tbuckley/cabot-search huggingface dataset:
Oxidant Stress and Aspirin-Insensitive Thromboxane Biosynthesis in Severe Unstable Angina
Authors: Francesco Cipollone, Giovanni Ciabattoni, Paola Patrignani, Massimo Pasquale, Domenico Di Gregorio, Tonino Bucciarelli, Giovanni Davı̀, Franco Cuccurullo, Carlo Patrono
Journal: Circulation (2000)

Background —Unstable angina is associated with enhanced lipid peroxidation and reduced antioxidant defenses. We have previously reported aspirin failure in the suppression of enhanced thromboxane (TX) biosynthesis in a subset of episodes of platelet activation in this setting. We tested the hypothesis that the in vivo formation of the F 2 -isoprostane 8-iso-prostaglandin (PG)F 2α , a bioactive product of arachidonic acid peroxidation, is enhanced in unstable angina and contributes to aspirin-insensitive TX biosynthesis. Methods and Results —Urine samples were obtained from patients with unstable angina (n=32), stable angina (n=32), or variant angina (n=4) and from 40 healthy subjects for the measurement of immunoreactive 8-iso-PGF 2α and 11-dehydro-TXB 2 . 8-Iso-PGF 2α excretion was significantly higher in patients with unstable angina (339±122 pg/mg creatinine) than in matched patients with stable angina (236±83 pg/mg creatinine, P =0.001) and control subjects (192±71 pg/mg creatinine, P &lt;0.0001). In patients with unstable angina, 8-iso-PGF 2α was linearly correlated with 11-dehydro-TXB 2 excretion (ρ=0.721, P &lt;0.0001) and inversely correlated with plasma vitamin E (ρ=−0.710, P =0.004). Spontaneous myocardial ischemia in patients with variant angina or ischemia elicited by a stress test in patients with stable angina was not accompanied by any change in 8-iso-PGF 2α excretion, thus excluding a role of ischemia per se in the induction of increased F 2 -isoprostane production. Conclusions —These findings establish a putative biochemical link between increased oxidant stress and aspirin-insensitive TX biosynthesis in patients with unstable angina and provide a rationale for dose-finding studies of antioxidants in this setting.
Regeneration of the endothelium as a novel therapeutic strategy for acute lung injury
Authors: Tohru Minamino, Issei Komuro
Journal: Journal of Clinical Investigation (2006)

Acute lung injury (ALI) is characterized by the influx of protein-rich edematous fluid into the airspaces due to increased permeability of the alveolar-capillary barrier. Inflammatory mediators are thought to play a critical role in the pathogenesis of this disorder. In this issue of the JCI, Zhao et al. report that the forkhead box M1 (FoxM1) transcription factor induces endothelial regeneration and thereby restores endothelial barrier function after ALI (see the related article beginning on page 2333). Their findings raise the intriguing possibility that the promotion of endothelial regeneration may be a novel therapeutic strategy for ALI.
Fatty Acids and Insulin Resistance
Authors: Guenther Boden
Journal: Diabetes Care (1996)

We have demonstrated that physiological elevations in plasma free fatty acid concentrations inhibit insulin-stimulated glucose uptake in a dose-dependent manner in normal control subjects and in patients with NIDDM. Two possible mechanisms were identified: 1) a fat-related inhibition of glucose transport or phosphorylation that appeared after 3-4 h of fat infusion and 2) a decrease in muscle glycogen synthase activity that appeared after 4-6 h of fat infusion. We conclude that elevations of plasma FFAs caused insulin resistance and hence may play a significant role in the pathogenesis of insulin resistance in obesity and NIDDM.
Low and middle income countries must do more to prevent spread of AIDS, experts say
Authors: B. Roehr
Journal: BMJ (2009)

The current path of HIV prevention and treatment in lower and middle income countries will result in a continued pandemic in 2031, the 50th anniversary of the recognition of the virus.

Costs will have escalated to $35bn (£21bn; €23bn), more than three times current expenditures, and more than a million people will continue to be infected each year.

