tbuckley/cabot-search huggingface dataset:
Human and experimental evidence supporting a role for osteopontin in alcoholic hepatitis
Authors: Oriol Morales-Ibanez, Marlene Domínguez, Sung H. Ki, Miguel Marcos, Javier F. Chaves, Eric Nguyen-Khac, Hakim Houchi, Silvia Affò, Pau Sancho-Bru, José Altamirano, Javier Michelena, Juan Carlos García-Pagán, Juan G. Abraldes, Vicente Arroyo, Juan Caballería, Francisco-Javier Laso, Bin Gao, Ramón Bataller
Journal: Hepatology (2013)

We identified, in the transcriptome analysis of patients with alcoholic hepatitis (AH), osteopontin (OPN) as one of the most up-regulated genes. Here, we used a translational approach to investigate its pathogenic role. OPN hepatic gene expression was quantified in patients with AH and other liver diseases. OPN protein expression and processing were assessed by immmunohistochemistry, western blotting and enzyme-linked immunosorbent assay. OPN gene polymorphisms were evaluated in patients with alcoholic liver disease. The role of OPN was evaluated in OPN−/− mice with alcohol-induced liver injury. OPN biological actions were studied in human hepatic stellate cells (HSCs) and in precision-cut liver slices. Hepatic expression and serum levels of OPN were markedly increased in AH, compared to normal livers and other types of chronic liver diseases, and correlated with short-term survival. Serum levels of OPN also correlated with hepatic expression and disease severity. OPN was mainly expressed in areas with inflammation and fibrosis. Two proteases that process OPN (thrombin and matrix metalloproteinase 7) and cleaved OPN were increased in livers with AH. Patients with AH had a tendency of a lower frequency of the CC genotype of the +1239C single-nucleotide polymorphism of the OPN gene, compared to patients with alcohol abuse without liver disease. Importantly, OPN−/− mice were protected against alcohol-induced liver injury and showed decreased expression of inflammatory cytokines. Finally, OPN was induced by lipopolysaccharide and stimulated inflammatory actions in HSCs. Conclusion: Human and experimental data suggest a role for OPN in the pathogenesis of AH. Further studies should evaluate OPN as a potential therapeutic target. (Hepatology 2013;58:1742–1756)
5-ht<sub>6</sub> Receptors as Emerging Targets for Drug Discovery
Authors: Theresa A. Branchek, Thomas P. Blackburn
Journal: The Annual Review of Pharmacology and Toxicology (2000)

5-ht 6 receptors are the latest serotonin receptors to be identified by molecular cloning. Their high affinity for a wide range of drugs used in psychiatry, coupled with their intriguing distribution in the brain, has stimulated significant interest. Antisense oligonucleotides, antipeptide antibodies, selective radioligands, knockout mice, and selective antagonists of the 5-ht 6 receptor have recently become available. Surprisingly, 5-ht 6 receptors appear to regulate cholinergic neurotransmission in the brain, rather than the expected interaction as modulators of dopaminergic transmission. This interaction predicts a possible role for 5-ht 6 receptor antagonists in the treatment of learning and memory disorders. Furthermore, polymorphisms in the sequence of the 5-ht 6 receptor gene may provide a genetic tool to further our understanding of the differential responses of patients to antipsychotic medications.
Fate of the Lower Apical Segment in Resections for Bronchiectasis
Authors: J. L. Collis
Journal: Thorax (1953)

In view of the common nature of the operation of lobectomy for bronchiectasis it is rather sur- prising to find how little unanimity there is with regard to the desirability of preserving the lower apical segment.A proper assessment of the position is only possible if the advantages of leaving that segment can be weighed against the complications which may follow, and it was with this in view that this survey was undertaken.
Asynchronous Coreceptor Downregulation after Positive Thymic Selection: Prolonged Maintenance of the Double Positive State in CD8 Lineage Differentiation Due to Sustained Biosynthesis of the CD4 Coreceptor
Authors: Thomas Barthlott, Hubertus Kohler, Klaus Eichmann
Journal: The Journal of Experimental Medicine (1997)

