tbuckley/cabot-search huggingface dataset:
Catabolic Pathways for Streptokinase, Plasmin, and Streptokinase Activator Complex in Mice
Authors: Steven L. Gonias, Monica Einarsson, Salvatore V. Pizzo
Journal: Journal of Clinical Investigation (1982)

The catabolic pathways of streptokinase, plasmin, and activator complex prepared with human plasminogen were studied in mice. 125I-streptokinase clearance occurred in the liver and was 50% complete in 15 min. Incubation with mouse plasma had no effect on the streptokinase clearance rate. Complexes of plasmin and α2-plasmin inhibitor were eliminated from the plasma by a specific and saturable pathway. Competition experiments demonstrated that this pathway is responsible for the clearance of injected plasmin. Streptokinase-plasminogen activator complex formed with either 125I-plasminogen or 125I-streptokinase cleared in the liver at a significantly faster rate than either of the uncomplexed proteins (50% clearance in <3 min). Streptokinase incubated with human plasma also demonstrated this accelerated clearance. p-Nitrophenyl-p′-guanidinobenzoate-HCl or pancreatic trypsin inhibitor-treated complex cleared slowly compared with untreated complex independent of which protein was radiolabeled. Significant competition for clearance was demonstrated between α2-macroglobulin-trypsin and activator complex only when the plasmin(ogen) was the radiolabeled moiety. Large molar excesses of α2-plasmin inhibitor-plasmin failed to retard the clearance of activator complex. Hepatic binding of streptokinase-plasmin, in liver perfusion experiments, was dependent upon prior incubation with plasma (8-10% uptake compared to a background of ∼ 2.5%). Substitution of human α2-macroglobulin for plasma also resulted in binding when the incubation was performed for 10 min at 37°C (7.5%). Electrophoresis experiments confirmed the transfer of 0.8 mol plasmin/mol α2-macroglobulin when activator complex was incubated at 37°C with α2-macroglobulin for 40 min. Streptokinase transfer from activator complex to α2-macroglobulin was negligible. The in vivo clearance of activator complex is proposed to involve active attack of the complex on the α2-macroglobulin "bait region," resulting in facilitated plasmin transfer. Dissociated streptokinase is rapidly bound and cleared by sites in the liver.
Neuroplastic Changes Occur Early in the Development of Pancreatic Ductal Adenocarcinoma
Authors: Rachelle E. Stopczynski, Daniel P. Normolle, Douglas J. Hartman, Haoqiang Ying, Jennifer J. DeBerry, Klaus Bielefeldt, Andrew D. Rhim, Ronald A. DePinho, Kathryn M. Albers, Brian M. Davis
Journal: Cancer Research (2014)

Perineural tumor invasion of intrapancreatic nerves, neurogenic inflammation, and tumor metastases along extrapancreatic nerves are key features of pancreatic malignancies. Animal studies show that chronic pancreatic inflammation produces hypertrophy and hypersensitivity of pancreatic afferents and that sensory fibers may themselves drive inflammation via neurogenic mechanisms. Although genetic mutations are required for cancer development, inflammation has been shown to be a precipitating event that can accelerate the transition of precancerous lesions to cancer. These observations led us to hypothesize that inflammation that accompanies early phases of pancreatic ductal adenocarcinoma (PDAC) would produce pathologic changes in pancreatic neurons and innervation. Using a lineage-labeled genetically engineered mouse model of PDAC, we found that pancreatic neurotrophic factor mRNA expression and sensory innervation increased dramatically when only pancreatic intraepithelial neoplasia were apparent. These changes correlated with pain-related decreases in exploratory behavior and increased expression of nociceptive genes in sensory ganglia. At later stages, cells of pancreatic origin could be found in the celiac and sensory ganglia along with metastases to the spinal cord. These results demonstrate that the nervous system participates in all stages of PDAC, including those that precede the appearance of cancer.
Regulation of Interleukin 4 Gene Transcription
Authors: EDDY A. WIERENGA, GERALD MESSER
Journal: American Journal of Respiratory and Critical Care Medicine (2000)