These are the key findings of the AIDS 2031 Project (www.aids2031.org), a consortium of organisations involved with the pandemic. The project has modelled current and alternative activities, seeking to determine “what can we do to move the epidemic in the most positive direction possible,” Robert Hecht, told a news conference in Washington, …
Lipoprotein‐associated phospholipase A<sub>2</sub> and risk of venous thrombosis in older adults
Authors: Nels Olson, Ellen S. O'Meara, Nancy S. Jenny, Aaron R. Folsom, Edwin G. Bovill, Curt D. Furberg, Susan R. Heckbert, Bruce M. Psaty, Mary Cushman
Journal: American Journal of Hematology (2008)

Lipoprotein-associated phospholipase A2 (Lp-PLA2) is an enzyme involved in inflammation and platelet function. Inherited deficiency and elevated levels are associated with atherosclerosis. Given potential common etiologies of atherosclerosis and venous thrombosis (VT), we hypothesized that low and high Lp-PLA2 would be associated with VT risk. Lp-PLA(2) mass and activity were measured in baseline samples of Cardiovascular Health Study participants (5,888 men and women age > or =65), excluding 354 reporting pre-baseline VT. The study endpoint was VT unrelated to cancer after 11.6 years follow-up. Hazard ratios were estimated using Cox proportional hazard models, adjusting for age, race, sex, and body-mass index. With 129 cases of VT, there was no association of Lp-PLA2 activity with risk. Adjusted hazard ratios were 1.19 (CI 0.62, 2.29) and 0.87 (CI 0.43, 1.76) for the lowest and highest decile, respectively, compared to the 10-25th percentile. Corresponding hazard ratios for Lp-PLA2 mass were 1.63 (CI 0.79, 3.34) and 1.33 (CI 0.61, 2.87). Results were robust to several definitions of low or high Lp-PLA2. While the association of Lp-PLA(2) levels with arterial disease events implies a role for this enzyme in atherogenesis, our findings suggest that it is not prothrombotic.
Drug dosing consideration in patients with acute and chronic kidney disease—a clinical update from Kidney Disease: Improving Global Outcomes (KDIGO)
Authors: Gary R. Matzke, George R. Aronoff, Arthur J. Atkinson, William M. Bennett, Brian S. Decker, Kai-Uwe Eckardt, Thomas Golper, Darren W. Grabe, Bertram Kasiske, Frieder Keller, Jan T. Kielstein, Ravindra Mehta, Bruce A. Mueller, Deborah A. Pasko, Franz Schaefer, Domenic A. Sica, Lesley A. Inker, Jason G. Umans, Patrick Murray
Journal: Kidney International (2011)
Nutrition in Clinical Medicine
Authors: Theodore B. Van Itallie, Jean Mayer, Fredrick J. Stare
Journal: New England Journal of Medicine (1954)

NUTRITION in clinical medicine has come to have several different connotations depending on whether one is thinking of diagnosis and specific treatment or of patient management. Under the first heading have fallen the "classic" deficiency diseases such as scurvy, rickets, beriberi and pellagra. Indeed, in the minds of many physicians the subject of nutrition has remained identified with these deficiency states, disorders rarely encountered in the United States and today readily treated.On the other hand, the part played by nutrition in patient management has often been neglected, particularly since, in the past, nutritional status was difficult to appraise and . . .
Barriers to the successful treatment of liver disease by hepatocyte transplantation
Authors: Kyle A. Soltys, Alejandro Soto-Gutiérrez, Masaki Nagaya, Kevin M. Baskin, Melvin Deutsch, Ryotaro Ito, Benjamin L. Shneider, Robert Squires, Jerry Vockley, Chandan Guha, Jayanta Roy-Chowdhury, Stephen C. Strom, Jeffrey L. Platt, Ira J. Fox
Journal: Journal of Hepatology (2010)

