan, D. B. Burgess, N. L. Lapp, A. Seaton, R. B. Reger
Journal: Thorax (1971)

The residual volume and total lung capacity of 1,455 working Pennsylvania coal miners were determined as part of a larger epidemiological study. The age of the subjects varied between 18 and 65 with a mean of 48·7 years. The total lung capacity of the subjects was determined from standard posteroanterior and lateral chest films while the forced vital capacity was determined by spirometry (O9Shea <i>et al.</i>, 1970). The effect of increasing radiographic category of simple coal workers9 pneumoconiosis on lung volumes was investigated. It was shown that the residual volume increased with radiographic category and that this occurred whether or not the miners had obstructive airways disease. The presence of obstruction had an additional effect over and above that due to coal dust alone, so that the largest increase in residual volume was found in miners who had both obstruction and radiographic evidence of simple coal workers9 pneumoconiosis.
The Macrophage at the Crossroads of Insulin Resistance and Atherosclerosis
Authors: Chien-Ping Liang, Seongah Han, Takafumi Senokuchi, Alan R. Tall
Journal: Circulation Research (2007)

The macrophage has emerged as an important player in the pathogenesis of both atherosclerosis and insulin resistance. Cross-talk between inflammatory macrophages and adipocytes may be involved in insulin resistance in peripheral tissues. Defective insulin signaling in cells of the arterial wall including macrophages may promote the development of atherosclerosis. Insulin resistant macrophages are more susceptible to endoplasmic reticulum stress and apoptosis in response to various stimuli such as nutrient deprivation, free cholesterol loading, and oxidized LDL. Increased apoptosis of insulin resistant macrophages and impaired phagocytic clearance of apoptotic cells by insulin resistant macrophages in atherosclerotic lesions may lead to enhanced postapoptotic necrosis, larger lipid-rich cores, increased inflammation, and more complex vulnerable plaques.
Molecular Pathways: Tumor Cells Co-opt the Brain-Specific Metabolism Gene<i>CPT1C</i>to Promote Survival
Authors: Patrick T. Reilly, Tak W. Mak
Journal: Clinical Cancer Research (2012)

Abstract The metabolic adaptations of cancer cells are receiving renewed attention as potential targets for therapeutic exploitation. Recent work has highlighted the importance of fatty acid catabolism through β-oxidation to cellular energy homeostasis. In this article, we describe recent preclinical studies suggesting that a gene usually expressed only in the brain, carnitine palmitoyltransferase (CPT)1C, promotes cancer cell survival and tumor growth. CTP1C confers rapamycin resistance on breast cancer cells, indicating that this gene may act in a pathway parallel to mTOR-enhanced glycolysis. Because of CPT1C's normally brain-restricted expression and the inability of most drugs to pass the blood–brain barrier, CPT1C may be an ideal candidate for specific small-molecule inhibition. We further speculate that concurrent targeting of CPT1C activity and glycolysis in tumor cells could be a highly effective anticancer approach. Clin Cancer Res; 18(21); 5850–5. ©2012 AACR.
Adaptation of cognitive function to hypoglycemia in healthy men.
Authors: B Fruehwald-Schultes, J Born, W Kern, A Peters, H L Fehm
Journal: Diabetes Care (2000)

