tbuckley/cabot-search huggingface dataset:
Novel STAT3 Phosphorylation Inhibitors Exhibit Potent Growth-Suppressive Activity in Pancreatic and Breast Cancer Cells
Authors: Li Lin, Brian Hutzen, Mingxin Zuo, Sarah Ball, Stephanie Deangelis, Elizabeth Foust, Bulbul Pandit, Michael A. Ihnat, Satyendra S. Shenoy, Samuel Kulp, Pui-Kai Li, Chenglong Li, James Fuchs, Jiayuh Lin
Journal: Cancer Research (2010)

The constitutive activation of signal transducer and activator of transcription 3 (STAT3) is frequently detected in most types of human cancer where it plays important roles in survival, drug resistance, angiogenesis, and other functions. Targeting constitutive STAT3 signaling is thus an attractive therapeutic approach for these cancers. We have recently developed novel small-molecule STAT3 inhibitors, known as FLLL31 and FLLL32, which are derived from curcumin (the primary bioactive compound of turmeric). These compounds are designed to bind selectively to Janus kinase 2 and the STAT3 Src homology-2 domain, which serve crucial roles in STAT3 dimerization and signal transduction. Here we show that FLLL31 and FLLL32 are effective inhibitors of STAT3 phosphorylation, DNA-binding activity, and transactivation in vitro, leading to the impediment of multiple oncogenic processes and the induction of apoptosis in pancreatic and breast cancer cell lines. FLLL31 and FLLL32 also inhibit colony formation in soft agar and cell invasion and exhibit synergy with the anticancer drug doxorubicin against breast cancer cells. In addition, we show that FLLL32 can inhibit the induction of STAT3 phosphorylation by IFNalpha and interleukin-6 in breast cancer cells. We also show that administration of FLLL32 can inhibit tumor growth and vascularity in chicken embryo xenografts as well as substantially reduce tumor volumes in mouse xenografts. Our findings highlight the potential of these new compounds and their efficacy in targeting pancreatic and breast cancers that exhibit constitutive STAT3 signaling.
THE ROLE OF OPSONINS IN NON-SPECIFIC IMMUNITY
Authors: Derrick Rowley
Journal: The Journal of Experimental Medicine (1960)

A study of the recoveries of radioactivity, and of viable bacteria following injection of P(32)-labelled E. coli into the mouse peritoneum, has indicated that the rapid decrease in viable bacteria which occurs is largely due to peritoneal events, and not to the transport of bacteria elsewhere. The serum from mice given lipopolysaccharides 48 hours previously, when used to pretreat bacteria before intraperitoneal injection, was found to stimulate phagocytosis to a greater extent than did pretreatment with normal serum. In addition, macrophages themselves were found to be affected by contact with lipopolysaccharides, either in vivo or in vitro in such a way as to promote their phagocytic abilities. It is suggested that the provocation of non-specific immunity by bacterial lipopolysaccharides involves two facets at least; firstly, an increase in the opsonic capacity of the serum, and secondly an increase in the inherent capacity of phagocytic cells to perform this function.
Gastroenterology: pathophysiology and clinical applications
Authors: R. Allan
Journal: Gut (1983)

structure and function and relation to the immune response.The liver is then considered as a whole in relation to its circulation and interaction with other organs.Finally, the major disease mechanisms, hepatocellular regeneration, cholestasis, fibro- genesis, neoplasia, and portal hypertension are considered.The practising hepatologist, gastroenterologist and even biochemist or pathologist will find this book hard to read.He (or she) must be encouraged to persevere, it represents the liver disease of tomorrow.It is fitting that this book is dedicated to Hans Popper, the founder of modern hepatology.He has himself contributed an excellent chapter on hepatocyte death.The book may seem costly, but it is a bargain for the material it contains.It is a must for hospital libraries.
Lack of Association Between 25(OH)D Levels and Incident Type 2 Diabetes in Older Women
Authors: Jennifer G. Robinson, JoAnn E. Manson, Joseph Larson, Simin Liu, Yiqing Song, Barbara V. Howard, Lawrence Phillips, James M. Shikany, Matthew Allison, J. David Curb, Karen C. Johnson, Nelson Watts
Journal: Diabetes Care (2011)

