tbuckley/cabot-search huggingface dataset:
Phase II trial of uracil and tegafur plus oral leucovorin: an effective oral regimen in the treatment of metastatic colorectal carcinoma.
Authors: R Pazdur, Y Lassere, V Rhodes, J A Ajani, S M Sugarman, Y Z Patt, D V Jones, A B Markowitz, J L Abbruzzese, B Bready
Journal: Journal of Clinical Oncology (1994)

PURPOSE To determine the activity and evaluate the toxicity of uracil and tegafur in a 4:1 molar concentration (UFT; Taiho Pharmaceutical Ltd, Tokyo, Japan) plus oral calcium leucovorin in the treatment of patients with advanced colorectal carcinoma. PATIENTS AND METHODS Forty-five patients with advanced, bidimensionally measurable metastatic colorectal carcinoma were enrolled onto the trial. None of the patients had received prior chemotherapy or biologic therapy for advanced disease. Patients received either 350 or 300 mg/m2/d UFT plus 150 mg/d leucovorin administered orally in divided daily doses every 8 hours for 28 days followed by a 7-day rest period. Response was evaluated after two courses of therapy. RESULTS Eighteen patients (three treated at 350 mg/m2/d and 15 at 300 mg/m2/d) had partial responses, and one patient had a complete response (response rate, 42.2%; 95% confidence interval, 28% to 58%). Responses were observed in sites that included liver (n = 18), lung (n = 6), and bone (n = 1). Of seven patients who received 350 mg/m2 UFT, prolonged grade 3 diarrhea developed in five; this resulted in a reduction in the UFT starting dose to 300 mg/m2/d in the remaining 38 patients. Grade 1 or 2 toxic effects included diarrhea, nausea, vomiting, abdominal cramping, anorexia, fatigue, oral mucositis, excessive lacrimation, and rash. Among 38 patients who received the 300-mg/m2/d dose, grade 3 toxic reactions included diarrhea (n = 4), vomiting (n = 2), abdominal cramping (n = 1), and fatigue (n = 2). CONCLUSION UFT 300 mg/m2/d plus oral leucovorin 150 mg/d administered for 28 days demonstrated significant activity against metastatic colorectal carcinoma. This oral regimen was well tolerated and devoid of the neutropenia or significant oral mucositis that complicates intravenous schedules of fluorouracil (5-FU) plus leucovorin. The results of this clinical trial will serve as the basis for a randomized phase III study to compare this oral schedule of UFT plus leucovorin with intravenous 5-FU plus leucovorin to determine the relative efficacy, impact on quality of life, and cost of the two regimens.
A revolution in drug discovery
Authors: N. Beeley
Journal: BMJ (2000)

<h3>ABSTRACT</h3> Paradoxically, oncogenes that drive cell cycle progression may also trigger pathways leading to senescence, thereby inhibiting the growth of tumorigenic cells. Along these lines, Y1 cells, which carry an amplification of Ras, become senescent after treatment with the mitogen FGF-2. To understand how FGF-2 promotes senescence, we profiled the epigenome, transcriptome, proteome, and phospho-proteome of Y1 cells stimulated with FGF-2. FGF-2 caused delayed acetylation of histone H4 and higher levels of H3K27me3. Sequencing analysis revealed decreased expression of cell cycle-related genes with concomitant loss of H3K27ac. In contrast, FGF-2 promoted the expression of p21, various cytokines, and MAPK-related genes. Nuclear envelope proteins, particularly lamin B1, displayed increased phosphorylation in response to FGF-2. Proteome analysis suggested alterations in cellular metabolism, as evident by modulated expression of enzymes involved in purine biosynthesis, tRNA aminoacylation, and the TCA cycle. Altogether, the response of Y1 cells to FGF-2 is consistent with oncogene-induced senescence. We propose that Y1 cells enter senescence due to deficient cyclin expression and high levels of p21, which may stem from DNA damage or TGFb signaling.
Hepatitis B-core antibody positive donors in liver transplantation and their impact on graft survival: Evidence from the Liver Match cohort study
Authors: Mario Angelico, Alessandra Nardi, Tania Marianelli, Lucio Caccamo, Renato Romagnoli, Giuseppe Tisone, Antonio D. Pinna, Alfonso W. Avolio, Stefano Fagiuoli, Patrizia Burra, Mario Strazzabosco, Alessandro Nanni Costa
Journal: Journal of Hepatology (2012)
Left Ventricular Ejection in Conscious Dogs:
Authors: MARK I. M. NOBLE, DIANA TRENCHARD, ABRAHAM GUZ
Journal: Circulation Research (1966)

