tbuckley/cabot-search huggingface dataset:
Bile acids in nonalcoholic steatohepatitis: Inserting nuclear receptors into the circle
Authors: Chiara Gabbi, Jan-Åke Gustafsson
Journal: Hepatology (2012)

We read with great interest the article by Tanaka et al.1 showing high serum levels of tauro-β-muricholic and taurocholic acid in two animal models of nonalcoholic steatohepatitis (NASH). Hepatic expression of transporters of bile acids from the circulation to the liver (Slc10a1/Slco1a1) was decreased, whereas those transporters that transfer bile acids to the blood (Abcc1/4) were increased. Given that canalicular bile acid pumps (Abcc2/Abcb11) were not significantly affected, this finding raises a crucial question: What is the hepatic bile acid concentration in NASH? If there is a decrease in liver bile acid content, one would expect a vicious circle aggravating NASH (Fig. 1). Autoregenerating vicious circle of nonalcoholic steatohepatitis. FXR, farnesoid x receptor; SHP, small heterodimer partner; SREBP-1c, sterol regulatory element binding protein-1c; TG, triglyceride; TGFβ, transforming growth factor β; TNFα, tumor necrosis factor α. Slc10a1, sodium/taurocholate transport protein; Slco, solute carrier organic anion transporter family member; Abcc, ATP-binding cassette sub- family C. Bile acids are ligands for farnesoid x receptor (FXR), which through its regulation of small heterodimer partner inhibits the transcriptional activation of sterol regulatory element binding protein-1c (SREBP-1c). SREBP1c stimulates fatty acid synthesis. Thus inhibition of SREBP1-c via bile-acid activation of FXR results in a reduction of fatty liver.2 Moreover, activated FXR has potent anti-inflammatory and antifibrotic actions.3 The finding of Tanaka et al. may have revealed a hitherto unrecognized vicious circle around NASH (Fig. 1), starting with diet-induced lipid accumulation and tumor necrosis factor α/transforming growth factor β inflammatory cascade, leading to a possible reduction in bile acid content of the liver. Decreased ligand activation of FXR leads to triglyceride accumulation, inflammation, and regeneration of the noxious circle. Interestingly, all of the pharmacological approaches capable of interrupting this vicious circle (i.e., by increasing the bile acid pool4 or inducing the expression of CYP7A1, the rate limiting enzyme in bile acid synthesis) have been shown to be beneficial for fatty liver and for NASH,5, 6 both in rodents and in humans. In conclusion, the measurement of hepatic bile acids in NASH is important to clarify the pathogenesis of NASH and identify new therapeutic options. Chiara Gabbi M.D., Ph.D.* , Jan-Åke Gustafsson M.D., Ph.D* , * Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX, Department of Biosciences and Nutrition, Karolinska Institutet, Novum, Sweden.
Intrinsic Molecular Subtypes of Glioma Are Prognostic and Predict Benefit From Adjuvant Procarbazine, Lomustine, and Vincristine Chemotherapy in Combination With Other Prognostic Factors in Anaplastic Oligodendroglial Brain Tumors: A Report From EORTC Study 26951
Authors: Lale Erdem-Eraslan, Lonneke A. Gravendeel, Johan de Rooi, Paul H.C. Eilers, Ahmed Idbaih, Wim G.M. Spliet, Wilfred F.A. den Dunnen, Johannes L. Teepen, Pieter Wesseling, Peter A.E. Sillevis Smitt, Johan M. Kros, Thierry Gorlia, Martin J. van den Bent, Pim J. French
Journal: Journal of Clinical Oncology (2012)

