tbuckley/cabot-search huggingface dataset:
A Chimeric Receptor with NKG2D Specificity Enhances Natural Killer Cell Activation and Killing of Tumor Cells
Authors: Yu-Hsiang Chang, John Connolly, Noriko Shimasaki, Kousaku Mimura, Koji Kono, Dario Campana
Journal: Cancer Research (2013)

Abstract Natural killer (NK) cells rely on surface receptors to distinguish healthy cells from cancer cells. We designed a receptor termed NKG2D-DAP10-CD3ζ that is composed of the NK cell activating molecule NKG2D plus 2 key signaling molecules, DAP10 and CD3ζ, and evaluated its capacity to promote cancer cell killing. Retroviral transduction of NKG2D-DAP10-CD3ζ markedly increased NKG2D surface expression in NK cells, which became consistently more cytotoxic than mock-transduced cells against leukemia and solid tumor cell lines. In contrast, there was no increase in cytotoxicity against nontransformed blood and mesenchymal cells. NKG2D blockade abrogated gains in cytotoxicity to cancer cells. Receptor stimulation triggered signal transduction, secretion of IFN-γ, GM-CSF, IL-13, MIP-1α, MIP-1β, CCL5, and TNF-α, and massive release of cytotoxic granules, which persisted after 48 hours of continuous stimulation. NKG2D-DAP10-CD3ζ–expressing NK cells had considerable antitumor activity in a mouse model of osteosarcoma, whereas activated NK cells were ineffective. Thus, the cytotoxic potential of NK cells against a wide spectrum of tumor subtypes could be markedly enhanced by expression of NKG2D-DAP10-CD3ζ receptors. The development of an electroporation method that permits rapid expression of the receptor in a large number of human NK cells facilitates clinical translation of this NK-based strategy for a generalized cellular therapy that may be useful to treat a wide range of cancers. Cancer Res; 73(6); 1777–86. ©2012 AACR.
The LXR–Idol Axis Differentially Regulates Plasma LDL Levels in Primates and Mice
Authors: Cynthia Hong, Stephanie M. Marshall, Allison L. McDaniel, Mark Graham, Joseph D. Layne, Lei Cai, Elena Scotti, Rima Boyadjian, Jason Kim, Brian T. Chamberlain, Rajendra K. Tangirala, Michael E. Jung, Loren Fong, Richard Lee, Stephen G. Young, Ryan E. Temel, Peter Tontonoz
Journal: Cell Metabolism (2014)
Repetitive stimulation of phrenic nerves in myasthenia gravis.
Authors: A Mier, C Brophy, J Moxham, M Green
Journal: Thorax (1992)

BACKGROUND: In the investigation of patients with myasthenia gravis, repetitive supramaximal stimulation of an affected peripheral nerve is commonly performed to detect abnormal transmission at the neuromuscular junction. A study was undertaken to determine whether abnormal transmission could similarly be detected during stimulation of the phrenic nerves. METHODS: The phrenic nerves were stimulated supramaximally with surface electrodes in 13 patients with myasthenia gravis and in 16 control subjects (six control patients with diaphragmatic weakness but not with myasthenia and ten normal subjects). The amplitude of diaphragm muscle action potentials was measured with surface electrodes during phrenic nerve stimulation at frequencies of 1-5 Hz for 3-4 seconds. RESULTS: In five patients with myasthenia gravis, a significant decrement (15-43% decrease) occurred in the amplitude of diaphragm muscle action potential during stimulation at 3 Hz. When stimulation frequency was reduced to 1 Hz, diaphragm muscle action potentials returned to their original amplitude within 4-5 seconds. The decrement in the amplitude of the diaphragm muscle action potential was reduced temporarily in three of four patients after the administration of intravenous edrophonium chloride (Tensilon). There was no significant change (&lt; 10% decrease) in the amplitude of diaphragm muscle action potentials during stimulation at increased frequencies either in the 16 control subjects or in eight of the patients with myasthenia gravis. CONCLUSION: A significant reduction in the amplitude of diaphragm muscle action potential occurred in five of 13 patients with myasthenia gravis during phrenic nerve stimulation at 3 Hz but in none of the control subjects. This may be a useful and non-invasive method for identifying patients with myasthenia gravis in whom weakness of the diaphragm is suspected.
Efficacy and safety of oral fumarate in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled phase IIb study
Authors: Ludwig Kappos, Ralf Gold, David H Miller, David G MacManus, Eva Havrdova, Volker Limmroth, Chris H Polman, Klaus Schmierer, Tarek A Yousry, Minhua Yang, Mefkûre Eraksoy, Eva Meluzinova, Ivan Rektor, Katherine T Dawson, Alfred W Sandrock, Gilmore N O'Neill
Journal: The Lancet (2008)
Role of Blimp-1 in programing Th effector cells into IL-10 producers
Authors: Christian Neumann, Frederik Heinrich, Katrin Neumann, Victoria Junghans, Mir-Farzin Mashreghi, Jonas Ahlers, Marko Janke, Christine Rudolph, Nadine Mockel-Tenbrinck, Anja A. Kühl, Markus M. Heimesaat, Charlotte Esser, Sin-Hyeog Im, Andreas Radbruch, Sascha Rutz, Alexander Scheffold
Journal: The Journal of Experimental Medicine (2014)

