tbuckley/cabot-search huggingface dataset:
Dissecting the Oncogenic and Tumorigenic Potential of Differentiated Human Induced Pluripotent Stem Cells and Human Embryonic Stem Cells
Authors: Zhumur Ghosh, Mei Huang, Shijun Hu, Kitchener D. Wilson, Devaveena Dey, Joseph C. Wu
Journal: Cancer Research (2011)

Pluripotent stem cells, both human embryonic stem cells (hESC) and human-induced pluripotent stem cells (hiPSC), can give rise to multiple cell types and hence have tremendous potential for regenerative therapies. However, the tumorigenic potential of these cells remains a great concern, as reflected in the formation of teratomas by transplanted pluripotent cells. In clinical practice, most pluripotent cells will be differentiated into useful therapeutic cell types such as neuronal, cardiac, or endothelial cells prior to human transplantation, drastically reducing their tumorigenic potential. Our work investigated the extent to which these differentiated stem cell derivatives are truly devoid of oncogenic potential. In this study, we analyzed the gene expression patterns from three sets of hiPSC- and hESC-derivatives and the corresponding primary cells, and compared their transcriptomes with those of five different types of cancer. Our analysis revealed a significant gene expression overlap of the hiPSC- and hESC-derivatives with cancer, whereas the corresponding primary cells showed minimum overlap. Real-time quantitative PCR analysis of a set of cancer-related genes (selected on the basis of rigorous functional and pathway analyses) confirmed our results. Overall, our findings suggested that pluripotent stem cell derivatives may still bear oncogenic properties even after differentiation, and additional stringent functional assays to purify these cells should be done before they can be used for regenerative therapy.
Differential Retention of Metabolic Genes Following Whole-Genome Duplication
Authors: J.-F. Gout, L. Duret, D. Kahn
Journal: Molecular Biology and Evolution (2009)

Classical studies in Metabolic Control Theory have shown that metabolic fluxes usually exhibit little sensitivity to changes in individual enzyme activity, yet remain sensitive to global changes of all enzymes in a pathway. Therefore, little selective pressure is expected on the dosage or expression of individual metabolic genes, yet entire pathways should still be constrained. However, a direct estimate of this selective pressure had not been evaluated. Whole-genome duplications (WGDs) offer a good opportunity to address this question by analyzing the fates of metabolic genes during the massive gene losses that follow. Here, we take advantage of the successive rounds of WGD that occurred in the Paramecium lineage. We show that metabolic genes exhibit different gene retention patterns than nonmetabolic genes. Contrary to what was expected for individual genes, metabolic genes appeared more retained than other genes after the recent WGD, which was best explained by selection for gene expression operating on entire pathways. Metabolic genes also tend to be less retained when present at high copy number before WGD, contrary to other genes that show a positive correlation between gene retention and preduplication copy number. This is rationalized on the basis of the classical concave relationship relating metabolic fluxes with enzyme expression.
Peripheral biomarkers of endometriosis: a systematic review
Authors: K. E. May, S. A. Conduit-Hulbert, J. Villar, S. Kirtley, S. H. Kennedy, C. M. Becker
Journal: Human Reproduction Update (2010)

Endometriosis is estimated to affect 1 in 10 women during the reproductive years. There is often delay in making the diagnosis, mainly due to the non-specific nature of the associated symptoms and the need to verify the disease surgically. A biomarker that is simple to measure could help clinicians to diagnose (or at least exclude) endometriosis; it might also allow the effects of treatment to be monitored. If effective, such a marker or panel of markers could prevent unnecessary diagnostic procedures and/or recognize treatment failure at an early stage. We used QUADAS (Quality Assessment of Diagnostic Accuracy Studies) criteria to perform a systematic review of the literature over the last 25 years to assess critically the clinical value of all proposed biomarkers for endometriosis in serum, plasma and urine. We identified over 100 putative biomarkers in publications that met the selection criteria. We were unable to identify a single biomarker or panel of biomarkers that have unequivocally been shown to be clinically useful. Peripheral biomarkers show promise as diagnostic aids, but further research is necessary before they can be recommended in routine clinical care. Panels of markers may allow increased sensitivity and specificity of any diagnostic test.
MRI criteria for dissemination in space in patients with clinically isolated syndromes: a multicentre follow-up study
Authors: Tijmen Korteweg, Mar Tintoré, Bernard Uitdehaag, Alex Rovira, Jette Frederiksen, David Miller, Kryshani Fernando, Massimo Filippi, Federica Agosta, Maria Rocca, Franz Fazekas, Christian Enzinger, Paul Matthews, Allyson Parry, Chris Polman, Xavier Montalban, Frederik Barkhof
Journal: The Lancet Neurology (2006)
Pathogenesis of shigella diarrhea. Serum anticytotoxin antibody response produced by toxigenic and nontoxigenic Shigella dysenteriae 1.
Authors: G T Keusch, M Jacewicz, M M Levine, R B Hornick, S Kochwa
Journal: Journal of Clinical Investigation (1976)