Induction of interleukin 4 (IL-4) transcription in helper T (Th) cells under physiological conditions follows from engagement of the T cell receptor by antigenic peptides presented by antigen-presenting cells in association with MHC class II molecules (1). This trigger will activate two intracellular signaling pathways crucial to IL-4 expression, that is, a protein kinase C (PKC)-dependent pathway leading to the synthesis of activator protein 1 (AP-1) family proteins and a calcium (Ca 2 1 )dependent pathway resulting in calcineurin-mediated dephosphorylation and nuclear translocation of preexisting cytosolic nuclear factor of activated T cells (NFAT). The PKC pathway is potentiated by CD28-mediated costimulation (2), whereas the Ca 2 1 pathway can be fully blocked by cyclosporin A and FK506 (3). Both the mouse and human IL-4 promoters contain five binding elements (designated P0 to P4) for the NFAT family of transcription factors, with only minimal interspecies variation with respect to their sequence, orientation, and location within the proximal 250 base pairs (bp) of the promoter region (4–6). The P0 element is located just upstream of the transcription start site and P4 is located at about 2 250 bp in the 5 9 -flanking region (Figure 1). Although all P elements to some extent contribute to IL-4 gene control, the major positive regulatory P elements seem to be P1 (4, 7) and P4 (reviewed in Reference 1). As are P2 and P3, both P1 and P4 are immediately flanked by sequences with affinity for AP-1 family proteins (8–10), allowing for cooperative binding with NFAT proteins. The strong reduction of IL-4 promoter activity as observed, for example, after mutation of either the P1NFATor the adjacent AP-1-binding motif (9) emphasizes the importance of collaborative NFAT/AP-1 binding at such composite elements. The proximal part of the IL-4 promoter region, containing the transcription start site (indicated as 1 1 in Figure 1) and the P0 and P1 elements, can function as a minimal promoter in reporter gene assays, conferring inducible expression and a certain degree of Th2-specific regulation (11, 12). Initial studies gave no indication of Th1or Th2-specific recruitment of particular NFAT or AP-1 family proteins to these sites (9, 13). Instead, the mechanism underlying the Th2 specificity of IL-4 expression may be based on quantitative differences in the availability of NFAT and/or AP-1 family proteins. Furthermore, because the cooperative DNA binding of NFAT and AP-1 proteins has an auxiliary function for the binding of other transcription factors (5, 14–16), these additional transcription factors are likely to be involved in tissue-specific IL-4 expression. Th2-SPECIFIC IL-4 GENE CONTROL
Recent Chemotherapy Reduces the Sensitivity of [<sup>18</sup>F]Fluorodeoxyglucose Positron Emission Tomography in the Detection of Colorectal Metastases
Authors: Timothy Akhurst, Tara J. Kates, Madhu Mazumdar, Henry Yeung, Elyn R. Riedel, Bryan M. Burt, Leslie Blumgart, William Jarnagin, Steven M. Larson, Yuman Fong
Journal: Journal of Clinical Oncology (2005)

[18F]2-fluoro-2-deoxyglucose (FDG) -positron emission tomography (PET) has become a useful tool in the assessment of patients with colorectal cancer. Patients often undergo chemotherapy as treatment for primary or metastatic colorectal malignancy. Because cytotoxic chemotherapy may decrease the cellular metabolic activity of tumor, we assessed the effects of chemotherapy on PET imaging.This is a prospective study examining detection of hepatic colorectal metastases by FDG-PET as related to use of chemotherapy. Pathologic analysis of the liver resection specimens was used as gold standard.There was significantly decreased tumor FDG uptake (as measured by the maximal standardized uptake value) in patients treated preoperatively with chemotherapy, resulting in less efficient detection of cancerous lesions. One biologic basis of this change in accuracy of PET was a significant decrease in the activity of the key glycolytic enzyme hexokinase in tumors from patients treated with chemotherapy.These results indicate that FDG-PET scanning should be interpreted in the context of concurrent cytotoxic therapy. FDG-PET scanning results may also be useful in assessment of response to such cytotoxic therapies.
Psychiatry and Group Medical Practice: The Diagnostic Process, Referral Patterns, and Utilization of Services
Authors: JAMES W. CRAWFORD, SUSAN CRAWFORD
Journal: American Journal of Psychiatry (1973)

Group practice has emerged during the past decade as a major organizational form for the delivery of health care. Psychiatry, however, has been found to be the least inclined of the larger medical specialties toward participation in such groups. The authors compare data on diagnosis and referral patterns from several groups. They found that short-term psychiatric care is consistently associated with a decrease in the utilization of ancillary and medical services within the group practice setting.
Return to play? Athletes with congenital long QT syndrome
Authors: Jonathan N Johnson, Michael J Ackerman
Journal: British Journal of Sports Medicine (2012)