Secretion of the immunosuppressive cytokine interleukin (IL) 10 by effector T cells is an essential mechanism of self-limitation during infection. However, the transcriptional regulation of IL-10 expression in proinflammatory T helper (Th) 1 cells is insufficiently understood. We report a crucial role for the transcriptional regulator Blimp-1, induced by IL-12 in a STAT4-dependent manner, in controlling IL-10 expression in Th1 cells. Blimp-1 deficiency led to excessive inflammation during Toxoplasma gondii infection with increased mortality. IL-10 production from Th1 cells was strictly dependent on Blimp-1 but was further enhanced by the synergistic function of c-Maf, a transcriptional regulator of IL-10 induced by multiple factors, such as the Notch pathway. We found Blimp-1 expression, which was also broadly induced by IL-27 in effector T cells, to be antagonized by transforming growth factor (TGF) β. While effectively blocking IL-10 production from Th1 cells, TGF-β shifted IL-10 regulation from a Blimp-1–dependent to a Blimp-1–independent pathway in IL-27–induced Tr1 (T regulatory 1) cells. Our findings further illustrate how IL-10 regulation in Th cells relies on several transcriptional programs that integrate various signals from the environment to fine-tune expression of this critical immunosuppressive cytokine.
A nationwide survey in Germany on fatal asthma and near-fatal asthma in children: different entities?
Authors: T Schmitz, R von Kries, M Wjst, A Schuster
Journal: European Respiratory Journal (2000)

In adults fatal and near-fatal asthma have similar clinical characteristics. Therefore, near-fatal asthma in adults can be used as a model for fatal asthma. A nationwide study on fatal and near-fatal asthma in children &lt;16 yrs was performed in order to assess whether, as in adults, near-fatal asthma can be used as a model for fatal asthma. From 1996 to 1998, all paediatric hospitals and paediatric pulmonologists in Germany were asked to report cases of fatal asthma and near-fatal asthma to a central survey unit (Erhebungseinheit fur seltene padiatrische Erkrankungen in Deutschland (ESPED)) on a monthly basis. All reports were followed by detailed questionnaires. Sixteen fatal and 45 near-fatal asthma cases were analysed. Fatal asthma patients were older than near-fatal asthma patients. Respiratory tract infections were frequently reported only in near-fatal asthma (47 versus 0%). The proportion of cases with rapid-type onset (duration of symptoms &lt; or =1 h) was higher in fatal asthma (53 versus 14%). Long-term regular treatment with short acting beta2-agonists was common in both groups, but the use of concomitant inhaled corticosteroids was significantly lower in fatal asthma cases. A high proportion of poor compliance was observed in both groups. As fatal and near-fatal asthma differ significantly in important clinical aspects, analysis of near-fatal asthma might be of limited value in elucidating the causes of fatal asthma in children.
Low sensitivity of type VII collagen enzyme-linked immunosorbent assay in epidermolysis bullosa acquisita: serration pattern analysis on skin biopsy is required for diagnosis
Authors: J.B. Terra, M.F. Jonkman, G.F.H. Diercks, H.H. Pas
Journal: British Journal of Dermatology (2013)

