tbuckley/cabot-search huggingface dataset:
Chemopreventive Effect of Silymarin on Liver Pathology in HBV X Protein Transgenic Mice
Authors: Yi-Fang Wu, Shu-Ling Fu, Cheng-Heng Kao, Chu-Wen Yang, Chao-Hsiung Lin, Ming-Ta Hsu, Ting-Fen Tsai
Journal: Cancer Research (2008)

Abstract There are currently limited therapeutic regimens available for effective treatment of hepatocellular carcinoma (HCC). Silymarin is a naturally derived polyphenolic antioxidant with hepatoprotective properties and is very widely used in clinical application; however, effect of silymarin on spontaneous HCC has not been studied. Silymarin was evaluated for its efficacy against spontaneous carcinogenesis using the HBV X protein (HBx) transgenic model. Silymarin was p.o. given to the HBx transgenic mice from 4 to 6 weeks of age. Our data indicated that silymarin has therapeutic effects on the early stages of liver damage, reversing fatty changes and recovering liver histopathology in a dose-dependent manner. To study the chemopreventive effects on the later stages of carcinogenesis, the mice at 13 months were split into a precancerous group and a group with significant liver carcinogenesis. After silymarin was given to the precancerous mice from 13 to 16 months of age, in contrast to an 80% incidence of HCC development in the untreated transgenic mice, no HCC was detected in any of these mice. Nonetheless, small hyperplastic nodules were detected in 86% of these precancerous mice. In the second group with notable HCC, silymarin was unable to block cancer progression. Although silymarin did not affect HBx expression, intracellular reactive oxygen species levels were decreased, cell proliferation was stimulated, and hepatocyte ultrastructure was found to significantly recover. In conclusion, silymarin exerts beneficial effects on the early stages of liver pathogenesis, preventing and delaying liver carcinogenesis. This drug should be considered as a potential chemopreventive agent for HBV-related hepatocarcinogenesis. [Cancer Res 2008;68(6):2033–42]
Long-term follow-up of an age-adapted C5R protocol followed by radiotherapy in 99 newly diagnosed primary CNS lymphomas: a prospective multicentric phase II study of the Groupe d’Etude des Lymphomes de l’Adulte (GELA)
Authors: H. Ghesquières, C. Ferlay, C. Sebban, D. Perol, A. Bosly, O. Casasnovas, O. Reman, B. Coiffier, H. Tilly, P. Morel, E. Van den Neste, P. Colin, C. Haioun, P. Biron, J.-Y. Blay
Journal: Annals of Oncology (2009)
Multicolor microRNA FISH effectively differentiates tumor types
Authors: Neil Renwick, Pavol Cekan, Paul A. Masry, Sean E. McGeary, Jason B. Miller, Markus Hafner, Zhen Li, Aleksandra Mihailovic, Pavel Morozov, Miguel Brown, Tasos Gogakos, Mehrpouya B. Mobin, Einar L. Snorrason, Harriet E. Feilotter, Xiao Zhang, Clifford S. Perlis, Hong Wu, Mayte Suárez-Fariñas, Huichen Feng, Masahiro Shuda, Patrick S. Moore, Victor A. Tron, Yuan Chang, Thomas Tuschl
Journal: Journal of Clinical Investigation (2013)

MicroRNAs (miRNAs) are excellent tumor biomarkers because of their cell-type specificity and abundance. However, many miRNA detection methods, such as real-time PCR, obliterate valuable visuospatial information in tissue samples. To enable miRNA visualization in formalin-fixed paraffin-embedded (FFPE) tissues, we developed multicolor miRNA FISH. As a proof of concept, we used this method to differentiate two skin tumors, basal cell carcinoma (BCC) and Merkel cell carcinoma (MCC), with overlapping histologic features but distinct cellular origins. Using sequencing-based miRNA profiling and discriminant analysis, we identified the tumor-specific miRNAs miR-205 and miR-375 in BCC and MCC, respectively. We addressed three major shortcomings in miRNA FISH, identifying optimal conditions for miRNA fixation and ribosomal RNA (rRNA) retention using model compounds and high-pressure liquid chromatography (HPLC) analyses, enhancing signal amplification and detection by increasing probe-hapten linker lengths, and improving probe specificity using shortened probes with minimal rRNA sequence complementarity. We validated our method on 4 BCC and 12 MCC tumors. Amplified miR-205 and miR-375 signals were normalized against directly detectable reference rRNA signals. Tumors were classified using predefined cutoff values, and all were correctly identified in blinded analysis. Our study establishes a reliable miRNA FISH technique for parallel visualization of differentially expressed miRNAs in FFPE tumor tissues.
Defective NKT cell development in mice and humans lacking the adapter SAP, the X-linked lymphoproliferative syndrome gene product
Authors: Benoit Pasquier, Luo Yin, Marie-Claude Fondanèche, Francis Relouzat, Coralie Bloch-Queyrat, Nathalie Lambert, Alain Fischer, Geneviève de Saint-Basile, Sylvain Latour
Journal: The Journal of Experimental Medicine (2005)