In several experimental systems analyzing the generation of single positive (SP) thymocytes from double positive (DP) thymocytes, CD4 SP cells have been shown to appear before CD8 SP cells. This apparent temporal asymmetry in the maturation of CD4 SP and CD8 SP thymocytes could either be due to divergent molecular differentiation programs of the two T cell lineages, or merely to slower degradation kinetics of the CD4 protein. To study this question in unmanipulated in vivo differentiation, we developed a four-color flow cytometry protocol which identifies a recently activated TCRintCD69pos thymocyte population containing DP cells and early CD4 SP cells but no CD8 SP cells. We show that these TCRintCD69pos thymocytes represent a transitory stage in the mainstream αβ T cell lineage. The precursors of the CD8 SP cells are contained in this population as incompletely selected DP cells. Moreover, we show that expression of both coreceptors in the TCRintCD69pos population depends on transcriptional and translational activity, thus excluding differences in turnover rates of the CD4 and CD8 proteins as the cause of the asynchrony in differentiation of the CD4 and CD8 lineages.
Fractal-related assembly of the axial filament in the demosponge Suberites domuncula: Relevance to biomineralization and the formation of biogenic silica
Authors: W MULLER, A BOREIKO, U SCHLOSMACHER, X WANG, M TAHIR, W TREMEL, D BRANDT, J KAANDORP, H SCHRODER
Journal: Biomaterials (2007)
Effect of Tumor Microenvironment on Tumor VEGF During Anti-VEGF Treatment: Systems Biology Predictions
Authors: Stacey D. Finley, Aleksander S. Popel
Journal: JNCI Journal of the National Cancer Institute (2013)

Vascular endothelial growth factor (VEGF) is known to be a potent promoter of angiogenesis under both physiological and pathological conditions. Given its role in regulating tumor vascularization, VEGF has been targeted in various cancer treatments, and anti-VEGF therapy has been used clinically for treatment of several types of cancer. Systems biology approaches, particularly computational models, provide insight into the complexity of tumor angiogenesis. These models complement experimental studies and aid in the development of effective therapies targeting angiogenesis.We developed an experiment-based, molecular-detailed compartment model of VEGF kinetics and transport to investigate the distribution of two major VEGF isoforms (VEGF121 and VEGF165) in the body. The model is applied to predict the dynamics of tumor VEGF and, importantly, to gain insight into how tumor VEGF responds to an intravenous injection of an anti-VEGF agent.The model predicts that free VEGF in the tumor interstitium is seven to 13 times higher than plasma VEGF and is predominantly in the form of VEGF121 (>70%), predictions that are validated by experimental data. The model also predicts that tumor VEGF can increase or decrease with anti-VEGF treatment depending on tumor microenvironment, pointing to the importance of personalized medicine.This computational study suggests that the rate of VEGF secretion by tumor cells may serve as a biomarker to predict the patient population that is likely to respond to anti-VEGF treatment. Thus, the model predictions have important clinical relevance and may aid clinicians and clinical researchers seeking interpretation of pharmacokinetic and pharmacodynamic observations and optimization of anti-VEGF therapies.
Polyp detection rate of ct colonography, how does this compare to conventional colonoscopy?
Authors: A. M. Verma, R. Verma, D. P. Bridge, S. Roche, R. J. Robinson
Journal: Gut (2011)

<h3>Introduction</h3> The national bowel cancer screening programme in the UK advocates colonoscopy to screen individuals with positive faecal occult blood tests. Alternative modalities include CT colonography (CTC). CTC has become the non-invasive investigation of choice to assess the colon. It has superseded Barium enema and has the added benefit of detecting extra-colonic pathology. However its role in detecting polyps less than 1cm in size is limited.1 There is limited literature comparing polyp detection of CT colonography with colonoscopy in clinical practice. <h3>Methods</h3> Reports for CTCs undertaken at University Hospitals Leicester in the last quarter of 2008 have been analysed and polyp detection rate has been calculated. This was compared to data for every colonoscopy undertaken in the same period. <h3>Results</h3> CTCs also revealed 13 cases of colonic tumours. Significant extra-colonic pathology was discovered in 20 cases. <h3>Conclusion</h3> Polyp detection is a key component of colonoscopy and is used as a quality indicator.2 Analysis of CTCs shows a polyp detection rate of 10.32%. For colonoscopy, polyp detection rate was 20.45%, indicating a higher quality examination. The two groups analysed differ, the colonoscopy group is larger (n = 714) and comprises of mainly middle aged patients (mean/median age = 55.75/58). CTC group is smaller (n = 281) with mainly elderly patients (mean age = 72.02, median = 76). However, as the incidence of colonic polyps increases with age,3 the difference in groups would tend to exaggerate the polyp detection of CTC and understate the polyp detection of colonoscopy when compared head to head. In summary CT colonography is significantly not as good for diagnosing colonic polyps when compared to colonoscopy. It is an excellent investigation for elderly patients for whom the presence of small polyps is less relevant and the incidence of other significant pathology (including extra-colonic) is higher.
Triple-Modality Screening Trial for Familial Breast Cancer Underlines the Importance of Magnetic Resonance Imaging and Questions the Role of Mammography and Ultrasound Regardless of Patient Mutation Status, Age, and Breast Density
Authors: Christopher C. Riedl, Nikolaus Luft, Clemens Bernhart, Michael Weber, Maria Bernathova, Muy-Kheng M. Tea, Margaretha Rudas, Christian F. Singer, Thomas H. Helbich
Journal: Journal of Clinical Oncology (2015)