To examine whether lower serum levels of serum 25-hydroxyvitamin (OH) D [25(OH)D] are associated with increased risk of developing type 2 diabetes.A post hoc analysis of three nested case-control studies of fractures, colon cancer, and breast cancer that measured serum 25(OH)D levels in women participating in the Women's Health Initiative (WHI) Clinical Trials and Observational Study who were free of prevalent diabetes at baseline. Diabetes was defined as self-report of physician diagnosis or receiving insulin or oral hypoglycemic medication. We used inverse probability weighting to make the study population representative of the WHI population as a whole. Weighted logistic regression models compared 25(OH)D levels (divided into quartiles, clinical cut points [<50, 50-<75, ≥ 75 nmol/L], or as a continuous variable) using the distribution of control subjects and adjusted for multiple confounding factors.Of 5,140 women (mean age 66 years) followed for an average of 7.3 years, 317 (6.2%) developed diabetes. Regardless of the cut points used or as a continuous variable, 25(OH)D levels were not associated with diabetes incidence in either age or fully adjusted models. Nor was any relationship found between 25(OH)D and incident diabetes when evaluated by strata of BMI, race/ethnicity, or randomization status in the Calcium Vitamin D trial.Lower serum 25(OH)D levels were not associated with increased risk of developing type 2 diabetes in this racially and ethnically diverse population of postmenopausal women.
Oral spironolactone improves acne vulgaris and reduces sebum excretion
Authors: A. GOODFELLOW, J. ALAGHBAND-ZADEH, G. CARTER, J.J. CREAM, S. HOLLAND, J. SCULLY, P. WISE
Journal: British Journal of Dermatology (1984)

In a consecutive series of thirty‐six male and female patients referred with severe acne, the effect of 3 months'treatment with placebo or spironolactone (50–200 mg daily) on sebum excretion and clinical and endocrine status was evaluated double‐blind. Twenty‐six patients completed the study. Abnormal free androgen indices were found in 27% of the original nineteen female subjects. Spironolactone reduced sebum excretion in all female subjects, but there was no correlation between sebum response and androgen status. The clinical response was dose‐dependent, with maximum subjective and objective benefit when spironolactone doses of 150–200 mg were used.
Impact of ankylosing spondylitis on sick leave, presenteeism and unpaid productivity, and estimation of the societal cost
Authors: Annelies Boonen, Tjinta Brinkhuizen, Robert Landewé, Désirée van der Heijde, Johan L Severens
Journal: Annals of the Rheumatic Diseases (2010)

To describe the influence of ankylosing apondylitis (AS) on sick leave, presenteeism and unpaid work restrictions and to estimate related productivity costs.142 consecutive and unselected patients with AS under the care of rheumatologists participated in a longitudinal observational study and completed the Health and Labour Questionnaire (HLQ) assessing disease-related sick leave, presenteeism and restrictions in unpaid work over the previous 2 weeks. Logistic regressions explored which explanatory variables were associated with work outcome. Productivity loss was valued in monetary terms.Among 72 patients in paid employment, 12% had sick leave over a period of 2 weeks and 53% experienced an adverse influence of AS on work productivity while at work. Over this period they reported on average of 5.8 h sick leave and 2.4 inefficient working hours, for which they estimated an extra 1.9 h were needed to complete unfinished work. Among all patients (n=137), 71% had experienced restrictions in unpaid work during the previous 2 weeks with 42% needing help for these tasks for an average of 8 h. The annual production costs for the total group were euro1451 (95% CI 425 to 2742) per patient for sick leave, euro967 (95% CI 503 to 1496) to compensate for hours worked inefficiently while at work and euro1930 (95% CI 1404 to 2471) to substitute loss of unpaid work production.Patients with AS not only have substantial sick leave but also experience restrictions while being at work and when performing unpaid tasks. Limitations in physical functioning are strongly associated with work restrictions. Societal costs of formal and informal care are comparable with the costs of sick leave and presenteeism combined.
A systematic approach to selecting starting pressure results in better sleep outcomes from CPAP titration studies
Authors: Stephen Gyulay, Jeffrey Pretto, Michael Hensley
Journal: European Respiratory Journal (2013)

Guidelines for CPAP titration studies recommend a low starting pressure (Pstart) and provide a titration algorithm to determine optimum therapeutic pressure (Popt). A low Pstart causes prolonged time at less than Popt resulting in lesser sleep time at therapeutic levels. We evaluated a systematic approach to selecting Pstart which enables more efficient CPAP titration. Methods: Pstart was empirically derived utilising markers of obesity and of OSA severity. 153 consecutive tests using the new-protocol Pstart were compared with 74 tests using the AASM recommended Pstart, with AASM titration algorithm (Kushida et al, J Clin Sleep Med 2008) used for all studies. Results: There were no between-group differences (standard versus new protocols) in age, gender distribution or OSA severity (AHI 47.4 vs. 39.6, p=0.2). Mean Popt was higher using the new protocol however time to achieve Popt was less and total sleep time (TST) at Popt was higher (table, mean (SD) shown). Succesful treatment (AHI  Discussion: Individual tailoring of Pstart for CPAP titration studies results in quicker attainment of Popt and longer sleep at this therapeutic level. This may result in a more favourable first-night CPAP experience with potentially more successful treatment outcomes.
Caseload of NHS plastic surgeons in Scotland, 2005–2006: analysis of Scottish hospital activity data
Authors: Colin T Brewster, Taimur Shoaib
Journal: Journal of the Royal Society of Medicine (2009)