The type VII collagen (coll VII) enzyme-linked immunosorbent assay (ELISA) has been reported to have high sensitivity (> 93%) and specificity (> 96%) for diagnosing epidermolysis bullosa acquisita (EBA) in patients who are seropositive on indirect immunofluorescence on salt-split skin (SSS).To investigate the added value of the coll VII ELISA in the laboratory diagnosis of SSS-positive and SSS-negative EBA and to correlate the ELISA index with disease episode.The coll VII ELISA was performed on banked sera of 28 patients with EBA: 15 SSS positive and 13 SSS negative. Sera from healthy blood donors (n = 17) and patients with other autoimmune blistering diseases (n = 29) served as controls. In four patients, the ELISA index was measured longitudinally. Serration pattern analysis by direct immunofluorescence has been prospectively performed since 2000 in 19 patients.The sensitivity in the SSS-positive group was 80% whereas it was 23% in the SSS-negative group. In the prospective EBA subset it was 45%. The sensitivity of u-serration pattern analysis on skin biopsy was 89%. Ten (53%) of these cases were seronegative with both ELISA and SSS, and would have been missed by serum analysis alone. Of the 46 control sera, one serum tested positive (specificity 97·8%). The coll VII ELISA correlated with disease activity over time in individual patients.The coll VII ELISA has limited added value in SSS-negative EBA cases. The ELISA test is valuable in differentiating EBA from antilaminin-332 mucous membrane pemphigoid and anti-p200 pemphigoid and in its ability to monitor patients with EBA serologically. U-serration pattern analysis on immunofluorescence skin biopsy is the gold standard for the diagnosis of EBA.
The novel sigma-2 receptor ligand SW43 stabilizes pancreas cancer progression in combination with gemcitabine
Authors: John R Hornick, Jinbin Xu, Suwanna Vangveravong, Zhude Tu, Jonathan B Mitchem, Dirk Spitzer, Peter Goedegebuure, Robert H Mach, William G Hawkins
Journal: Molecular Cancer (2010)

Abstract Background Sigma-2 receptors are over-expressed in proliferating cancer cells, making an attractive target for the targeted treatment of pancreatic cancer. In this study, we investigated the role of the novel sigma-2 receptor ligand SW43 to induce apoptosis and augment standard chemotherapy. Results The binding affinity for sigma-2 ligands is high in pancreas cancer, and they induce apoptosis with a rank order of SV119 &lt; SW43 &lt; SRM in vitro . Combining these compounds with gemcitabine further increased apoptosis and decreased viability. Our in vivo model showed that sigma-2 ligand treatment decreased tumor volume to the same extent as gemcitabine. However, SW43 combination treatment with gemcitabine was superior to the other compounds and resulted in stabilization of tumor volume during treatment, with minimal toxicities. Conclusions This study shows that the sigma-2 ligand SW43 has the greatest capacity to augment gemcitabine in a pre-clinical model of pancreas cancer and has provided us with the rationale to move this compound forward with clinical investigations for patients with pancreatic cancer.
Mental Disorders and Suicide Among Young Rural Chinese: A Case-Control Psychological Autopsy Study
Authors: Jie Zhang, Shuiyuan Xiao, Liang Zhou
Journal: American Journal of Psychiatry (2010)

Objective The authors examined the prevalence and distribution of mental disorders in rural Chinese 15–34 years of age who committed suicide. They hypothesized that mental illness is a risk factor for suicide in this population and that the prevalence of mental illness is lower in females than in males. Method In this case-control psychological autopsy study, face-to-face interviews were conducted to collect information from proxy informants for 392 suicide victims and 416 living comparison subjects. Five categories of DSM-IV mental disorders (mood disorders, schizophrenia and other psychotic disorders, substance use disorders, anxiety disorders, and other axis I disorders) at the time of death or interview were assessed using the Chinese version of the Structured Clinical Interview for DSM-IV. Sociodemographic variables, social support, and life events were also assessed. Results The prevalence of current mental illness was 48.0% for suicide victims and 3.8% for comparison subjects. Among suicide victims, mental illness was more prevalent in males than in females (55.1% compared with 39.3%). A strong association between mental illness and suicide was observed after adjustment for sociodemographic characteristics. Other risk factors included having a lower education level, not being currently married, having a lower level of social support, and having a history of recent and long-term life events. Additive interactions were observed between mental illness and lower level of social support. Conclusions Although mental illness is a strong risk factor for suicide, it is less prevalent among rural Chinese young people who committed suicide, particularly females, in comparison with other populations in China and in the West.
Prophylactic Efficacy of Topical Temporin A and RNAIII-Inhibiting Peptide in a Subcutaneous Rat Pouch Model of Graft Infection Attributable to Staphylococci With Intermediate Resistance to Glycopeptides
Authors: Oscar Cirioni, Andrea Giacometti, Roberto Ghiselli, Giorgio Dell’Acqua, Yael Gov, Wojciech Kamysz, Jerzy Łukasiak, Federico Mocchegiani, Fiorenza Orlando, Giuseppina D’Amato, Naomi Balaban, Vittorio Saba, Giorgio Scalise
Journal: Circulation (2003)