SAP is an adaptor protein expressed in T cells and natural killer cells. It plays a critical role in immunity, as it is mutated in humans with X-linked lymphoproliferative syndrome (XLP), a fatal immunodeficiency characterized by an abnormal response to Epstein-Barr virus (EBV) infection. SAP interacts with the SLAM family receptors and promotes transduction signal events by these receptors through its capacity to recruit and activate the Src kinase FynT. Because it has been previously established that FynT is selectively required for the development of NKT cells, we examined NKT cells in SAP-deficient mice and in humans with XLP. In the absence of SAP, the development of NKT cells is severely impaired both in mice and in humans. These results imply that SAP is a potent regulator of NKT cell development. They also identify for the first time a defect in NKT cells associated with a human primary immunodeficiency, revealing a potential role of NKT cells in the immune response to EBV.
Nuclear Receptors and Their Selective Pharmacologic Modulators
Authors: Thomas P. Burris, Laura A. Solt, Yongjun Wang, Christine Crumbley, Subhashis Banerjee, Kristine Griffett, Thomas Lundasen, Travis Hughes, Douglas J. Kojetin
Journal: Pharmacological Reviews (2013)

Nuclear receptors are ligand-activated transcription factors and include the receptors for steroid hormones, lipophilic vitamins, sterols, and bile acids. These receptors serve as targets for development of myriad drugs that target a range of disorders. Classically defined ligands that bind to the ligand-binding domain of nuclear receptors, whether they are endogenous or synthetic, either activate receptor activity (agonists) or block activation (antagonists) and due to the ability to alter activity of the receptors are often termed receptor "modulators." The complex pharmacology of nuclear receptors has provided a class of ligands distinct from these simple modulators where ligands display agonist/partial agonist/antagonist function in a tissue or gene selective manner. This class of ligands is defined as selective modulators. Here, we review the development and pharmacology of a range of selective nuclear receptor modulators.
Identification of a Novel Tumor Suppressor Gene <i>p34</i> on Human Chromosome 6q25.1
Authors: Min Wang, Haris G. Vikis, Yian Wang, Dongmei Jia, Daolong Wang, Laura J. Bierut, Joan E. Bailey-Wilson, Christopher I. Amos, Susan M. Pinney, Gloria M. Petersen, Mariza de Andrade, Ping Yang, Jonathan S. Wiest, Pamela R. Fain, Ann G. Schwartz, Adi Gazdar, John Minna, Colette Gaba, Henry Rothschild, Diptasri Mandal, Elena Kupert, Daniela Seminara, Yan Liu, Avinash Viswanathan, Ramaswamy Govindan, Marshall W. Anderson, Ming You
Journal: Cancer Research (2007)

Abstract In this study, we observed loss of heterozygosity (LOH) in human chromosomal fragment 6q25.1 in sporadic lung cancer patients. LOH was observed in 65% of the 26 lung tumors examined and was narrowed down to a 2.2-Mb region. Single-nucleotide polymorphism (SNP) analysis of genes located within this region identified a candidate gene, termed p34. This gene, also designated as ZC3H12D, C6orf95, FLJ46041, or dJ281H8.1, carries an A/G nonsynonymous SNP at codon 106, which alters the amino acid from lysine to arginine. Nearly 73% of heterozygous lung cancer tissues with LOH and the A/G SNP also exhibited loss of the A allele. In vitro clonogenic and in vivo nude mouse studies showed that overexpression of the A allele exerts tumor suppressor function compared with the G allele. p34 is located within a recently mapped human lung cancer susceptibility locus, and association of the p34 A/G SNP was tested among these families. No significant association between the less frequent G allele and lung cancer susceptibility was found. Our results suggest that p34 may be a novel tumor suppressor gene involved in sporadic lung cancer but it seems not to be the candidate familial lung cancer susceptibility gene linked to chromosomal region 6q23-25. [Cancer Res 2007;67(1):93–9]
CCl4−induced toxicity in isolated hepatocytes: The importance of direct solvent injury
Authors: Marc L. Berger, Harshika Bhatt, Burton Combes, Ronald W. Estabrook
Journal: Hepatology (1986)