Summary Objective To assess the contemporary caseload of NHS plastic surgeons. Design Descriptive study. Setting Scotland. Methods Analysis of routinely collected NHS hospital activity data relating to the financial year 2005–2006. Main outcome measures Number of inpatient/day-case episodes and bed-days by principal diagnosis and main operative procedure. Results During the study period, 12,844 inpatient and 9439 day-case episodes were recorded in 19,166 patients, accounting for 36,300 bed-days. There were more female patients, especially among middle-age groups. Socioeconomic deprivation was more common than expected (P &lt; 0.0001), especially among younger age groups and male patients. In terms of episodes, the most common categories of diagnosis were neoplasms (28.4%) and injuries, including burns (22.4%). However, injuries accounted for a higher proportion of bed-days (37.3%) than neoplasms (23.8%). Only approximately half of all surgical procedures were assigned to the skin chapter of the OPCS-4 classification. Conclusions Despite some limitations, this study provides an insight into the current caseload of NHS plastic surgeons working in Scotland. The data suggest that cosmetic surgery for purely aesthetic reasons represents a relatively small part of NHS plastic surgery activity in Scotland, and that the majority of caseload is in reconstructive plastic surgery.
How should federal policy reflect recent research in the area of intrauterine exposure to environmental hazards?
Authors: J R Reigart
Journal: Environmental Health Perspectives (1995)

Present policy neither evaluates nor adequately protects the fetus from the effects of intrauterine exposure to environmental hazards. Some examples are intrauterine lead and methylmercury exposure and intrauterine PCB exposures. A sound policy based on a few basic principles can be developed to protect the fetus from harm from intrauterine exposures.
Origin and Maintenance of a Broad-Spectrum Disease Resistance Locus in Arabidopsis
Authors: Shunyuan Xiao, Brent Emerson, Kumrop Ratanasut, Elaine Patrick, Carmel O'Neill, Ian Bancroft, John G. Turner
Journal: Molecular Biology and Evolution (2004)

The broad-spectrum mildew resistance genes RPW8.1 and RPW8.2 define a unique type of plant disease resistance (R) gene, and so far homologous sequences have been found in Arabidopsis thaliana only, which suggests a recent origin. In addition to RPW8.1 and RPW8.2, the RPW8 locus contains three homologs of RPW8, HR1, HR2, and HR3, which do not contribute to powdery mildew resistance. To investigate whether RPW8 has originated recently, and if so the processes involved, we have isolated and analyzed the syntenic RPW8 loci from Arabidopsis lyrata, and from Brassica rapa and B. oleracea. The A. lyrata locus contains four genes orthologous to HR1, HR2, HR3, and RPW8.2, respectively. Two syntenic loci have been characterized in Brassica; one locus contains three genes and is present in both B. oleracea and B. rapa, and the other locus contains a single gene and is detected in B. rapa only. The Brassica homologs have highest similarity to HR3. Sequence analyses suggested that the RPW8 gene family in Brassicaceae originated from an HR3-like ancestor gene through a series of duplications and that RPW8.1 and RPW8.2 evolved from functional diversification through positive selection several MYA. Examination of the sequence polymorphism of 32 A. thaliana accessions at the RPW8 locus and their disease reaction phenotypes revealed that the polymorphic RPW8 locus defines a major source of resistance to powdery mildew diseases. A possible evolutionary mechanism by which functional polymorphism at the AtRPW8 locus has been maintained in contemporary populations of A. thaliana is discussed.
The risk of azathioprine-induced pancreatitis depends on genetic variants in the HLA gene region
Authors: P. C. A. Dubois
Journal: Gut (2011)