Treatment of patients with liver disease by hepatocyte transplantation has expanded dramatically over the last decade, especially for treatment of patients with liver-based metabolic disorders. While much progress has been made, full realization of its potential has not been reached. Treatment of acute liver failure has been hampered by a number of factors, but the efficacy of hepatocyte transplantation in treating this entity could be better determined through a multi-institutional trial using a uniform and standardized treatment strategy. The barriers to treating chronic liver failure resulting from cirrhosis are more extensive. Novel strategies are being developed to safely precondition patients with liver-directed radiation therapy in order to enhance donor hepatocyte survival, long-term engraftment and improve treatment of patients with life-threatening liver-based genetic deficiencies. This work could soon be translated to the clinic. Once hepatocyte transplantation has been shown to effectively replace organ transplantation for a portion of patients with liver failure and life-threatening liver metabolic diseases, it is likely that multiple novel sources of donor hepatocytes will be developed, making cell therapy available and effective for a broad population of patients with liver disorders.
Abstract ES08-1: Imaging tumor response: Challenges of heterogeneity
Authors: D Piwnica-Worms
Journal: Cancer Research (2013)

Abstract Large-scale sequencing analyses of solid cancers have identified extensive genetic inter-tumor and intra-tumor heterogeneity, which likely contribute to treatment failure and drug resistance. For example, recent unbiased whole genome sequencing approaches have highlighted the complexity of the mutational landscape of ER+ luminal breast cancers. In 46 breast tumors, 82,000 total somatic mutations and 2,000 tier 1 mutations were identified. While pathway signatures enabled the evaluation of mutations with low recurrence frequency where statistical comparisons conventionally were underpowered, this massive heterogeneity presents an enormous challenge for therapy and prognostic assessment of cancer. Furthermore, cells have evolved complex molecular networks to sense cues from the environment and transmit them throughout the cell to elicit appropriate biological responses. These signaling pathways require certain elemental properties, such as sensitivity, reversibility, a capacity to be regulated, and robustness, that are crucial to reliably maintaining the organization and function of cells within organisms. These molecular networks comprise sets of recurring regulation patterns, manifest as network motifs, which link together in a variety of combinations to create a web of connectivity within a given signaling pathway or between multiple cascades. Using a kB5-IkBα-FLuc bioluminescent reporter as one example, we rigorously evaluated the dynamics of IkBa degradation and subsequent NF-kB transcriptional activity in response to diverse modes of TNFα stimulation in isogenic tumor cells. Tremendous heterogeneity in the transcriptional amplitudes of responding cells was observed, which was greater than the heterogeneity in the transcriptional kinetics of responsive cells. Thus, systems heterogeneity was observed even in isogenic cells, further adding to the complexity of cellular responses and their associated signaling networks. One must conclude that inter-tumor and intra-tumor heterogeneity at the level of cancer genes and systems responses may have important consequences for targeted molecular imaging strategies that commonly lack spatial and temporal resolution in their depiction of tumor phenotypes. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr ES08-1.
Chemerin suppresses murine allergic asthma by inhibiting <scp>CCL</scp>2 production and subsequent airway recruitment of inflammatory dendritic cells
Authors: L. Zhao, W. Yang, X. Yang, Y. Lin, J. Lv, X. Dou, Q. Luo, J. Dong, Z. Chen, Y. Chu, R. He
Journal: Allergy (2014)

Abstract Background Chemerin has been implicated to play opposing roles, either pro‐inflammatory or anti‐inflammatory, in various tissue inflammation processes primarily through the regulation of tissue recruitment of immune cells. However, the effect of chemerin in allergic asthma has not yet been explored. We sought to investigate the role of chemerin in the murine model of allergic asthma and explore the underlying mechanism. Methods We examined the effect of intranasal (i.n.) administration of chemerin during antigen challenge in murine models of asthma. Moreover, we examined whether administration of CCL 2 or bone marrow‐derived dendritic cells ( BMDC s) transfer reversed the effects of chemerin on ovalbumin‐induced asthma. We finally examined the effect of chemerin on CCL 2 expression in activated lung epithelial cells in vitro . Results The administration of chemerin attenuated allergic airway inflammation and airway hyperreactivity during antigen challenge. Chemerin treatment caused significant decreases in BALF CD4 + T‐cell accumulation and mRNA expression of Th2‐attracting chemokines, CCL17 and CCL22, which was accompanied by significantly decreased BALF CD11c + CD11b + inflammatory DC accumulation and CCL2 production. Furthermore, airway administration of exogenous CCL2 or adoptive transfer of CD11c + CD11b + BMDCs abrogated the suppressive effects of chemerin on allergic asthma. Finally, in vitro study showed that chemerin inhibited CCL2 secretion by low‐dose LPS‐stimulated lung epithelial cells, which led to decreased chemotaxis of BMDCs. Conclusions Our study demonstrates that chemerin plays a protective role in allergic asthma by suppressing airway recruitment of inflammatory CD 11c + CD 11b + DC s through the inhibition of CCL 2 secretion by active lung epithelial cells.
CYP2D6 Genotype Should Not Be Used for Deciding About Tamoxifen Therapy in Postmenopausal Breast Cancer
Authors: James M. Rae, Meredith Regan, Brian Leyland-Jones, Daniel F. Hayes, Mitch Dowsett
Journal: Journal of Clinical Oncology (2013)