The maximum acceleration of blood from the left ventricle was studied in conscious dogs in which ascending aortic blood flow was measured with an electromagnetic flowmeter; normal values at rest ranged between 5 and 11 g . The left ventricular myocardium was stimulated with intracoronary injections of calcium gluconate and isopropylnorepinephrine; maximum acceleration, peak flow, and the rate of rise of left ventricular pressure were the only parameters, measured or derived, that showed a consistent increase. The largest increase always occurred in maximum acceleration. Changes of posture, with the presumed associated changes in end diastolic dimensions, did not alter the maximum acceleration. The results suggested that maximum acceleration was closely related to the maximum force exerted by the heart in initial systole, and to the maximum initial velocity of shortening of left ventricular muscle. Temporary regional myocardial ischaemia produced larger and earlier decreases in maximum acceleration than in other parameters measured suggesting that it was a sensitive index of myocardial contractile function.
Gene Transfer of Heat-Shock Protein 70 Reduces Infarct Size In Vivo After Ischemia/Reperfusion in the Rabbit Heart
Authors: Shinji Okubo, Oliver Wildner, Maulik R. Shah, Jeya C. Chelliah, Michael L. Hess, Rakesh C. Kukreja
Journal: Circulation (2001)

Background —Heat-shock protein 70 (HSP 70) plays a role in myocardial protection. No studies are available, however, to show that direct gene transfer of HSP 70 reduces myocardial infarction in vivo. Methods and Results —Rabbit hearts were injected with vehicle or Ad.HSP70 at 3 sites (1.5×10 9 pfu, 50 μL/site) in the left ventricle (LV). Four days later, hearts were removed, and expression of inducible (HSP 70) and constitutive (HSC 70) proteins was measured in the LV and right ventricle (RV). Subsets of 5 to 7 animals in the vehicle-, Ad.lacZ-, and Ad.HSP70-treated groups were subjected to 30 minutes of ischemia and 3 hours of reperfusion. Infarct size was measured by tetrazolium staining. Increased expression of HSP 70 was observed in LV injected with Ad.HSP70 compared with vehicle-treated hearts. HSP 70 was undetectable in RV, the noninjected region of the heart. The expression of HSC 70 remained unchanged in hearts treated with vehicle or Ad.HSP70. Infarct size (% risk area) decreased to 24.5±2.8 in Ad.HSP70-injected hearts compared with 41.9±2.8 and 42.7±2.5 in the vehicle- and Ad.LacZ-treated hearts ( P &lt;0.01). The infarct size was not different between the vehicle- and Ad.LacZ-treated hearts ( P &gt;0.05). The risk areas (% of LV) were not different among the 3 groups, ie, 50.1±5.2, 47.7±3.5, and 53.3±2.9 in vehicle-, Ad.lacZ-, and Ad.HSP70-treated groups ( P &gt;0.05). Conclusions —Direct gene delivery of HSP 70 in vivo reduces the severity of ischemic injury in the heart.
A NEW GROWTH FACTOR REQUIRED BY CERTAIN HEMOLYTIC STREPTOCOCCI
Authors: D. W. Woolley
Journal: The Journal of Experimental Medicine (1941)

A new factor essential for the growth of hemolytic streptococci of Lancefield's group A has been demonstrated. It has not been possible to identify this factor with any other known growth factor. The active substance occurred in liver as a water-soluble, alcohol-insoluble, non-dialyzable material. It could be rendered dialyzable by treatment in strong alcohol with HCl, but not by many less drastic procedures. The most active concentrates prepared gave a maximal effect when approximately 10 gamma per cc. were added.
Maternal Care, Gene Expression, and the Transmission of Individual Differences in Stress Reactivity Across Generations
Authors: Michael J Meaney
Journal: Annual Review of Neuroscience (2001)