<h3>Introduction</h3> Acute pancreatitis occurs in around 2% of inflammatory bowel disease patients exposed to azathioprine or 6-mercaptopurine and is an important limiting toxicity of these thiopurine antimetabolites. Factors determining the risk of pancreatitis are unknown: the risk is not related to dose, though it may occur more commonly in individuals with Crohn9s disease than in other disorders. Recently genome-wide association studies (GWASs) identified common genetic variants conferring substantial effects on risk for other idiosyncratic drug reactions (<i>SCOL1B</i> variants in simvastatin-induced myopathy and <i>HLA-B5701</i> in flucloxacillin-induced liver injury). We hypothesised that the risk of pancreatitis was similarly determined by unknown common genetic variants of large effect size and that such variants might enable stratification of individuals for pancreatitis risk prior to commencing thiopurine therapy. <h3>Methods</h3> We performed a genome-wide association study (GWAS, Stage 1) of thiopurine-induced pancreatitis, genotyping 55 UK and Dutch cases and comparing these with 5782 previously genotyped population controls. We genotyped cases using Illumina 670-Quad custom and 1M-Duo SNP arrays. In total, 535 753 SNPs passed quality controls in all Stage 1 samples with a further 384 513 SNPs available for 40 of the cases and 4936 of the controls from the UK. 43 SNPs from 32 independent genomic loci showing evidence of association with thiopurine-induced pancreatitis (P<sub>GWAS</sub> &lt;10<sup>−4</sup>) were included in the design of an autoimmune disease genotyping array (Illumina Immunochip) to facilitate follow-up genotyping. Follow-up (Stage 2) genotyping was performed in 13 New Zealand cases and 47 thiopurine-exposed IBD controls and 12 Spanish cases and 352 population controls. <h3>Results</h3> Meta-analysis of all cases and controls from Stage 1 and 2, stratified by country, for 43 SNPs identified in the GWAS phase and a further 28 082 SNPs from auto-immune disease candidate regions present on the Illumina Immunochip (including 17 631 SNPs in the 20 Mb broad HLA region on chromosome 6) was performed. rs2647087, mapping 28 Kb from the closest gene <i>HLA-DQA2</i>, showed the strongest association (p=3.89×10<sup>−6</sup>) with thiopurine-induced pancreatitis in our study (OR for risk allele = 2.69). <h3>Conclusion</h3> Genetic association in the HLA gene region suggests an immune-mediated pathogenesis of thiopurine-induced pancreatitis possibly involving HLA-restricted T cell activation. Identification of the causal HLA alleles is the next priority and may enable clinically useful stratification of individuals for pancreatitis risk prior to starting thiopurine treatment.
The (virtual) conceptual necessity of quantum probabilities in cognitive psychology
Authors: Reinhard Blutner, Peter beim Graben
Journal: Behavioral and Brain Sciences (2013)

Abstract We propose a way in which Pothos &amp; Busemeyer (P&amp;B) could strengthen their position. Taking a dynamic stance, we consider cognitive tests as functions that transfer a given input state into the state after testing. Under very general conditions, it can be shown that testable properties in cognition form an orthomodular lattice. Gleason's theorem then yields the conceptual necessity of quantum probabilities (QP).
Self-Monitoring of Blood Glucose: The Use of the First or the Second Drop of Blood
Authors: Johanna Hortensius, Robbert J. Slingerland, Nanne Kleefstra, Susan J.J. Logtenberg, Klaas H. Groenier, Sebastiaan T. Houweling, Henk J.G. Bilo
Journal: Diabetes Care (2011)

There is no general agreement regarding the use of the first or second drop of blood for glucose monitoring. This study investigated whether capillary glucose concentrations, as measured in the first and second drops of blood, differed ≥ 10% compared with a control glucose concentration in different situations.Capillary glucose concentrations were measured in two consecutive drops of blood in the following circumstances in 123 patients with diabetes: without washing hands, after exposing the hands to fruit, after washing the fruit-exposed hands, and during application of different amounts of external pressure around the finger. The results were compared with control measurements.Not washing hands led to a difference in glucose concentration of ≥ 10% in the first and in the second drops of blood in 11% and 4% of the participants, respectively. In fruit-exposed fingers, these differences were found in 88% and 11% of the participants, respectively. Different external pressures led to ≥ 10% differences in glucose concentrations in 5-13% of the participants.We recommend washing the hands with soap and water, drying them, and using the first drop of blood for self-monitoring of blood glucose. If washing hands is not possible, and they are not visibly soiled or exposed to a sugar-containing product, it is acceptable to use the second drop of blood after wiping away the first drop. External pressure may lead to unreliable readings.
Insulin receptor substrate-1 variants in non-insulin-dependent diabetes.
Authors: M Laakso, M Malkki, P Kekäläinen, J Kuusisto, S S Deeb
Journal: Journal of Clinical Investigation (1994)