al 1 regarding our current knowledge about the importance of CYP2D6 status when prescribing tamoxifen concluded that results from ongoing prospective studies in the metastatic/neoadjuvant setting will not help to close the circle on this topic.We do agree with their conclusion that published retrospective studies-so far-do not provide sufficient evidence to determine whether or not CYP2D6 testing should be performed in daily practice.However, we believe that two registered, ongoing, prospective studies in the neoadjuvant/metastatic setting (the European CYPTAMBRUT-2 study [Study to Assess Response to Tamoxifen in (cT3)/Inoperable Locally Advanced/Metastatic Estrogen Receptor-Positive Breast Cancer by the "Tamoxifen Activity Score" Based on Drug Interaction and Polymorphisms in Genes Coding for Tamoxifen Metabolising Enzymes] and the study of the Eastern Cooperative Oncology Group E3108 [Tamoxifen Citrate in Treating Patients With Metastatic or Recurrent Breast Cancer]) will provide answers that are not available from retrospective studies and which are likely to be relevant in the adjuvant setting.Although metastatic breast cancer differs in many respects from early breast cancer, in which tamoxifen helps to eradicate subclinical disseminated disease, metabolic pathways of tamoxifen for efficacy are disease-stage independent.It is unlikely that endoxifen levels matter in the adjuvant setting if they do not matter in the metastatic setting.However, if endoxifen levels do matter in metastatic disease, it does probably but not necessarily follow that this applies in the adjuvant setting.As principal investigators of the European CYPTAMBRUT-2 study, we would like to stress that this study includes only patients in the first-line metastatic/neoadjuvant setting.Patients with hormoneinsensitive or aromatase inhibitor-refractory disease were excluded from this study, as were premenopausal women.The study has so far recruited 240 of 260 patients.
"Yellow card" announcement used to head off concerns, experts claim
Authors: L. Eaton
Journal: BMJ (2003)

Two leading experts in drug safety and efficacy claim that their calls for a major review of the United Kingdom's “yellow card” system for monitoring drug safety were headed off by a government announcement that an inquiry into the system was under way.

Andrew Herxheimer, emeritus fellow with the UK Cochrane Centre, and Charles Medawar, director of the consumer research group Social Audit, presented evidence to the Committee on Safety of Medicines in July. This followed a survey they had carried out for the BBC after its screening in October 2002 of a Panorama programme on the selective serotonin reuptake inhibitor paroxetine (Seroxat). The programme had highlighted concerns with the drug. A second Panorama programme in May 2003 …
Abstract LB-310: Single cell genome sequencing reveals clonal stability and diversity in breast cancer
Authors: Yong Wang, Nicholas Navin, Jill Waters, Marco Leung, Anna Unruh, Xiuqing Shi, Whijae Roh, Ken Chen, Paul Scheet, Selina Vattathil, Han Liang, Asha Multani, Hong Zhang, Funda Meric-Bernstam, Franziska Michor, Rui Zhao
Journal: Cancer Research (2014)