Intrinsic glioma subtypes (IGSs) are molecularly similar tumors that can be identified based on unsupervised gene expression analysis. Here, we have evaluated the clinical relevance of these subtypes within European Organisation for Research and Treatment of Cancer (EORTC) 26951, a randomized phase III clinical trial investigating adjuvant procarbazine, lomustine, and vincristine (PCV) chemotherapy in anaplastic oligodendroglial tumors. Our study includes gene expression profiles of formalin-fixed, paraffin-embedded (FFPE) clinical trial samples.Gene expression profiling was performed in 140 samples, 47 fresh frozen samples and 93 FFPE samples, on HU133_Plus_2.0 and HuEx_1.0_st arrays, respectively.All previously identified six IGSs are present in EORTC 26951. This confirms that different molecular subtypes are present within a well-defined histologic subtype. Intrinsic subtypes are highly prognostic for overall survival (OS) and progression-free survival (PFS). They are prognostic for PFS independent of clinical (age, performance status, and tumor location), molecular (1p/19q loss of heterozygosity [LOH], IDH1 mutation, and MGMT methylation), and histologic parameters. Combining known molecular (1p/19q LOH, IDH1) prognostic parameters with intrinsic subtypes improves outcome prediction (proportion of explained variation, 30% v 23% for each individual group of factors). Specific genetic changes (IDH1, 1p/19q LOH, and EGFR amplification) segregate into different subtypes. We identified one subtype, IGS-9 (characterized by a high percentage of 1p/19q LOH and IDH1 mutations), that especially benefits from PCV chemotherapy. Median OS in this subtype was 5.5 years after radiotherapy (RT) alone versus 12.8 years after RT/PCV (P = .0349; hazard ratio, 2.18; 95% CI, 1.06 to 4.50).Intrinsic subtypes are highly prognostic in EORTC 26951 and improve outcome prediction when combined with other prognostic factors. Tumors assigned to IGS-9 benefit from adjuvant PCV.
CORRECTION AND RETRIBUTION IN THE CRIMINAL LAW
Authors: LAWRENCE FRIEDMAN
Journal: American Journal of Psychiatry (1957)

Dr. Board's objectives can only tend toward a happier society. His failure to distinguish between suggestion and analysis prejudices his worthwhile objectives in the following ways: 1. It leaves him unarmed against the resistences of society which go unrecognized. 2. It compromises the effect of the psychiatrist's most potent weapons,—expert advice and education, by concealing them in a tendentious special plea for the values of the psychiatrist. 3. In the manner of so many current political positions, it blurs the meaning of society's conflicting values by insisting that they are perfectly realized in the tissue of compromises and violations that alone can give them expression. 4. Finally, one suspects that there will come a time when the psychiatrist, accustomed to the stationary ethical foundation he has artfully built and unprepared for the heaving sea of felt principles, will feel in himself the upsurge of the rejected "contaminant" and be overcome by a moral malaise without remedy.
A method for estimating macromolecular reflection by human synovium, using measurements of intra-articular half lives
Authors: J R Levick
Journal: Annals of the Rheumatic Diseases (1998)

Recent studies show that very large macromolecules in synovial fluid, such as hyaluronan and large proteoglycans, are partially reflected by the synovial lining during fluid drainage, and thus selectively retained within the cavity. Size selective molecular reflection is a fundamental property of membranes, and a method for quantifying the reflective behaviour of human synovium could be of value in several pathophysiological areas. The method proposed here is based on the intra-articular half lives of the macromolecule of interest and of a smaller, easily cleared protein such as albumin. The key relation is derived from the law of conservation of mass, using simple algebra. It is found that, when the intra-articular half lives of albumin and a macromolecular test solute are determined simultaneously, the reflected fraction of the test solute is given by the complement of the half life ratio. Examples are given. Intra-articular half lives can thus be used to consider such questions as whether immune complexes are significantly reflected by the synovial surface, how the reflective property changes in arthritides or with treatment, and how significantly reflection might influence the intra-articular concentration of large "markers" of joint disease activity.
The importance of study design for detecting differentially abundant features in high-throughput experiments
Authors: Huaien Luo, Juntao Li, Burton Kuan Hui Chia, Paul Robson, Niranjan Nagarajan
Journal: Genome biology (2014)

High-throughput assays, such as RNA-seq, to detect differential abundance are widely used. Variable performance across statistical tests, normalizations, and conditions leads to resource wastage and reduced sensitivity. EDDA represents a first, general design tool for RNA-seq, Nanostring, and metagenomic analysis, that rationally selects tests, predicts performance, and plans experiments to minimize resource wastage. Case studies highlight EDDA's ability to model single-cell RNA-seq, suggesting ways to reduce sequencing costs up to five-fold and improving metagenomic biomarker detection through improved test selection. EDDA's novel mode-based normalization for detecting differential abundance improves robustness by 10% to 20% and precision by up to 140%.
Overperfusion, hypoxia, and increased pressure cause only hydrostatic pulmonary edema in anesthetized sheep.
Authors: C C Landolt, M A Matthay, K H Albertine, P J Roos, J P Wiener-Kronish, N C Staub
Journal: Circulation Research (1983)