Insulin receptor substrate-1 (IRS-1) plays an important role in insulin-stimulated signaling mechanisms. Therefore, we investigated the frequency and clinical significance of variants in the coding region of this gene in patients with non-insulin-dependent diabetes (NIDDM). Initial screening included a population-based sample of 40 Finnish patients with typical NIDDM. Applying single strand conformation polymorphism analysis the following amino acid substitutions were found among the 40 NIDDM patients: Gly818-Arg, Ser892Gly, and Gly971Arg. The first two variants have not been previously reported. Additional samples of 72 patients with NIDDM and 104 healthy control subjects with completely normal oral glucose tolerance test and a negative family history of diabetes were screened. The most common polymorphism was the Gly971Arg substitution which was found in 11 (9.8%) of 112 NIDDM patients and in 9 (8.7%) of 104 control subjects. The Gly818Arg substitution was found in 2 (1.8%) of NIDDM patients and in 2 (1.9%) of control subjects, and the Ser892Gly substitution was found in 3 (2.7%) NIDDM patients and in 1 (1.0%) control subject. The Gly971Arg substitution was not associated with an impairment in insulin secretion capacity (estimated by insulin responses in an oral glucose tolerance test or by the hyperglycemic clamp) or insulin action (estimated by the euglycemic clamp). Of the three amino acid substitutions observed Ser892Gly is the most interesting one since it abolishes one of the potential serine phosphorylation sites (SPGE) which is located immediately NH2-terminal to the only SH2 binding site of growth factor receptor-bound protein (GRB2), and thus could potentially influence some aspects of signal transduction and metabolic response to insulin.
Citrullination of CXCL8 by peptidylarginine deiminase alters receptor usage, prevents proteolysis, and dampens tissue inflammation
Authors: Paul Proost, Tamara Loos, Anneleen Mortier, Evemie Schutyser, Mieke Gouwy, Samuel Noppen, Chris Dillen, Isabelle Ronsse, René Conings, Sofie Struyf, Ghislain Opdenakker, Prabhat C. Maudgal, Jo Van Damme
Journal: The Journal of Experimental Medicine (2008)

Biological functions of proteins are influenced by posttranslational modifications such as on/off switching by phosphorylation and modulation by glycosylation. Proteolytic processing regulates cytokine and chemokine activities. In this study, we report that natural posttranslational citrullination or deimination alters the biological activities of the neutrophil chemoattractant and angiogenic cytokine CXCL8/interleukin-8 (IL-8). Citrullination of arginine in position 5 was discovered on 14% of natural leukocyte-derived CXCL8(1–77), generating CXCL8(1–77)Cit5. Peptidylarginine deiminase (PAD) is known to citrullinate structural proteins, and it may initiate autoimmune diseases. PAD efficiently and site-specifically citrullinated CXCL5, CXCL8, CCL17, CCL26, but not IL-1β. In comparison with CXCL8(1–77), CXCL8(1–77)Cit5 had reduced affinity for glycosaminoglycans and induced less CXCR2-dependent calcium signaling and extracellular signal-regulated kinase 1/2 phosphorylation. In contrast to CXCL8(1–77), CXCL8(1–77)Cit5 was resistant to thrombin- or plasmin-dependent potentiation into CXCL8(6–77). Upon intraperitoneal injection, CXCL8(6–77) was a more potent inducer of neutrophil extravasation compared with CXCL8(1–77). Despite its retained chemotactic activity in vitro, CXCL8(1–77)Cit5 was unable to attract neutrophils to the peritoneum. Finally, in the rabbit cornea angiogenesis assay, the equally potent CXCL8(1–77) and CXCL8(1–77)Cit5 were less efficient angiogenic molecules than CXCL8(6–77). This study shows that PAD citrullinates the chemokine CXCL8, and thus may dampen neutrophil extravasation during acute or chronic inflammation.
Profiling of Circulating MicroRNAs Reveals Common MicroRNAs Linked to Type 2 Diabetes That Change With Insulin Sensitization
Authors: Francisco J. Ortega, Josep M. Mercader, José María Moreno-Navarrete, Oscar Rovira, Ester Guerra, Eduardo Esteve, Gemma Xifra, Cristina Martínez, Wifredo Ricart, Jennifer Rieusset, Sophie Rome, Monika Karczewska-Kupczewska, Marek Straczkowski, José Manuel Fernández-Real
Journal: Diabetes Care (2014)

OBJECTIVEThis study sought to identify the profile of circulating microRNAs (miRNAs) in type 2 diabetes (T2D) and its response to changes in insulin sensitivity.