Competitive sports participation for athletes with congenital long QT syndrome (LQTS) is guided by the 2005 36th Bethesda Conference and the 2005 European Society of Cardiology (ESC) guidelines. The purpose of this study was to determine the prevalence and outcomes of patients with LQTS who chose to remain athletes following their diagnosis.Records of all patients between 6 and 40 years of age who were first evaluated in Mayo Clinic's LQTS Clinic from July 2000 to November 2010 were reviewed, for documentation of athletic participation after LQTS diagnosis and LQTS-related events during follow-up. Average follow-up was 5.5±3.4 years.The cohort included 353 patients with LQTS (199 females, mean age 17±11 years, mean QTc 472±42 ms), of whom 182 had LQT1, 130 had LQT2, 37 had LQT3 and 4 had multiple LQTS mutations. The majority of patients (223, 63%) were either not involved in sports (88%) or chose to discontinue sports (12%) following evaluation. 130 patients (37%, 60 females, mean age 11±7 years, mean QTc 471±46 ms) remained in competitive athletics, including 20 with implantable cardioverter defibrillators (ICDs). Of these 130, 70 (54%) were genotype-positive/phenotype-negative and competing contrary to ESC guidelines but within the Bethesda guidelines. None of these athletes had a sport-related event. Of the 60 LQTS athletes continuing in sports contrary to both the Bethesda and ESC guidelines (genotype-positive/phenotype-positive), only one had a sporting-related event with appropriate ICD shock.Athletes and their families are fully capable of self-disqualification. Among those athletes with LQTS who chose to remain in competitive sports, a low rate of cardiac events and no deaths were observed in over 650 athlete-years of follow-up. Current guideline-based recommendations for disqualification may be excessive for this disease.
Safety and efficacy of combination of etanercept and methotrexate compared to treatment with etanercept only in patients with juvenile idiopathic arthritis (JIA): preliminary data from the German JIA Registry
Authors: G Horneff, F De Bock, I Foeldvari, H J Girschick, H Michels, D Moebius, H Schmeling
Journal: Annals of the Rheumatic Diseases (2008)

Objective: Etanercept monotherapy has been studied and approved for treatment of polyarticular juvenile idiopathic arthritis (JIA). The following study evaluates the safety and efficacy of combination therapy of etanercept and methotrexate compared to etanercept monotherapy in JIA. Methods: We perfomed an open, non-randomised study on patients who had previously failed to respond to at least one disease-modifying antirheumatic drug (DMARD). A total of 722 patients with JIA in whom at least 1 item of follow-up data was recorded were identified; of these, 118 patients treated with further slow acting drugs were excluded. In all, 504 patients were treated with a combination of etanercept and methotrexate. A total of 100 patients treated with etanercept only were in the control group. Efficacy was calculated using the American College of Rheumatology paediatric scores for 30, 50 and 70% improvement (PedACR30/50/70). Adverse events (AEs) and serious adverse events (SAEs) were reported. Results: After 12 months 55 patients in the monotherapy group and 376 patients in the etanercept and methotrexate group were available for comparison. For the intention to treat analysis, 65 patients discontinuing treatment prematurely were included. All activity parameters decreased significantly in both treatment groups. After 12 months 81%/74%/62% of patients of the etanercept and methotrexate group and 70%/63%/45% of patients of the etanercept monotherapy group achieved PedACR30/50/70 scores, respectively (p&lt;0.05 for PedACR30, p&lt;0.01 for PedACR70). The likelihood of achieving a PedACR70 increased with combination therapy with an odds ratio of 2.1 (95% CI 1.2 to 3.5). In total, 25 infectious and 23 non-infectious SAEs including 3 malignancies occurred in the etanercept and methotrexate group, and 1 infectious and 3 non-infectious SAEs occurred in the single etanercept group. Conclusions: The patients’ disease activity improved during etanercept monotherapy and etanercept and methotrexate combination therapy. Tolerability in both treatment groups was comparable.
Predicting Harms and Benefits in Translational Trials: Ethics, Evidence, and Uncertainty
Authors: Jonathan Kimmelman, Alex John London
Journal: PLoS Medicine (2011)

First-in-human clinical trials represent a critical juncture in the translation of laboratory discoveries. However, because they involve the greatest degree of uncertainty at any point in the drug development process, their initiation is beset by a series of nettlesome ethical questions [1]: has clinical promise been sufficiently demonstrated in animals? Should trial access be restricted to patients with refractory disease? Should trials be viewed as therapeutic? Have researchers adequately minimized risks?

The resolution of such ethical questions inevitably turns on claims about future events like harms, therapeutic response, and clinical translation. Recurrent failures in clinical translation, like Eli Lilly's Alzheimer candidate semagacestat, highlight the severe limitations of current methods of prediction. In this case, patients in the active arm of the placebo-controlled trial had earlier onset of dementia and elevated rates of skin cancer [2].