▪ Abstract Naturally occurring variations in maternal care alter the expression of genes that regulate behavioral and endocrine responses to stress, as well as hippocampal synaptic development. These effects form the basis for the development of stable, individual differences in stress reactivity and certain forms of cognition. Maternal care also influences the maternal behavior of female offspring, an effect that appears to be related to oxytocin receptor gene expression, and which forms the basis for the intergenerational transmission of individual differences in stress reactivity. Patterns of maternal care that increase stress reactivity in offspring are enhanced by stressors imposed on the mother. These findings provide evidence for the importance of parental care as a mediator of the effects of environmental adversity on neural development.
Free, soluble interleukin-17 protein during severe inflammation in human airways
Authors: M. Laan, L. Palmberg, K. Larsson, A. Lindén
Journal: European Respiratory Journal (2002)

Studies in rodents indicate that the cytokine, interleukin (IL)-17, links the activation of T-lymphocytes to neutrophilic inflammation. The aim of the current study was to determine whether free, soluble IL-17 protein can be released during severe inflammation in human airways. Fifteen healthy subjects were exposed to a swine confinement in order to induce severe inflammation characterized by high neutrophil numbers in the airways. Bronchoalveolar lavage (BAL) fluid was harvested 2 weeks prior to and 24 h after this exposure and the concentration of IL-17 protein was measured using an enzyme-linked immunosorbent assay. Total and cell differential counts were also performed in BAL fluid. Prior to exposure to the swine confinement, the concentration of IL-17 in BAL fluid was low (&lt;7.8 pg·mL −1 ) in 14 out of 15 subjects. However, exposure to the swine confinement caused an increase in IL-17 in 13 out of 15 subjects (median IL-17 concentration of 26.9 pg·mL −1 ). This exposure also caused a 51-fold increase in the concentration of neutrophils in BAL fluid. To conclude, free, soluble interleukin-17 protein can be released during severe inflammation characterized by high neutrophil numbers in human airways. The significance of interleukin-17 in inflammatory airway diseases therefore deserves further evaluation.
Hyposplenism in inflammatory bowel disease.
Authors: F P Ryan, R C Smart, C D Holdsworth, F E Preston
Journal: Gut (1978)

Splenic function was assessed in 35 patients with ulcerative colitis and 20 patients with Crohn's disease. Hyposplenism was diagnosed if there were Howell-Jolly bodies in the peripheral blood film or if there was prolongation of clearance from the peripheral blood of injected 51-Cr-labelled heat-damaged red blood cells. Thirteen of the patients with ulcerative colitis had hyposplenism as compared with only one patient with Crohn's disease. Conversely, heat-damaged red cell clearance values faster than the normal range were found in six out of the 20 patients with Crohn's disease. Four patients with hyposplenism and ulcerative colitis developed life-threatening septicaemia in the early postcolectomy period, two of these being further complicated by disseminated intravascular coagulation.
The B cell transcription program mediates hypomethylation and overexpression of key genes in Epstein-Barr virus-associated proliferative conversion
Authors: Henar Hernando, Claire Shannon-Lowe, Abul B Islam, Fatima Al-Shahrour, Javier Rodríguez-Ubreva, Virginia C Rodríguez-Cortez, Biola M Javierre, Cristina Mangas, Agustín F Fernández, Maribel Parra, Henri-Jacques Delecluse, Manel Esteller, Eduardo López-Granados, Mario F Fraga, Nuria López-Bigas, Esteban Ballestar
Journal: Genome biology (2013)

Epstein-Barr virus (EBV) infection is a well characterized etiopathogenic factor for a variety of immune-related conditions, including lymphomas, lymphoproliferative disorders and autoimmune diseases. EBV-mediated transformation of resting B cells to proliferating lymphoblastoid cells occurs in early stages of infection and is an excellent model for investigating the mechanisms associated with acquisition of unlimited growth.We investigated the effects of experimental EBV infection of B cells on DNA methylation profiles by using high-throughput analysis. Remarkably, we observed hypomethylation of around 250 genes, but no hypermethylation. Hypomethylation did not occur at repetitive sequences, consistent with the absence of genomic instability in lymphoproliferative cells. Changes in methylation only occurred after cell divisions started, without the participation of the active demethylation machinery, and were concomitant with acquisition by B cells of the ability to proliferate. Gene Ontology analysis, expression profiling, and high-throughput analysis of the presence of transcription factor binding motifs and occupancy revealed that most genes undergoing hypomethylation are active and display the presence of NF-κB p65 and other B cell-specific transcription factors. Promoter hypomethylation was associated with upregulation of genes relevant for the phenotype of proliferating lymphoblasts. Interestingly, pharmacologically induced demethylation increased the efficiency of transformation of resting B cells to lymphoblastoid cells, consistent with productive cooperation between hypomethylation and lymphocyte proliferation.Our data provide novel clues on the role of the B cell transcription program leading to DNA methylation changes, which we find to be key to the EBV-associated conversion of resting B cells to proliferating lymphoblasts.
British psychiatry and its discontents – my experience
Authors: Robin Eastwood
Journal: Journal of the Royal Society of Medicine (2010)