Overperfusion (high pressure and flow through a restricted microvascular bed) has been suggested as the mechanism for both microembolic and high altitude pulmonary edema. In eighteen anesthetized, ventilated sheep, we measured pulmonary hemodynamics, lung lymph flow, and lymph:plasma protein concentration ratio. After a 2-hour stable baseline, we resected 65% of lung mass (right lung and left upper lobe) and gave whole blood transfusions to maintain cardiac output. During overperfusion of the left lower lobe, lymph flow increased moderately (5.8 +/- 2.3 to 7.7 +/- 3.8 ml/hr) and lymph:plasma protein concentration decreased (0.73 +/- 0.08 to 0.64 +/- 0.08). After a 2-hour stable period, we decreased inspired oxygen in 10 sheep (Pao2 = 40 +/- 3 mm Hg). With added alveolar hypoxia, pulmonary artery pressure increased modestly, but lymph flow and the lymph:plasma protein concentration ratio did not change. In eight sheep (four hypoxic, four normoxic), we raised left atrial pressure approximately 12 cm H2O for 2 hours. Lymph flow rose (10.8 +/- 3.8 ml/h) and lymph:plasma protein concentration decreased further (0.52 +/- 0.07). At each step, lymph:plasma protein concentration decreased, as predicted for the calculated rise in microvascular pressure. There was no evidence that overperfusion, with or without alveolar hypoxia, increased lung endothelial barrier protein permeability.
Defective Vav expression and impaired F-actin reorganization in a subset of patients with common variable immunodeficiency characterized by T-cell defects
Authors: Silvia Rossi Paccani, Marianna Boncristiano, Laura Patrussi, Cristina Ulivieri, Andreas Wack, Silvia Valensin, Tim R. Hirst, Amedeo Amedei, Gianfranco del Prete, John L. Telford, Mario M. D'Elios, Cosima T. Baldari
Journal: Blood (2005)
Eligibility and Response Guidelines for Phase II Clinical Trials in Androgen-Independent Prostate Cancer: Recommendations From the Prostate-Specific Antigen Working Group
Authors: Glenn J. Bubley, Michael Carducci, William Dahut, Nancy Dawson, Danai Daliani, Mario Eisenberger, William D. Figg, Boris Freidlin, Susan Halabi, Gary Hudes, Maha Hussain, Richard Kaplan, Charles Myers, William Oh, Daniel P. Petrylak, Eddie Reed, Bruce Roth, Oliver Sartor, Howard Scher, Jonathan Simons, Vickie Sinibaldi, Eric J. Small, Matthew R. Smith, Donald L. Trump, Robin Vollmer, George Wilding
Journal: Journal of Clinical Oncology (1999)

PURPOSE: Prostate-specific antigen (PSA) is a glycoprotein that is found almost exclusively in normal and neoplastic prostate cells. For patients with metastatic disease, changes in PSA will often antedate changes in bone scan. Furthermore, many but not all investigators have observed an association between a decline in PSA levels of 50% or greater and survival. Since the majority of phase II clinical trials for patients with androgen-independent prostate cancer (AIPC) have used PSA as a marker, we believed it was important for investigators to agree on definitions and values for a minimum set of parameters for eligibility and PSA declines and to develop a common approach to outcome analysis and reporting. We held a consensus conference with 26 leading investigators in the field of AIPC to define these parameters. RESULT: We defined four patient groups: (1) progressive measurable disease, (2) progressive bone metastasis, (3) stable metastases and a rising PSA, and (4) rising PSA and no other evidence of metastatic disease. The purpose of determining the number of patients whose PSA level drops in a phase II trial of AIPC is to guide the selection of agents for further testing and phase III trials. We propose that investigators report at a minimum a PSA decline of at least 50% and this must be confirmed by a second PSA value 4 or more weeks later. Patients may not demonstrate clinical or radiographic evidence of disease progression during this time period. Some investigators may want to report additional measures of PSA changes (ie, 75% decline, 90% decline). Response duration and the time to PSA progression may also be important clinical end point. CONCLUSION: Through this consensus conference, we believe we have developed practical guidelines for using PSA as a measurement of outcome. Furthermore, the use of common standards is important as we determine which agents should progress to randomized trials which will use survival as an end point.
Impact of Sexual Abuse on the HIV-Risk-Related Behavior of Adolescents in Intensive Psychiatric Treatment
Authors: L K Brown, K J Lourie, C Zlotnick, J Cohn
Journal: American Journal of Psychiatry (2000)