Various authoritative accounts of human research ethics state that decision-making about risk and benefit should be careful, systematic, and non-arbitrary [3]–[5]. Yet, these sources provide little guidance about what kinds of evidence stakeholders should use to ensure their estimates of such events ground responsible ethical decisions. In this article, we suggest that investigators, oversight bodies, and sponsors often base their predictions on a flawed and inappropriately narrow preclinical evidence base.
Inhibition of PI3K/mTOR pathways in glioblastoma and implications for combination therapy with temozolomide
Authors: G. Prasad, T. Sottero, X. Yang, S. Mueller, C. D. James, W. A. Weiss, M.-Y. Polley, T. Ozawa, M. S. Berger, D. T. Aftab, M. D. Prados, D. A. Haas-Kogan
Journal: Neuro-Oncology (2011)

Due to its molecular heterogeneity and infiltrative nature, glioblastoma multiforme (GBM) is notoriously resistant to traditional and experimental therapeutics. To overcome these hurdles, targeted agents have been combined with conventional therapy. We evaluated the preclinical potential of a novel, orally bioavailable PI3K/mTOR dual inhibitor (XL765) in in vitro and in vivo studies. In vivo serially passaged human GBM xenografts that are more genetically stable than GBM cell lines in culture were used for all experiments. Biochemical downstream changes were evaluated by immunoblot and cytotoxicity by colorimetric ATP-based assay. For in vivo experiments, human xenograft GBM 39 grown intracranially in nude mice was altered to express luciferase to monitor tumor burden by optical imaging. XL765 resulted in concentration-dependent decreases in cell viability in vitro. Cytotoxic doses resulted in specific inhibition of PI3K signaling. Combining XL765 with temozolomide (TMZ) resulted in additive toxicity in 4 of 5 xenografts. In vivo, XL765 administered by oral gavage resulted in greater than 12-fold reduction in median tumor bioluminescence compared with control (Mann–Whitney test p = 0.001) and improvement in median survival (logrank p = 0.05). TMZ alone showed a 30-fold decrease in median bioluminescence, but the combination XL765 + TMZ yielded a 140-fold reduction in median bioluminescence (Mann-Whitney test p = 0.05) with a trend toward improvement in median survival (logrank p = 0.09) compared with TMZ alone. XL765 shows activity as monotherapy and in combination with conventional therapeutics in a range of genetically diverse GBM xenografts.
Progression of radiographic damage in patients with ankylosing spondylitis: defining the central role of syndesmophytes
Authors: X Baraliakos, J Listing, M Rudwaleit, H Haibel, J Brandt, J Sieper, J Braun
Journal: Annals of the Rheumatic Diseases (2007)

Structural changes such as erosions, syndesmophytes and ankylosis are characteristic of ankylosing spondylitis (AS). These can be quantified by the modified Stokes Anklylosing Spondylitis Spinal Score (mSASSS). It is unknown which radiographic feature is most relevant for the assessment of change and the prediction of future damage in AS.To analyse radiographic progression in AS by using different assessments to define the most important changes.Spinal radiographs of 116 patients with AS were scored by the mSASSS at baseline (BL) and after 2 years. Radiographic progression was assessed by differentiating (1) any change; (2) progression to syndesmophytes/ankylosis (definite change); and (3) changes exceeding the smallest detectable change (SDC) as predefined. A growth angle of 45 degrees was used to differentiate syndesmophytes from spondylophytes.Some radiographic progression after 2 years was detected in 42% of patients, novel syndesmophytes in 31% of patients, and, using the SDC (calculated at 2 mSASSS units) as cut-off, progression was seen in 28% of patients. Thus, in 74% of the patients changes were because of syndesmophytes and/or ankylosis. Using the predefined cut-off, only 12% of all syndesmophytes were spondylophytes. Patients with such changes were of older age. Definite radiographic progression was found in 44% of the patients with syndesmophytes/ankylosis at BL (n = 57) versus 19% (p = 0.03) of the patients without such changes (n = 59).Syndesmophytes and ankylosis are the most relevant structural changes in AS, and also in the mSASSS. Development of just one syndesmophyte within 2 years indicates progression of structural changes in AS; this is relevant for clinical practice. Syndesmophytes are the best predictors of radiographic progression.
Differential expression of mRNA for guanylyl cyclase-linked endothelium-derived relaxing factor receptor subunits in rat kidney.
Authors: K Ujiie, J G Drewett, P S Yuen, R A Star
Journal: Journal of Clinical Investigation (1993)