I am impressed by the review by Brian Cooper of psychiatry in Britain.1 He is an erstwhile colleague of mine. As a Professor of Psychiatric Epidemiology he gave it forensic attention. I have been in psychiatry since 1964, and have been an academic in London, Hobart, Toronto, and St Louis. Latterly, I have been a clinician in Plymouth. I have to say that my English experience in recent years has been disappointing and unexciting. Professor Cooper talks of the decline of psychiatry as a medical career and he is absolutely right. As said, it is not recruiting sufficient British graduates. Furthermore, the situation is becoming unacceptable as the subject is thought of by some as an odd specialty. However, before all is lost we need to remember certain epidemiological facts. One in five people in the UK and other countries will develop an affective disorder (anxiety and depression) during their lifetimes; and the World Health Organization has predicted that by 2020 depressive illness will be the commonest medical condition in the world. So let us get serious.
Association of polymorphisms in the peroxisome proliferator-activated receptor gene and osteoarthritis of the knee
Authors: S Cheng, H Afif, J Martel-Pelletier, M Benderdour, J-P Pelletier, G Hilal, P Haraoui, J-P Raynauld, D Choquette, H Fahmi
Journal: Annals of the Rheumatic Diseases (2006)

<b>Objectives:</b> To study the association between two common polymorphisms in the peroxisome proliferator-activated receptor γ (<i>PPARγ</i>) gene and susceptibility to, and severity of, osteoarthritis in a French-Canadian population. <b>Methods:</b> Genomic DNA was obtained from 172 patients with osteoarthritis and 210 ethnically matched healthy controls. Genotyping for the polymorphisms in the <i>PPARγ</i> gene (Pro12Ala and C1431T) was carried out using polymerase chain reaction–restriction fragment length polymorphism. The standard Kellgren–Lawrence grading score and the French version of the Western Ontario and McMaster Universities Osteoarthritis Index were used to assess the radiological and functional severity of the disease. Estimated haplotypes were generated using the expectation maximisation algorithm. Genotype and allele frequencies were analysed using the χ<sup>2</sup> test. <b>Results:</b> Genotype and allele frequencies for either polymorphism in the <i>PPARγ</i> gene did not differ significantly between patients with osteoarthritis and controls. Moreover, no significant differences were observed after stratification of patients according to age at disease onset, radiological or functional severity. Similarly, haplotype analysis of both polymorphisms in the <i>PPARγ</i> gene showed no association of any haplotype with susceptibility to, or severity of, osteoarthritis. <b>Conclusion:</b> These findings suggest that the examined polymorphisms in the <i>PPARγ</i> gene do not contribute to susceptibility to, or severity of, osteoarthritis in the French-Canadian population.
Mechanisms of Resistance of Malaria Parasites to Antifolates
Authors: Aric Gregson, Christopher V. Plowe
Journal: Pharmacological Reviews (2005)

Antifolate antimalarial drugs interfere with folate metabolism, a pathway essential to malaria parasite survival. This class of drugs includes effective causal prophylactic and therapeutic agents, some of which act synergistically when used in combination. Unfortunately, the antifolates have proven susceptible to resistance in the malaria parasite. Resistance is caused by point mutations in dihydrofolate reductase and dihydropteroate synthase, the two key enzymes in the folate biosynthetic pathway that are targeted by the antifolates. Resistance to these drugs arises relatively rapidly in response to drug pressure and is now common worldwide. Nevertheless, antifolate drugs remain first-line agents in several sub-Saharan African countries where chloroquine resistance is widespread, at least partially because they remain the only affordable, effective alternative. New antifolate combinations that are more effective against resistant parasites are being developed and in one case, recently introduced into use. Combining these antifolates with drugs that act on different targets in the parasite should greatly enhance their effectiveness as well as deter the development of resistance. Molecular epidemiological techniques for monitoring parasite drug resistance may contribute to development of strategies for prolonging the useful therapeutic life of this important class of drugs.
Spontaneous massive haemothorax in von Recklinghausen's disease.
Authors: A J Larrieu, S A Hashimoto, P Allen
Journal: Thorax (1982)