The serum antitoxin response to the cytotoxin contained in preparations of Shigella dysenteriae 1 (Shiga's bacillus) exotoxin was studied in natural and experimental infections of man. Natural infection resulted in the rapid appearance of toxin-neutralizing antibody, which disappeared some time between 9 and 18 mo after infection. Experimental infection of human volunteers provided the opportunity to study immunoglobulin class of the antibody in sera obtained serially from 7 to 50 days after infection. Neutralizing antibody was present only in the IgM fraction isolated by sucrose density gradient ultracentrifugation. This was confirmed by the use of solid-phase immunoaffinity chromatography. Even though the time-course and immunoglobulin class of the antitoxin antibody response was similar to that previously observed for anti-O polysaccharide antibody, the biologically active cytotoxin was shown to be highly susceptible to destruction by proteolytic enzymes. Sera from subjects infected with a virulent invasive chlorate-resistant Shiga mutant thought to be "nontoxigenic" also contained antibody which was similarly restricted to the IgM fraction. Biologically active cytotoxin was recovered when this mutant organism was grown in liquid media with controlled ion concentration. The mutant cytotoxin was heat labile, neutralized by antiwild-type cytotoxin antibody, and was separable by isoelectric focusing into two fractions with pI 7.2 and 6.1 like the wild-type toxin. These studies show that cytotoxin antigen is produced during in vivo infection with Shiga bacilli, resulting in a serum antitoxin antibody response. Without explanation is the restriction of the antibody to the IgM class and lack of evidence for an IgG antibody to the protein cytotoxin. Finally, mutant strain 725, previously designated "nontoxigenic," was shown to produce biologically active cytotoxin in vitro and, in experimentally infected volunteers, to result in a serum IgM antibody similar to that observed during infection with the wild-type strain.
Pharmacologic Suppression of Hepatic ATP-Binding Cassette Transporter 1 Activity in Mice Reduces High-Density Lipoprotein Cholesterol Levels but Promotes Reverse Cholesterol Transport
Authors: Shigenori Yamamoto, Hiroyuki Tanigawa, Xiaoyu Li, Yohei Komaru, Jeffrey T. Billheimer, Daniel J. Rader
Journal: Circulation (2011)

The role of hepatic ATP-binding cassette transporter 1 (ABCA1) in maintaining plasma high density lipoprotein cholesterol (HDL-C) levels is well established, but its role in reverse cholesterol transport (RCT) is unclear. Probucol is a compound that reduces HDL-C levels but also reduces atherosclerosis in animal models and xanthomas in humans. The aim of the present study was to test the hypothesis that probucol inhibits hepatic ABCA1 activity, thereby reducing HDL-C levels but promoting RCT from macrophages.Wild-type (WT) C57BL/6 mice and scavenger receptor class B type I (SR-BI) knockout mice were fed a chow diet containing 0.5% probucol or normal chow for 2 weeks. In WT mice, probucol, despite decreasing HDL-C by >80%, effectively maintained macrophage RCT. In SR-BI knockout mice, probucol also substantially reduced HDL-C but significantly increased macrophage RCT. Furthermore, probucol significantly enhanced the excretion of HDL-derived cholesterol into feces in both WT and SR-BI knockout mice. Probucol inhibited ABCA1-dependent cholesterol efflux from mouse primary hepatocytes, and this effect was shown to be responsible for the effect of probucol on increasing the fecal excretion of HDL-derived cholesterol in vivo.We demonstrate that pharmacological inhibition of hepatic ABCA1 activity with probucol reduced HDL-C levels but promoted RCT through diversion of HDL-derived cholesterol from efflux back into plasma instead to excretion in the bile. These results explain the beneficial effects of probucol on atherosclerosis and xanthomas despite its HDL-lowering effects and suggest that inactivation of hepatic ABCA1 leads to increased RCT despite reducing plasma HDL-C levels.
Reducing Adolescent Pregnancy Through School and Community-Based Education
Authors: Murray L. Vincent
Journal: JAMA (1987)