OBJECTIVE: This study compared the HIV-risk-related behaviors and attitudes of adolescents with and without a history of sexual abuse who were in intensive psychiatric treatment. METHOD: Adolescent patients (N=208) completed measures of psychological functioning and HIV-related knowledge, attitudes, and behaviors. RESULTS: Among sexually active adolescents in psychiatric treatment (N=116), those with a history of abuse reported significantly less condom self-efficacy (emotional ability to use condoms), less knowledge of HIV, less impulse control, less frequent use and purchase of condoms, and significantly higher rates of sexually transmitted diseases than their peers. Multiple logistic regression indicated that a history of sexual abuse was strongly associated with inconsistent condom use. CONCLUSIONS: Sexual abuse was associated with HIV-risk-related attitudes and behaviors among adolescents in psychiatric treatment. Clinicians should thus view a history of sexual abuse as a marker for sexual behavior that puts adolescents at risk for HIV.
The Genetic Background of Pancreatic Cancer: Genes That Might Be Biomarkers or Indicators of Metastasis to the Lung
Authors: Apostolou Panagiotis, Toloudi Maria, Kourtidou Eleni, Vlachou Ioanna, Mimikakou Georgia, Chatziioannou Marina, Papasotiriou Ioannis
Journal: Annals of Oncology (2014)
Regulation of Bone Mass by Serotonin: Molecular Biology and Therapeutic Implications
Authors: Gerard Karsenty, Vijay K. Yadav
Journal: Annual Review of Medicine (2011)

The molecular elucidation of two human skeletal dysplasias revealed that they are caused by an increase or a decrease in the synthesis of serotonin by enterochromaffin cells of the gut. This observation revealed a novel and powerful endocrine means to regulate bone mass. Exploiting these findings in the pharmacological arena led to the demonstration that inhibiting synthesis of gut-derived serotonin could be an effective means to treat low-bone-mass diseases such as osteoporosis.
Tumor Boards and the Quality of Cancer Care
Authors: N. L. Keating, M. B. Landrum, E. B. Lamont, S. R. Bozeman, L. N. Shulman, B. J. McNeil
Journal: JNCI Journal of the National Cancer Institute (2012)

Despite the widespread use of tumor boards, few data on their effects on cancer care exist. We assessed whether the presence of a tumor board, either general or cancer specific, was associated with recommended cancer care, outcomes, or use in the Veterans Affairs (VA) health system. We surveyed 138 VA medical centers about the presence of tumor boards and linked cancer registry and administrative data to assess receipt of stage-specific recommended care, survival, or use for patients with colorectal, lung, prostate, hematologic, and breast cancers diagnosed in the period from 2001 to 2004 and followed through 2005. We used multivariable logistic regression to assess associations of tumor boards with the measures, adjusting for patient sociodemographic and clinical characteristics. All statistical tests were two-sided. Most facilities (75%) had at least one tumor board, and many had several cancer-specific tumor boards. Presence of a tumor board was associated with only seven of 27 measures assessed (all P < .05), and several associations were not in expected directions. Rates of some recommended care (eg, white blood cell growth factors with cyclophosphamide, adriamycin, vincristine, and prednisone in diffuse large B-cell lymphoma) were lower in centers with hematologic-specialized tumor boards (39.4%) than in centers with general tumor boards (61.3%) or no tumor boards (56.4%; P = .002). Only one of 27 measures was statistically significantly associated with tumor boards after applying a Bonferroni correction for multiple comparisons. We observed little association of multidisciplinary tumor boards with measures of use, quality, or survival. This may reflect no effect or an effect that varies by structural and functional components and participants' expertise.
Multicenter phase II trial of Genexol-PM, a novel Cremophor-free, polymeric micelle formulation of paclitaxel, with cisplatin in patients with advanced non-small-cell lung cancer
Authors: D.-W. Kim, S.-Y. Kim, H.-K. Kim, S.-W. Kim, S.W. Shin, J.S. Kim, K. Park, M.Y. Lee, D.S. Heo
Journal: Annals of Oncology (2007)
Purification, biochemical, and immunological characterisation of a major food allergen: different immunoglobulin E recognition of the apo- and calcium-bound forms of carp parvalbumin
Authors: A Bugajska-Schretter
Journal: Gut (2000)