Bacteria that adhere to implanted medical devices play an important role in industry and in modern medicine. Staphylococci are among the most common pathogens that cause biomaterial infections. Vascular prosthetic graft infection is one of the most feared complications that the vascular surgeon treats, frequently resulting in prolonged hospitalization, organ failure, amputation, and death. A rat model was used to investigate the topical efficacies of temporin A and the quorum-sensing inhibitor RNAIII-inhibiting protein (RIP) as prophylactic agents of vascular prosthetic graft infections caused by Staphylococcus aureus and Staphylococcus epidermidis with intermediate resistance to glycopeptides.Graft infections were established in the back subcutaneous tissue of adult male Wistar rats by implantation of Dacron prostheses 1 cm2 followed by topical inoculation with 2x10(7) colony-forming units of bacterial strains. The study included, for each staphylococcal strain, a control group (no graft contamination), a contaminated group that did not receive antibiotic prophylaxis, and 6 contaminated groups that received grafts soaked with temporin A, RIP, rifampin, temporin A plus RIP, RIP plus rifampin, or temporin A plus RIP. The infection was evaluated by quantitative agar culture. When tested alone, temporin A and RIP showed comparable efficacies, and their efficacies were significantly higher than that of rifampin against both strains. All combinations showed efficacies significantly higher than that of each single compound. The combinations of temporin A and RIP exerted the strongest antistaphylococcal efficacies, eliminating infection by 100%.The results of the present study make these molecules potentially useful for antimicrobial chemoprophylaxis in vascular surgery.
Soluble guanylate cyclase stimulator riociguat prevents fibrotic tissue remodeling and improves survival in salt-sensitive Dahl rats
Authors: Johannes-Peter Stasch, Sandra Geschka, Bettina Lawrenz, Yuliya Sharkovska, Berthold Hocher, Oleg V. Evgenov, Axel Kretschmer
Journal: European Respiratory Journal (2011)

Direct stimulation of soluble guanylate cyclase (sGC) is an emerging therapeutic approach to the management of cardiopulmonary disorders associated with endothelial dysfunction. Novel sGC stimulators, including riociguat, have a dual mode of action: they sensitize sGC to endogenously produced nitric oxide (NO) and also directly stimulate sGC independently of NO. Little is known about their effects on tissue remodeling and degeneration and survival in experimental malignant hypertension. Mortality, hemodynamics and biomarkers of tissue remodeling and degeneration were assessed in Dahl salt-sensitive rats maintained on a high salt diet and treated with riociguat (3 or 10 mg/kg/d) for 14 weeks. Riociguat markedly attenuated systemic hypertension, improved systolic heart function and increased survival. Histological examination of the heart and kidneys revealed that riociguat significantly ameliorated fibrotic tissue remodeling and degeneration. Correspondingly, mRNA expression of the pro-fibrotic biomarkers osteopontin (OPN), tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) and plasminogen activator inhibitor-1 (PAI-1) in the myocardium and the renal cortex was attenuated by riociguat. In addition, riociguat reduced plasma and urinary levels of OPN, TIMP-1, and PAI-1. Riociguat markedly improves survival and attenuates systemic hypertension and systolic dysfunction, as well as fibrotic tissue remodeling in the myocardium and the renal cortex in a rodent model of pressure and volume overload. These findings suggest a therapeutic potential of sGC stimulators in providing organ protection in diseases associated with impaired cardio-renal functions.
Phylogenetic Estimation of Timescales Using Ancient DNA: The Effects of Temporal Sampling Scheme and Uncertainty in Sample Ages
Authors: Martyna Molak, Eline D. Lorenzen, Beth Shapiro, Simon Y.W. Ho
Journal: Molecular Biology and Evolution (2012)

Abstract In recent years, ancient DNA has increasingly been used for estimating molecular timescales, particularly in studies of substitution rates and demographic histories. Molecular clocks can be calibrated using temporal information from ancient DNA sequences. This information comes from the ages of the ancient samples, which can be estimated by radiocarbon dating the source material or by dating the layers in which the material was deposited. Both methods involve sources of uncertainty. The performance of Bayesian phylogenetic inference depends on the information content of the data set, which includes variation in the DNA sequences and the structure of the sample ages. Various sources of estimation error can reduce our ability to estimate rates and timescales accurately and precisely. We investigated the impact of sample-dating uncertainties on the estimation of evolutionary timescale parameters using the software BEAST. Our analyses involved 11 published data sets and focused on estimates of substitution rate and root age. We show that, provided that samples have been accurately dated and have a broad temporal span, it might be unnecessary to account for sample-dating uncertainty in Bayesian phylogenetic analyses of ancient DNA. We also investigated the sample size and temporal span of the ancient DNA sequences needed to estimate phylogenetic timescales reliably. Our results show that the range of sample ages plays a crucial role in determining the quality of the results but that accurate and precise phylogenetic estimates of timescales can be made even with only a few ancient sequences. These findings have important practical consequences for studies of molecular rates, timescales, and population dynamics.
NSAIDs and Cancer Prevention: Targets Downstream of COX-2
Authors: Yong I. Cha, Raymond N. DuBois
Journal: Annual Review of Medicine (2006)