Endothelium-derived relaxing factor (EDRF) has profound effects on the renal vasculature, the glomerular mesangium, and also affects renal salt excretion. EDRF stimulates guanylyl cyclases, which are thought to be heterodimers comprised of alpha and beta subunits. Two alpha and two beta isoforms have been identified thus far. However, the molecular composition of in vivo guanylyl cyclase-linked EDRF receptors is unknown. We used polymerase chain reaction to clone a portion of the rat alpha 2 subunit. Guanylyl cyclase-linked EDRF receptor mRNA was detected in microdissected renal structures using a reverse transcription/polymerase chain reaction assay. The interlobular artery/afferent arteriole contained mRNA for the alpha 1, alpha 2, and beta 1 subunits; a faint beta 2 band was found in 29% of experiments. In contrast, the cortical collecting duct contained mRNA only for alpha 1 and beta 2 subunits. We conclude that guanylyl cyclase-linked EDRF receptor subunit isoforms are independently and heterogeneously expressed in the renal vasculature and cortical collecting duct, suggesting that several different EDRF receptors exist in vivo. These data suggest that the tubule receptor is composed of alpha 1/beta 2. The vasculature may contain at least two different EDRF receptors (alpha 1/beta 1 and alpha 2/beta 1). Some beta 2 may also be expressed, allowing for even greater heterogeneity.
Effect of seasonal allergic rhinitis on airway mucosal absorption of chromium-51 labelled EDTA.
Authors: L Greiff, P Wollmer, C Svensson, M Andersson, C G Persson
Journal: Thorax (1993)

BACKGROUND--Hyperpermeability of the airway mucosa is thought to be characteristic of allergic rhinitis and asthma. Nine subjects with seasonal rhinitis caused by birch pollen were studied and the nasal mucosal absorption of chromium-51 labelled EDTA was examined both in an asymptomatic period before the season and late into the season when significant allergic rhinitis symptoms were present. METHODS--A nasal pool device was used to keep a concentration of the absorption tracer in contact with a larger part of the mucosa of the ipsilateral nasal cavity. Absorption was allowed for 15 minutes and measured as the radioactivity appearing in the 24 hour urine sample. RESULTS--The nasal absorption of 51Cr-EDTA in subjects with seasonal allergic rhinitis was less during active disease than before the season. CONCLUSIONS--An airway epithelial barrier that is subject to prolonged eosinophilic inflammation may not be disrupted but may rather increase its functional tightness.
Metabolic Syndrome and Inflammatory Responses to Long-Term Particulate Air Pollutants
Authors: Jiu-Chiuan Chen, Joel Schwartz
Journal: Environmental Health Perspectives (2008)

BackgroundHuman data linking inflammation with long-term particulate matter (PM) exposure are still lacking. Emerging evidence suggests that people with metabolic syndrome (MS) may be a more susceptible population.ObjectivesOur goal was to examine potential inflammatory responses associated with long-term PM exposure and MS-dependent susceptibility.MethodsWe conducted secondary analyses of white blood cell (WBC) count and MS data from The Third National Health and Nutrition Examination Survey and PM10 (PM with aerodynamic diameter < 10 μm) data from the U.S. Environmental Protection Agency Aerometric Information Retrieval System. Estimated 1-year PM10 exposures were aggregated at the centroid of each residential census-block group, using distance-weighted averages from all monitors in the residing and adjoining counties. We restricted our analyses to adults (20–89 years of age) with normal WBC (4,000–11,000 × 106/L), no existing cardiovascular disease, complete PM10 and MS data, and living in current residences > 1 year (n = 2,978; age 48.5 ± 17.8 years). Mixed-effects models were constructed to account for autocorrelation and potential confounders.ResultsAfter adjustment for demographics, socioeconomic factors, lifestyles, residential characteristics, and MS, we observed a statistically significant association between WBC count and estimated local PM10 levels (p = 0.035). Participants from the least polluted areas (1-year PM10 < 1st quartile cutoff: 27.8 μg/m3) had lower WBC counts than the others (difference = 145 × 106/L; 95% confidence interval, 10–281). We also noted a graded association between PM10 and WBC across subpopulations with increasing MS components, with 91 × 106/L difference in WBC for those with no MS versus 214, 338, and 461 × 106/L for those with 3, 4, and 5 metabolic abnormalities (trend-test p = 0.15).ConclusionsOur study revealed a positive association between long-term PM exposure and hematological markers of inflammation and supported the hypothesized MS-dependent susceptibility.