To evaluate the breast cancer screening efficacy of mammography, ultrasound, and magnetic resonance imaging (MRI) in a high-risk population and in various population subgroups.In a single-center, prospective, nonrandomized comparison study, BRCA mutation carriers and women with a high familial risk (> 20% lifetime risk) for breast cancer were offered screening with mammography, ultrasound, and MRI every 12 months. Diagnostic performance was compared between individual modalities and their combinations. Further comparisons were based on subpopulations dichotomized by screening rounds, mutation status, age, and breast density.There were 559 women with 1,365 complete imaging rounds included in this study. The sensitivity of MRI (90.0%) was significantly higher (P < .001) than that of mammography (37.5%) and ultrasound (37.5%). Of 40 cancers, 18 (45.0%) were detected by MRI alone. Two cancers were found by mammography alone (a ductal carcinoma in situ [DCIS] with microinvasion and a DCIS with < 10-mm invasive areas). This did not lead to a significant increase of sensitivity compared with using MRI alone (P = .15). No cancers were detected by ultrasound alone. Similarly, of 14 DCISs, all were detected by MRI, whereas mammography and ultrasound each detected five DCISs (35.7%). Age, mutation status, and breast density had no influence on the sensitivity of MRI and did not affect the superiority of MRI over mammography and ultrasound.MRI allows early detection of familial breast cancer regardless of patient age, breast density, or risk status. The added value of mammography is limited, and there is no added value of ultrasound in women undergoing MRI for screening.
Whole-genome screening indicates a possible burst of formation of processed pseudogenes and Alu repeats by particular L1 subfamilies in ancestral primates
Authors: Kazuhiko Ohshima, Masahira Hattori, Tetsusi Yada, Takashi Gojobori, Yoshiyuki Sakaki, Norihiro Okada
Journal: Genome biology (2003)

Abundant pseudogenes are a feature of mammalian genomes. Processed pseudogenes (PPs) are reverse transcribed from mRNAs. Recent molecular biological studies show that mammalian long interspersed element 1 (L1)-encoded proteins may have been involved in PP reverse transcription. Here, we present the first comprehensive analysis of human PPs using all known human genes as queries.The human genome was queried and 3,664 candidate PPs were identified. The most abundant were copies of genes encoding keratin 18, glyceraldehyde-3-phosphate dehydrogenase and ribosomal protein L21. A simple method was developed to estimate the level of nucleotide substitutions (and therefore the age) of PPs. A Poisson-like age distribution was obtained with a mean age close to that of the Alu repeats, the predominant human short interspersed elements. These data suggest a nearly simultaneous burst of PP and Alu formation in the genomes of ancestral primates. The peak period of amplification of these two distinct retrotransposons was estimated to be 40-50 million years ago. Concordant amplification of certain L1 subfamilies with PPs and Alus was observed.We suggest that a burst of formation of PPs and Alus occurred in the genome of ancestral primates. One possible mechanism is that proteins encoded by members of particular L1 subfamilies acquired an enhanced ability to recognize cytosolic RNAs in trans.
Angiotensin II Blockade in Kidney Transplant Recipients
Authors: Hassan N. Ibrahim, Scott Jackson, Jeffery Connaire, Arthur Matas, Arthur Ney, Behzad Najafian, Ann West, Nicole Lentsch, Jensina Ericksen, Jenny Bodner, Bertram Kasiske, Michael Mauer
Journal: Journal of the American Society of Nephrology (2013)