Preclinical and clinical studies have clearly shown a benefit of nonsteroidal anti-inflammatory drug (NSAID) use in reducing cancer risk. However, the adverse gastrointestinal and cardiovascular side effects associated with NSAIDs and COX-2 selective inhibitors (coxibs) have provoked more scrutiny of the precise role of specific downstream mediators in the prostaglandin (PG) signaling cascade. NSAIDs and coxibs inhibit PG biosynthesis. One of the PGs produced at high levels in the tumor microenvironment is PGE(2), which is thought to play a major role in cancer progression. Thus, a better understanding of PGE(2) signaling could enable identification of novel and safer therapeutic targets downstream of the cyclooxygenase enzymes. We review the emerging molecular mechanisms by which COX-2-derived PGE(2) is involved in cancer progression and delineate potential opportunities for development of novel pharmacologic approaches utilizing this pathway.
Obesity and the Food Environment: Income and Ethnicity Differences Among People With Diabetes
Authors: Jessica C. Jones-Smith, Andrew J. Karter, E. Margaret Warton, Maggi Kelly, Ellen Kersten, Howard H. Moffet, Nancy Adler, Dean Schillinger, Barbara A. Laraia
Journal: Diabetes Care (2013)

It is unknown whether any association between neighborhood food environment and obesity varies according to individual income and/or race/ethnicity. The objectives of this study were to test whether there was an association between food environments and obesity among adults with diabetes and whether this relationship differed according to individual income or race/ethnicity.Subjects (n = 16,057) were participants in the Diabetes Study of Northern California survey. Kernel density estimation was used to create a food environment score for each individual's residence address that reflected the mix of healthful and unhealthful food vendors nearby. Logistic regression models estimated the association between the modeled food environment and obesity, controlling for confounders, and testing for interactions between food environment and race/ethnicity and income.The authors found that more healthful food environments were associated with lower obesity in the highest income groups (incomes 301-600% and >600% of U.S. poverty line) among whites, Latinos, and Asians. The association was negative, but smaller and not statistically significant, among high-income blacks. On the contrary, a more healthful food environment was associated with higher obesity among participants in the lowest-income group (<100% poverty threshold), which was statistically significant for black participants in this income category.These findings suggest that the availability of healthful food environments may have different health implications when financial resources are severely constrained.
Systematic screening of polyphosphate (poly P) levels in yeast mutant cells reveals strong interdependence with primary metabolism.
Authors: Florian M Freimoser, Hans Caspar Hürlimann, Claude A Jakob, Thomas P Werner, Nikolaus Amrhein
Journal: Genome biology (2006)

Abstract Background Inorganic polyphosphate (poly P) occurs universally in all organisms from bacteria to man. It functions, for example, as a phosphate and energy store, and is involved in the activation and regulation of proteins. Despite its ubiquitous occurrence and important functions, it is unclear how poly P is synthesized or how poly P metabolism is regulated in higher eukaryotes. This work describes a systematic analysis of poly P levels in yeast knockout strains mutated in almost every non-essential gene. Results After three consecutive screens, 255 genes (almost 4% of the yeast genome) were found to be involved in the maintenance of normal poly P content. Many of these genes encoded proteins functioning in the cytoplasm, the vacuole or in transport and transcription. Besides reduced poly P content, many strains also exhibited reduced total phosphate content, showed altered ATP and glycogen levels and were disturbed in the secretion of acid phosphatase. Conclusion Cellular energy and phosphate homeostasis is suggested to result from the equilibrium between poly P, ATP and free phosphate within the cell. Poly P serves as a buffer for both ATP and free phosphate levels and is, therefore, the least essential and consequently most variable component in this network. However, strains with reduced poly P levels are not only affected in their ATP and phosphate content, but also in other components that depend on ATP or free phosphate content, such as glycogen or secreted phosphatase activity.