CCl 4 is proposed to induce cellular injury through its metabolites that are generated by a cytochrome P–450 dependent step. These free radical products can interact with membrane structures, thereby generating lipid peroxides. The latter process has been implicated as a major mechanism of CCl 4 hepatoxicity, although this relationship has been difficult to demonstrate when using isolated hepatocyte preparations. This report demonstrates that there are at least two mechanisms by which CCl 4 induces injury in isolated hepatocytes. One occurs within minutes of exposure to CCl 4 and is characterized by modest malondialdehyde formation and no decline in cellular–reduced glutathione. SKF 525A, metyrapone and promethazine did not protect against this early damage. A second phase of damage, evident particularly after 3 hr, is characterized by a marked increase in malondialdehyde formation, a fall in cellular glutathione and substantial further cellular damage. These changes could be moderated by the cytochrome P–450 inhibitors and promethazine, and antioxidant. Further examination of the initial phase of damage reveals an immediate dose–related inhibition of O 2 consumption. This could not be prevented by SKF 525A or metyrapone and was associatedwith loss of ability to stimulate mitochondrial respiration with dinitrophenol. Rapid recovery to initial O 2 consumption rates occurred with time as CCl 4 evaporated from the incubation system. This was associated with a partial return of dinitrophenol stimulation of mitochondrial O 2 consumption despite significant glutamate dehydrogenase release. A portion of this recovery could be inhibited by SKF 525A, suggesting that some O 2 consumption was due to CCl 4 metabolism and ensuing lipid peroxidation. These data suggest that early CCl 4 toxicity is adirect consequence of its solvent properties and is partially reversible; subsequent damage may be mediated by lipid peroxidation. This solvent injury has not been previously recognized and may have relevance not only to a reversible toxicityas demonstrated with isolated hepatocytes but also in vivo as well.
Falls and fractures services in UK are "unacceptable," audit concludes
Authors: A. O'Dowd
Journal: BMJ (2011)

Wide variation in the quality and approach of UK services for dealing with falls and fractures means that patients are poorly served, says a major national clinical audit.

In light of the audit, the emerging GP commissioning consortiums have been urged to use a government package for preventing falls and fractures among elderly people, published in 2009, to improve services.

The audit, published on 18 May, says that the variation in quality of NHS services for care and prevention of falls and fractures is “unacceptable.” A key problem, it says, is that in many areas there is a large gap between what NHS organisations claim to provide, in terms of commissioning, protocols, or structure of services, and what clinical audit shows is actually provided.

Elderly patients …
Amyloidosis in the rheumatic diseases.
Authors: V Dhillon, P Woo, D Isenberg
Journal: Annals of the Rheumatic Diseases (1989)

ReviewAmyloidosis in the rheumatic diseases Amyloidosis is a heterogeneous group of diseases with different clinical manifestations but characte- rised by the histological finding of amyloid deposits.Amyloid is a dense insoluble waxy substance found extracellularly, disrupting the structure and function of vital organs.This review focuses on the amyloido- sis that complicates rheumatic diseases (and other chronic inflammatory diseases)-reactive systemic amyloidosis.The protein subunit of reactive amy- loid is termed amyloid A (AA).Reactive amyloidosis reduces the prognosis of patients, with death often occurring from renal failure.It is thus important to be aware of which rheumatic diseases are likely to be complicated by amyloidosis and of newer methods of diagnosis.on July 12,
Changes in Effective Regurgitant Orifice Throughout Systole in Patients With Mitral Valve Prolapse
Authors: Maurice Enriquez-Sarano, Lawrence J. Sinak, A. Jamil Tajik, Kent R. Bailey, James B. Seward
Journal: Circulation (1995)