Spontaneous massive intrathoracic bleeding is infrequent and usually secondary to pulmonary infarction, arteriovenous fistula, neoplasm, ruptured aortic aneurysm, rupture of pleural adhesions, and, rarely, endometriosis of the pleura.1We wish to document another cause of spontaneous massive haemothorax in a patient with disseminated neurofibromatosis (von Recklinghausen's disease).Bleeding was from a vascular Schwannoma in the right posterior mediastinum.There is only one other published compar- able patient with this type of exsanguinating haemo- thorax.2
African-American and Hispanic ethnicities, renal involvement and obesity predispose to hypertension in systemic lupus erythematosus: results from LUMINA, a multiethnic cohort (LUMINAXLV)
Authors: S. Chaiamnuay, A. M Bertoli, J. M Roseman, G. McGwin, M. Apte, S. Duran, L. M Vila, J. D Reveille, G. S Alarcon
Journal: Annals of the Rheumatic Diseases (2006)

To examine the predictors of the occurrence of hypertension in a large multiethnic US cohort.There were 614 patients with systemic lupus erythematoses (SLE; > or = 4 American College of Rheumatology revised criteria) with < or = 5 years of disease duration at entry into the cohort (T0) and of Hispanic (Texan or Puerto Rican), African-American or Caucasian ethnicity. T0 variables were compared between patients who did and did not develop hypertension (blood pressure > or = 140/90 mm Hg on at least two occasions and/or the use of antihypertensive drugs) after T0. Significant and clinically relevant variables were then examined by a stepwise logistic regression model.A total of 379 patients without hypertension at T0 were included (patients who developed hypertension prior to SLE diagnosis (n = 126) or before T0 (n = 109) were excluded). Predictors of hypertension were African-American and Texan-Hispanic ethnicities, renal involvement and a higher body mass index.Traditional cardiovascular risk factors, disease-related factors and ethnicity play a role in the occurrence of hypertension in patients with SLE. Controlling renal involvement and optimising body weight may prevent the occurrence of hypertension.
Heterozygous and Homozygous Factor H Deficiencies Associated with Hemolytic Uremic Syndrome or Membranoproliferative Glomerulonephritis
Authors: Marie-Agnès Dragon-Durey, Véronique Frémeaux-Bacchi, Chantal Loirat, Jacques Blouin, Patrick Niaudet, Georges Deschenes, Paul Coppo, Wolf Herman Fridman, Laurence Weiss
Journal: Journal of the American Society of Nephrology (2004)

ABSTRACT. Factor H (FH) is the major regulatory protein of the complement alternative pathway, with a structure consisting of a tandem array of 20 homologous units, called short consensus repeats (SCR). Reported are 16 FH-deficient patients. Among six patients with homozygous deficiency, four presented with membranoproliferative glomerulonephritis, and two with atypical hemolytic uremic syndrome (HUS). The ten other patients had heterozygous FH deficiency and developed atypical HUS. HUS onset occurred from birth to midadulthood, and disease progression was variable. Four children with homozygous or heterozygous FH deficiency and HUS underwent renal transplantation, which was successful in three but failed as a result of recurrence of HUS in one patient. All but one patient exhibited alternative pathway-mediated complement consumption, with no detectable FH antigenic levels or with 50% immunochemical or functional FH levels in the case of complete or partial deficiency, respectively. The molecular mechanisms of the deficiency were documented in all cases by exon-specific sequencing analysis. These mechanisms included nucleotide substitutions, insertion, or deletion located in SCR 2, 7, 11, 13, 15, and 20, leading to an amino acid substitution or to a stop codon. This report emphasizes the variability in the clinical progression of kidney diseases associated with FH deficiencies. Genetic analysis reveals the molecular abnormalities associated with FH deficiencies to be polymorphous.