Interstitial fibrosis/tubular atrophy (IF/TA) contributes to the loss of kidney allografts, and treatment or preventive options are lacking. We conducted a double-blind, randomized, placebo-controlled trial to determine whether angiotensin II blockade prevents the expansion of the cortical interstitial compartment, the precursor of fibrosis. We randomly assigned 153 transplant recipients to receive losartan, 100 mg (n=77), or matching placebo (n=76) within 3 months of transplantation, continuing treatment for 5 years. The primary outcome was a composite of doubling of the fraction of renal cortical volume occupied by interstitium from baseline to 5 years or ESRD from IF/TA. In the intention-to-treat analysis, using only patients with adequate structural data, the primary endpoint occurred in 6 of 47 patients who received losartan and 12 of 44 who received placebo (odds ratio [OR], 0.39; 95% confidence interval [CI], 0.13-1.15; P=0.08). We found no significant effect of losartan on time to a composite of ESRD, death, or doubling of creatinine level. In a secondary analysis, losartan seemed to reduce the risk of a composite of doubling of interstitial volume or all-cause ESRD (OR, 0.36; 95% CI, 0.13-0.99; P=0.05), but this finding requires validation. In conclusion, treatment with losartan did not lead to a statistically significant reduction in a composite of interstitial expansion or ESRD from IF/TA in kidney transplant recipients.
Blockade of Paclitaxel-Induced Thymidine Phosphorylase Expression Can Accelerate Apoptosis in Human Prostate Cancer Cells
Authors: Nobuyuki Kikuno, Nobuko Moriyama-Gonda, Tateki Yoshino, Tatsuaki Yoneda, Shinji Urakami, Masaharu Terashima, Manabu Yoshida, Hirofumi Kishi, Kazushi Shigeno, Hiroaki Shiina, Mikio Igawa
Journal: Cancer Research (2004)

Recently, survival benefit by chemotherapy using paclitaxel (PTX) and the induction of thymidine phosphorylase (TP) by PTX have been reported in several solid tumors. On the other hand, TP confers antiapoptotic effect on tumor cells through inhibition of caspase-8 activation in vitro. On the basis of these previous observations, we hypothesized that (a) TP can be induced after PTX treatment in human prostate cancer (PC) and (b) blockade of PTX-induced TP expression can enhance the apoptotic processes in human PC cells. PTX was used to find TP expression in all eight hormone-refractory PC cases after chemotherapy; however, cleaved caspase-8 was not expressed after chemotherapy in the six hormone-refractory PC cases with strong TP expression. In PC cell lines (PC-3, DU 145, and LNCaP), TP expression after PTX treatment was clearly up-regulated in a dose-dependent manner. Cell viability of PC cell lines treated with PTX and TP antisense was significantly reduced in a time-dependent and dose-dependent manner compared with the PTX treatment alone. Likewise, apoptotic index of PC cells treated with PTX and TP antisense was significantly increased in comparison with PTX alone. After complete blockade of PTX-induced TP translation by TP antisense transfection, cleaved form of caspase-3 and poly(ADP-ribose) polymerase was increased, and this exaggeration of apoptosis also ran parallel with caspase-8 activation in a PTX dose-dependent manner. However, in PC cell lines treated with TP antisense alone, neither caspase-3 nor poly(ADP-ribose) polymerase was cleaved despite caspase-8 activation. These results indicate that PTX-induced TP up-regulation is associated with decreased caspase-8 activation. This study is the first report showing that blockade of PTX-induced TP expression could exaggerate the processing of apoptosis in PC cells treated with PTX. Our results provide preclinical evidence that TP could be a new molecular target for enhancing the potency of PTX-mediated apoptosis in PC cells.
IMMUNOLOGICAL STUDIES IN RELATION TO THE SUPRARENAL GLAND
Authors: J. Marmorston-Gottesman, David Perla
Journal: The Journal of Experimental Medicine (1928)

The effect of subcutaneous injections of varying amounts of epinephrine on the hemolysin formation of normal adult albino rats was studied. In one group of experiments the rats received 0.4 mg. per kilo per day in two injections during 3 days prior and 4 days subsequent to the injection of sheep cells. Another series received the same daily amounts but only during 4 days subsequent to the injection of antigen. A third series received the same daily amounts only during 1 day prior and 2 days subsequent to the injection of sheep cells. In a second group of experiments smaller amounts of epinephrine were given during 3 days prior and 4 days subsequent to the injection of antigen. The amounts used were 1/5th, 1/20th, 1/40th, and 1/60th the daily quantity of epinephrine injected in the first group of experiments.
HEPATITIS B IN MENTAL HANDICAP HOSPITALS
Authors: Jennifer Green, Pierre Van Damme, André Meheus, G.L. French, H. Tinsley, J.S. Tam, R.C.K. Chan, H.G.S. Murray, S.P. Tyrer, A.A. Codd, R.G. Thomson, M.D. Rawlins, P.F.W. James
Journal: The Lancet (1989)
Soluble CD23 (Fc epsilon RII) and interleukin 1 synergistically induce early human thymocyte maturation.
Authors: M D Mossalayi, J C Lecron, A H Dalloul, M Sarfati, J M Bertho, H Hofstetter, G Delespesse, P Debre
Journal: The Journal of Experimental Medicine (1990)