OBJECTIVE: Antecedent hypoglycemia reduces hypoglycemic counterregulation and symptoms, thereby provoking the hypoglycemia unawareness syndrome. The effects of antecedent hypoglycemia on hypoglycemia-induced cognitive dysfunction are less well established. RESEARCH DESIGN AND METHODS: To determine whether antecedent hypoglycemia also reduces hypoglycemic cognitive dysfunction, we performed stepwise hypoglycemic clamp experiments (4.1, 3.6, 3.1, and 2.6 mmol/l) during a 6-h period in 30 young healthy men. A total of 15 subjects additionally received a 2.5-h antecedent hypoglycemic clamp (3.1 mmol/l) on the preceding day (prior-hypo group), whereas the other 15 subjects did not (control group). Cognitive function was assessed by auditory-evoked brain potentials (AEBPs) and reaction time during a vigilance task and short-term memory recall. Tests were performed during the stepwise hypoglycemic clamp at baseline and at each hypoglycemic plateau. RESULTS: In both groups, performance on all measures of cognitive function deteriorated during stepwise hypoglycemia (all P &amp;lt; 0.01). However, after antecedent hypoglycemia, the hypoglycemia-induced decrease in the amplitude of the P3 of the AEBP was distinctly reduced compared with the control condition (P &amp;lt; 0.05). Also, short-term memory performance was less impaired in the prior-hypo group than in the control group (P &amp;lt; 0.005), and a minor hypoglycemic impairment of reaction time (P &amp;lt; 0.05) was evident in the prior-hypo group. CONCLUSIONS: Data provide evidence that a single episode of mild antecedent hypoglycemia (3.1 mmol/l) attenuates several aspects of cognitive dysfunction during subsequent hypoglycemia 18-24 h later.
In Melanoma, <i>RAS</i> Mutations Are Accompanied by Switching Signaling from BRAF to CRAF and Disrupted Cyclic AMP Signaling
Authors: Nicolas Dumaz, Robert Hayward, Jan Martin, Lesley Ogilvie, Douglas Hedley, John A. Curtin, Boris C. Bastian, Caroline Springer, Richard Marais
Journal: Cancer Research (2006)

Abstract Melanocytes require the RAS/RAF/MEK/ERK and the cyclic AMP (cAMP) signaling pathways to maintain the fine balance between proliferation and differentiation. We have investigated how cross-talk between these pathways affects melanoma progression. We show that cAMP suppresses CRAF activity in melanocytes and that this is essential to suppress the oncogenic potential of CRAF in these cells. As a consequence, BRAF alone is responsible for signaling to MEK. However, when RAS is mutated in melanoma, the cells switch their signaling from BRAF to CRAF. This switch is accompanied by dysregulated cAMP signaling, a step that is necessary to allow CRAF to signal to MEK. Thus, a fundamental switch in RAF isoform usage occurs when RAS is mutated in melanoma, and this occurs in the context of disrupted cAMP signaling. These data have important implications for the development of therapeutic strategies to treat this life-threatening disease. (Cancer Res 2006; 66(19): 9483-91)
Determinants of Outcome in Melanoma Patients With Cerebral Metastases
Authors: K.M. Fife, M.H. Colman, G.N. Stevens, I.C. Firth, D. Moon, K.F. Shannon, R. Harman, K. Petersen-Schaefer, A.C. Zacest, M. Besser, G.W. Milton, W.H. McCarthy, J.F. Thompson
Journal: Journal of Clinical Oncology (2004)

To analyze prognostic factors, effects of treatment, and survival for patients with cerebral metastases from melanoma.All melanoma patients with cerebral metastases treated at the Sydney Melanoma Unit between 1952 and 2000 were identified. From 1985 to 2000, patients were diagnosed and treated using consistent modern techniques and this cohort was analyzed in detail. Multivariate analysis of prognostic factors for survival was performed.A total of 1137 patients with cerebral metastases were identified; 686 were treated between 1985 and 2000. For these 686 patients, the median time from primary diagnosis to cerebral metastasis was 3.1 years (range, 0 to 41 years). A total of 646 patients (94%) have died as a result of melanoma. The median survival from the time of diagnosis of cerebral metastasis was 4.1 months (range, 0 to 17.2 years). Treatment was as follows: surgery and postoperative radiotherapy, 158 patients; surgery alone, 47 patients; radiotherapy alone, 236 patients; and supportive care alone, 210 patients. Median survival according to treatment received for these four groups was 8.9, 8.7, 3.4, and 2.1 months, respectively; the differences between surgery and nonsurgery groups were statistically significant. On multivariate analysis, significant factors associated with improved survival were surgical treatment (P <.0001), no concurrent extracerebral metastases (P <.0001), younger age (P =.0007), and longer disease-free interval (P =.036). Prognostic factors analysis confirmed the important influence of patient selection on treatment received.This large series documents the characteristics of patients who developed cerebral metastases from melanoma. Median survival was dependent on treatment, which in turn was dependent on patient selection.