Abstract Human breast cancers often display intratumor genomic heterogeneity. This clonal diversity confounds the clinical diagnosis and basic research of cancer, because single samples may not represent that tumor as a whole. Sequencing breast tumor cohorts en masse has identified many prevalent mutations, but has limited ability for resolving subclonal diversity. Here, we developed a whole-genome and exome single-cell sequencing approach (Nuc-Seq) using G2/M cells. To validate our method, we applied Nuc-Seq to sequence the whole genomes of two single cells from a genetically monoclonal breast cancer cell line (SK-BR-3) at high coverage depth (61X ± 5 sem, n=2) and breadth (83.70% ± 3.40 sem, n=2) to detect somatic mutations. Our analysis suggests that Nuc-Seq generates low allelic dropout rates (9.73% ± 2.19%) and low false positive error rates for point mutations (FPR = 1.24e-6). We then applied this method to sequence single normal and tumor cells from an estrogen-receptor positive breast cancer and a triple-negative ductal carcinoma at base-pair resolution. In parallel, we performed single cell copy number profiling. In both tumors, we observed a large number of rare variants that were not detected by sequencing the bulk tumor en masse. In contrast, we find that single cell copy number profiles are highly similar. Our data suggest that aneuploid rearrangements occurred early in tumor evolution and remained highly stable as the tumor mass expanded. In contrast we find that point mutations evolved gradually, generating extensive clonal diversity. Many of the diverse mutations were shown to occur at low frequencies (0.03 -10%) in the tumor mass by targeted duplex sequencing. Mathematical modeling suggests that the triple-negative tumor cells have an increased mutation rate (13.3X), while the ER+ tumor cells do not. These findings have important implications for the diagnosis, therapeutic treatment and evolution of chemoresistance in breast cancer. Citation Format: Yong Wang, Nicholas Navin, Jill Waters, Marco Leung, Anna Unruh, Xiuqing Shi, Whijae Roh, Ken Chen, Paul Scheet, Selina Vattathil, Han Liang, Asha Multani, Hong Zhang, Funda Meric-Bernstam, Franziska Michor, Rui Zhao. Single cell genome sequencing reveals clonal stability and diversity in breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-310. doi:10.1158/1538-7445.AM2014-LB-310
Gains in Bone Mineral Density with Resolution of Vitamin D Intoxication
Authors: John S. Adams
Journal: Annals of Internal Medicine (1997)

Background: Vitamin D intoxication is associated with the mobilization of skeletal calcium. Objective: To ascertain how the resolution of vitamin D intoxication affects bone density. Design: Case series. Setting: Referral service for metabolic bone disease in a tertiary care teaching hospital. Patients: Four patients with osteoporosis who were each using several nonprescription dietary supplements and were found to have fasting hypercalciuria. Intervention: Discontinuation of use of dietary supplements. Measurements: Serial measurement of serum levels of 25-hydroxyvitamin D, ratio of fasting urinary calcium to creatinine, and bone mineral density for 3 years. Results: Discontinuation of use of dietary supplements resulted in the normalization of serum levels of 25-hydroxyvitamin D, the normalization of the ratio of urinary calcium to creatinine, and a mean annual increase in bone mineral density (±SD) of 1.9% ± 0.6%. Conclusions: Occult vitamin D intoxication was detected in patients who were using dietary supplements that contained an unadvertised high level of vitamin D. Resolution of vitamin D intoxication was associated with a rebound in bone mineral density.
Adrenal Cortical Carcinoma Localized by Radiocholesterol Uptake
Authors: DWIGHT K. OXLEY, DAVID B. KAMINSKY, RICHARD J. MAHLER
Journal: Clinical Nuclear Medicine (1977)

Many benign adrenal neoplasms can be visualized because they concentrate labeled cholesterol derivatives. In previously described cases of adrenal carcinoma neither the tumor nor the contralateral adrenal was visualized on examination by radiocholesterol imaging. The authors report a patient with Cushing's syndrome due to an adrenal carcinoma which labeled intensely with radiocholesterol. A scintigram showing significant concentration of these agents in a hormonally active tumor is not necessarily evidence for a benign lesion.
Health Care's Response to Women Exposed to Partner Violence
Authors: C. Nadine Wathen, Harriet L. MacMillan
Journal: JAMA (2012)

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