The ability of human thymus-derived CD7+CD2-CD3- cells to acquire mature T cell antigens was assessed. Purified CD7+ thymocytes were incubated with rIL-1, rIL-2, and/or recombinant soluble CD23 (rsCD23). Short-term incubation of these cells with only rsCD23 + rIL-1 induced mature T cell antigen expression on at least half of the cells. The induction of CD2 was functionally significant, as these cells became able to respond to CD2 triggering and could proliferate in response to IL-2. Possible sources of CD23 in the thymus are under investigation.
Acquired Resistance to EGFR Inhibitors Is Associated with a Manifestation of Stem Cell–like Properties in Cancer Cells
Authors: Kazuhiko Shien, Shinichi Toyooka, Hiromasa Yamamoto, Junichi Soh, Masaru Jida, Kelsie L. Thu, Shinsuke Hashida, Yuho Maki, Eiki Ichihara, Hiroaki Asano, Kazunori Tsukuda, Nagio Takigawa, Katsuyuki Kiura, Adi F. Gazdar, Wan L. Lam, Shinichiro Miyoshi
Journal: Cancer Research (2013)

Acquired resistance to EGF receptor (EGFR) tyrosine kinase inhibitor (TKI) is a critical problem in the treatment of lung cancer. Although several mechanisms have been shown to be responsible for acquired resistance, all mechanisms have not been uncovered. In this study, we investigated the molecular and cellular profiles of the acquired resistant cells to EGFR-TKI in EGFR-mutant lung cancers. Four EGFR-mutant cell lines were exposed to gefitinib by stepwise escalation and high-concentration exposure methods, and resistant sublines to gefitinib were established. The molecular profiles and cellular phenotypes of these resistant sublines were characterized. Although previously reported, alterations including secondary EGFR T790M mutation, MET amplification, and appearance of epithelial-to-mesenchymal transition (EMT) features were observed, these 2 drug-exposure methods revealed different resistance mechanisms. The resistant cells with EMT features exhibited downregulation of miRNA-200c by DNA methylation. Furthermore, the HCC827-derived subline characterized by the high-concentration exposure method exhibited not only EMT features but also stem cell-like properties, including aldehyde dehydrogenase isoform 1 (ALDH1A1) overexpression, increase of side-population, and self-renewal capability. Resistant sublines with stem cell-like properties were resistant to conventional chemotherapeutic agents but equally sensitive to histone deacetylase and proteasome inhibitors, compared with their parental cells. ALDH1A1 was upregulated in clinical samples with acquired resistance to gefitinib. In conclusion, our study indicates that the manner of EGFR-TKI exposure influences the mechanism of acquired resistance and the appearance of stem cell-like property with EGFR-TKI treatment.
Correction of the single breath carbon monoxide transfer factor in exercise for variations in alveolar oxygen pressure.
Authors: A H Kendrick, G Laszlo
Journal: Thorax (1994)

BACKGROUND--Carbon monoxide transfer factor (TLCO) varies inversely with the partial pressure of alveolar oxygen (PAO2). During exercise the PAO2 in the alveolar gas sample bag decreases so the TLCO increases more than would be expected from the effects of exercise alone. The effects of PAO2 on the estimation of TLCO during exercise have been investigated and studies have been performed to determine whether it is appropriate to standardise to a PAO2 of 16 kPa. METHODS--TLCO was estimated at rest and at a single level of exercise in six normal subjects using test gas mixtures of 0.3% carbon monoxide, 14% helium, and oxygen in three different percentages (17%, 21%, and 27%), remainder nitrogen. In three of the subjects an incremental exercise test with estimates of oxygen consumption (VO2) and cardiac frequency (fC) was also performed using a mixture containing 18% oxygen. RESULTS--TLCO decreased as levels of inspired oxygen increased. When standardised to a PAO2 of 16 kPa TLCO became independent of the inspired oxygen concentration. The significance of the curvilinear relations of TLCO and transfer coefficient to VO2 and fC improved. CONCLUSION--The single breath breath holding TLCO should be standardised to a PAO2 of 16 kPa when estimated during exercise.