Background In patients with mitral valve prolapse, spontaneous changes of the effective regurgitant orifice during systole are not well documented. Such changes can now be analyzed by use of the proximal isovelocity surface area method, but the changes raise concern about the reliability of this method for assessing overall severity of regurgitation in these patients. Methods and Results In a prospective study of 42 patients with mitral valve prolapse, the effective mitral regurgitant orifice was calculated at four phases of systole (early, mid, mid-late, and late) as the ratio of regurgitant flow to regurgitant velocity by use of the proximal isovelocity surface area method. Throughout systole, the effective regurgitant orifice increased significantly, from 32±27 mm 2 in early systole to 41±27 in midsystole, 55±30 in mid-late systole, and 107±66 mm 2 during late systole ( P &lt;.0001). Phasic regurgitant volume increased from early to mid-late systole but decreased in late systole. For quantitation of the overall effective regurgitant orifice, four approaches using the proximal isovelocity surface area were compared with simultaneously performed quantitative Doppler echocardiography (54±30 mm 2 ) and quantitative two-dimensional echocardiography (51±29 mm 2 ). All correlations were good ( r &gt;.95), but overestimation was considerable when the largest flow convergence was used (70±39 mm 2 ; both P &lt;.0001), significant when the simple mean of the four phases was used (59±36 mm 2 ; P =.005 and P =.0007, respectively), mild when a weighted mean of the four phases was used (55±33 mm 2 ; P =.41 and P =.01, respectively), and no overestimation was observed when the effective regurgitant orifice calculated at maximum regurgitant velocity was used (54±30 mm 2 ; P =.29 and P =.17, respectively). Conclusions Phasic changes of mitral regurgitation are observed in patients with mitral valve prolapse. The effective regurgitant orifice increases throughout systole. Regurgitant volume also increases initially but tends to decrease in late systole. These changes can lead to overestimation of the overall degree of regurgitation, but properly timed measurements made by use of the proximal isovelocity surface area method allow an accurate estimation of the overall effective regurgitant orifice.
Resampling the N9741 Trial to Compare Tumor Dynamic Versus Conventional End Points in Randomized Phase II Trials
Authors: Manish R. Sharma, Elizabeth Gray, Richard M. Goldberg, Daniel J. Sargent, Theodore G. Karrison
Journal: Journal of Clinical Oncology (2014)

The optimal end point for randomized phase II trials of anticancer therapies remains controversial. We simulated phase II trials by resampling patients from N9741, a randomized phase III trial of chemotherapy regimens for metastatic colorectal cancer, and compared the power of various end points to detect the superior therapy (FOLFOX [infusional fluorouracil, leucovorin, and oxaliplatin] had longer overall survival than both IROX [irinotecan plus oxaliplatin] and IFL [irinotecan and bolus fluorouracil plus leucovorin]).Tumor measurements and progression-free survival (PFS) data were obtained for 1,471 patients; 1,002 had consistently measured tumors and were resampled (5,000 replicates) to simulate two-arm, randomized phase II trials with α = 0.10 (one sided) and 20 to 80 patients per arm. End points included log ratio of tumor size at 6, 12, and 18 weeks relative to baseline; time to tumor growth (TTG), estimated using a nonlinear mixed-effects model; and PFS. Arms were compared using rank sum tests for log ratio and TTG and a log-rank test for PFS.For FOLFOX versus IFL, TTG and PFS had similar power, with both exceeding the power of log ratio at 18 weeks; for FOLFOX versus IROX, TTG and log ratio at 18 weeks had similar power, with both exceeding the power of PFS. The best end points exhibited > 80% power with 60 to 80 patients per arm.TTG is a powerful end point for randomized phase II trials of cytotoxic therapies in metastatic colorectal cancer; it was either comparable or superior to PFS and log ratio at 18 weeks. Additional studies will be needed to clarify the potential of TTG as a phase II end point.
Asthma Symptoms and Rhinovirus In A Longitudinal Children's Cohort
Authors: Euan R. Tovey, S. Stelzer-Braid, B.G. Toelle, C.M. Willenborg, H.K. Reddel, F.L. Garden, A. Jaffe, R. Strachan, B.G. Oliver, Y.C. Belessis, G.B. Marks, W.D. Rawlinson
Journal: Journal of Allergy and Clinical Immunology (2014)
PERITHELIOMA SIMULATING PANCREATIC CYST
Authors: R. E. Smith
Journal: BMJ (1919)