<h3>BACKGROUND</h3> Almost 4% of the population suffer from food allergy which is an adverse reaction to food with an underlying immunological mechanism. <h3>AIMS</h3> To characterise one of the most frequent IgE defined food allergens, fish parvalbumin. <h3>METHODS</h3> Tissue and subcellular distribution of carp parvalbumin was analysed by immunogold electron microscopy and cell fractionation. Parvalbumin was purified to homogeneity, analysed by mass spectrometry and circular dichroism (CD) spectroscopy, and its allergenic activity was analysed by IgE binding and basophil histamine release tests. <h3>RESULTS</h3> The isoelectric point (pI) 4.7 form of carp parvalbumin, a three EF-hand calcium-binding protein, was purified to homogeneity. CD analysis revealed a remarkable stability and refolding capacity of calcium-bound parvalbumin. This may explain why parvalbumin, despite cooking and exposure to the gastrointestinal tract, can sensitise patients. Purified parvalbumin reacted with IgE of more than 95% of individuals allergic to fish, induced dose-dependent basophil histamine release and contained, on average, 83% of the IgE epitopes present in other fish species. Calcium depletion reduced the IgE binding capacity of parvalbumin which, according to CD analysis, may be due to conformation-dependent IgE recognition. <h3>CONCLUSIONS</h3> Purified carp parvalbumin represents an important cross reactive food allergen. It can be used for in vitro and in vivo diagnosis of fish-induced food allergy. Our finding that the apo-form of parvalbumin had a greatly reduced IgE binding capacity indicates that this form may be a candidate for safe immunotherapy of fish-related food allergy.
Microrna-124 targets flotillin-1 to regulate proliferation and migration in breast cancer
Authors: Laisheng Li, Jinmei Luo, Bo Wang, Dong Wang, Xinhua Xie, Linjing Yuan, Jiaoli Guo, Shaoyan Xi, Jie Gao, Xiaoti Lin, Yanan Kong, Xiangdong Xu, Hailing Tang, Xiaoming Xie, Min Liu
Journal: Molecular Cancer (2013)

MicroRNAs (miRNAs) have been documented as playing important roles in cancer development. In this study, we investigated the role of miR-124 in breast cancer and clarified the regulation of flotillin-1 (FLOT1) by miR-124.The expression levels of miR-124 were examined in breast cancer cell lines and patient specimens using quantitative reverse transcription-PCR. The clinicopathological significance of the resultant data was later analyzed. Next, we explored the function of miR-124 to determine its potential roles on cancer cell growth and migration in vitro. A luciferase reporter assay was conducted to confirm the target gene of miR-124, and the results were validated in cell lines and patient specimens.We found that miR-124 expression was significantly downregulated in breast cancer cell lines and patient specimen compared with normal cell lines and paired adjacent normal tissues (P < 0.0001), respectively. MiR-124 was also associated with tumor node metastasis (TNM) stage (P = 0.0007) and lymph node metastasis (P = 0.0004). In breast cancer cell lines, the ectopic expression of miR-124 inhibited cell growth and migration in vitro. Moreover, we identified the FLOT1 gene as a novel direct target of miR-124, and miR-124 ectopic expression significantly inhibited FLOT1. Luciferase assays confirmed that miR-124 could directly bind to the 3' untranslated region of FLOT1 and suppress translation. Moreover, FLOT1 was widely upregulated, and inversely correlated with miR-124 in breast cancer tissues. Consistent with the effect of miR-124, the knockdown of FLOT1 significantly inhibited breast cancer cell growth and migration. We also observed that the rescue expression of FLOT1 partially restored the effects of miR-124.Our study demonstrated that miR-124 might be a tumor suppressor in breast cancer via the regulation of FLOT1. This microRNA could serve as a potential diagnostic marker and therapeutic target for breast cancer.
Medication for Attention Deficit–Hyperactivity Disorder and Criminality
Authors: Paul Lichtenstein, Linda Halldner, Johan Zetterqvist, Arvid Sjölander, Eva Serlachius, Seena Fazel, Niklas Långström, Henrik Larsson
Journal: New England Journal of Medicine (2012)

Attention deficit-hyperactivity disorder (ADHD) is a common disorder that has been associated with criminal behavior in some studies. Pharmacologic treatment is available for ADHD and may reduce the risk of criminality.Using Swedish national registers, we gathered information on 25,656 patients with a diagnosis of ADHD, their pharmacologic treatment, and subsequent criminal convictions in Sweden from 2006 through 2009. We used stratified Cox regression analyses to compare the rate of criminality while the patients were receiving ADHD medication, as compared with the rate for the same patients while not receiving medication.As compared with nonmedication periods, among patients receiving ADHD medication, there was a significant reduction of 32% in the criminality rate for men (adjusted hazard ratio, 0.68; 95% confidence interval [CI], 0.63 to 0.73) and 41% for women (hazard ratio, 0.59; 95% CI, 0.50 to 0.70). The rate reduction remained between 17% and 46% in sensitivity analyses among men, with factors that included different types of drugs (e.g., stimulant vs. nonstimulant) and outcomes (e.g., type of crime).Among patients with ADHD, rates of criminality were lower during periods when they were receiving ADHD medication. These findings raise the possibility that the use of medication reduces the risk of criminality among patients with ADHD. (Funded by the Swedish Research Council and others.).