PERITHELIOMA SIMULATING PANCREATIC CYST.[MAinT II D.A.H. without Symptoms.Patients diagnosed D.A.H. unaccompanied by symptoms are quite frequent, but may nearly always be dischlarged to full duty after a short period of training.The most common is the " youthful type of arrhythmia."In many cases these patients are admitted to hospital with a febrile illness, and during convalescence the heart is found to be irregular and the diagnosis is then changed to D.A.H. " by new disease supervening."The cases which exhibit this physiological irregularity most markedly have slower pulse rates thlan the normal 72.They are rapidly
The magnitude and breadth of hepatitis C virus–specific CD8+ T cells depend on absolute CD4+ T-cell count in individuals coinfected with HIV-1
Authors: Arthur Y. Kim, Georg M. Lauer, Kei Ouchi, Marylyn M. Addo, Michaela Lucas, Julian Schulze zur Wiesch, Joerg Timm, Melinda Boczanowski, Jared E. Duncan, Alysse G. Wurcel, Deborah Casson, Raymond T. Chung, Rika Draenert, Paul Klenerman, Bruce D. Walker
Journal: Blood (2005)
Reduced BMPR2 expression induces GM-CSF translation and macrophage recruitment in humans and mice to exacerbate pulmonary hypertension
Authors: Hirofumi Sawada, Toshie Saito, Nils P. Nickel, Tero-Pekka Alastalo, Jason P. Glotzbach, Roshelle Chan, Leila Haghighat, Gabriele Fuchs, Michael Januszyk, Aiqin Cao, Ying-Ju Lai, Vinicio de Jesus Perez, Yu-Mee Kim, Lingli Wang, Pin-I Chen, Edda Spiekerkoetter, Yoshihide Mitani, Geoffrey C. Gurtner, Peter Sarnow, Marlene Rabinovitch
Journal: The Journal of Experimental Medicine (2014)

Idiopathic pulmonary arterial hypertension (PAH [IPAH]) is an insidious and potentially fatal disease linked to a mutation or reduced expression of bone morphogenetic protein receptor 2 (BMPR2). Because intravascular inflammatory cells are recruited in IPAH pathogenesis, we hypothesized that reduced BMPR2 enhances production of the potent chemokine granulocyte macrophage colony-stimulating factor (GM-CSF) in response to an inflammatory perturbation. When human pulmonary artery (PA) endothelial cells deficient in BMPR2 were stimulated with tumor necrosis factor (TNF), a twofold increase in GM-CSF was observed and related to enhanced messenger RNA (mRNA) translation. The mechanism was associated with disruption of stress granule formation. Specifically, loss of BMPR2 induced prolonged phospho-p38 mitogen-activated protein kinase (MAPK) in response to TNF, and this increased GADD34–PP1 phosphatase activity, dephosphorylating eukaryotic translation initiation factor (eIF2α), and derepressing GM-CSF mRNA translation. Lungs from IPAH patients versus unused donor controls revealed heightened PA expression of GM-CSF co-distributing with increased TNF and expanded populations of hematopoietic and endothelial GM-CSF receptor α (GM-CSFRα)–positive cells. Moreover, a 3-wk infusion of GM-CSF in mice increased hypoxia-induced PAH, in association with increased perivascular macrophages and muscularized distal arteries, whereas blockade of GM-CSF repressed these features. Thus, reduced BMPR2 can subvert a stress granule response, heighten GM-CSF mRNA translation, increase inflammatory cell recruitment, and exacerbate PAH.
A selective endothelin-receptor antagonist to reduce blood pressure in patients with treatment-resistant hypertension: a randomised, double-blind, placebo-controlled trial
Authors: Michael A Weber, Henry Black, George Bakris, Henry Krum, Stuart Linas, Robert Weiss, Jennifer V Linseman, Brian L Wiens, Marshelle S Warren, Lars H Lindholm
Journal: The Lancet (2009)
Functional divergence of human genioglossus motor units with respiratory-related activity
Authors: S. Tsuiki, T. Ono, Y Ishiwata, T Kuroda
Journal: European Respiratory Journal (2000)

The genioglossus muscle has at least two types of motor unit with respiratory-related activity. Inspiratory motor units show phasic activity during inspiration, whereas inspiratory/expiratory motor units show phasic inspiratory activity superimposed on tonic activity. The purpose of this study was to investigate the physiological roles of these different genioglossus motor units. The unitary activities of 12 inspiratory and 12 inspiratory/expiratory motor units were recorded using fine-wire electrodes during quiet nasal breathing in eight normal adult males. The mean interspike interval and the SD of successive spikes were calculated for inspiratory and inspiratory/expiratory motor units, respectively. Scattergrams of the mean interspike interval versus SD were constructed for the two groups of motor units. The effects of changes in head position on the firing activity and the patterns of distribution of the mean interspike interval versus its SD were significantly different for inspiratory and inspiratory/expiratory motor units. These results suggest that the inspiratory and inspiratory/expiratory motor units have different functional roles in respiration; inspiratory motor units may be phasically active to counteract intraluminal negative pressure during inspiration, whereas inspiratory/expiratory motor units may be tonically active to maintain tongue posture.