The resident population of the western portion of a South Carolina county has undergone a public health information and education intervention since October 1982. The purpose of the intervention has been to reduce the occurrence of unintended pregnancies among unmarried adolescents. Intervention messages are targeted at parents, teachers, ministers and representatives of churches, community leaders, and children enrolled in the public school system. The messages emphasize development of decision-making and communication skills, self-esteem enhancement, and understanding human reproductive anatomy, physiology, and contraception. The estimated rate of pregnancy ([live births plus fetal deaths plus induced abortions] per 1000 female population) for females aged 14 to 17 years in the county's western portion has declined remarkably since the intervention began, and the changes are statistically significant when compared with three sociodemographically similar counties and also with the eastern portion of the county.
PROLIFERATION OF B AND T CELLS IN MIXED LYMPHOCYTE CULTURES
Authors: Leif C. Andersson, Stig Nordling, Pekka Häyry
Journal: The Journal of Experimental Medicine (1973)

Electrophoretically fractionated CBA/Ca spleen T cells alone respond to allogeneic cells in one-way MLC and to PHA. They do not respond to E. coli LPS. B cells alone do not respond to allogeneic cells nor to PHA, but do respond to LPS. When karyotypically distinguishable syngeneic mixtures of T and B lymphocytes are stimulated with allogeneic cells, at the most 5% of mitoses on 5–9th culture day are of B cell origin. This indicates that B cells are not substantially recruited to proliferate in the MLC.
Pulmonary function involvement in scleroderma
Authors: Daniela Gologanu, Teodora Gartonea, Simona Caraiola, Doina Nitescu, Magda Parvu, Cristian Baicus, Razvan Ionescu
Journal: European Respiratory Journal (2013)

Scleroderma is a systemic disease characterized by a severe inflammatory process with exuberant fibrosis. The pulmonary involvement (interstitial disease and/or pulmonary hypertension) is one of the first causes of mortality and morbidity.

Aim: To describe the functional involvement of the pulmonary disease in scleroderma.

Subjects and methods: Scleroderma patients with pulmonary involvement who performed pulmonary function tests (spirometry, diffusion capacity DLco, pulmonary volumes), walking tests, chest X-ray and echocardiography in 2012.

Results: 24 patients were studied, mean age 52 years, 23 women; 9 had limited cutaneous scleroderma, 12 had interstitial radiologic involvement; 16 patients had exertional dyspnoea and 5 of them exercise desaturation.

Five patients had normal pulmonary function testing. Although the mean values were normal for volumes and flows (FVC 88%, FEV1 85%, TLC 84% of the predicted values), 8 patients had restriction. Mean DLco was 68.7% (range 44–101%); decrease of DLco was found in 19 patients (79%); in 11 of them this was the only resting functional abnormality. Among patients with diffusion capacity impairment, only 14 had exertional dyspnoea and only 9 had pulmonary radiologic abnormalities.

Echocardiography was performed in 15 patients and 2 of them had pulmonary hypertension with normal pulmonary volumes and impaired diffusion capacity.

Conclusion: Complex pulmonary function tests including DLco are necessary for scleroderma patients with pulmonary involvement. The DLco is abnormal in the majority of cases, even without exertional dyspnoea or restriction. The echocardiographic evaluation is useful even in patients with mild decrease in DLco, due to the worse prognosis of pulmonary hypertension.
Overexpression of the Mitochondrial Folate and Glycine–Serine Pathway: A New Determinant of Methotrexate Selectivity in Tumors
Authors: Alexei Vazquez, Philip M. Tedeschi, Joseph R. Bertino
Journal: Cancer Research (2012)

Previous studies have documented the roles of transport via the reduced folate carrier, retention via polyglutamylation, and increased levels of the target enzyme, dihydrofolate reductase in sensitivity to methotrexate. Recent studies have shown that the mitochondrial enzymes in the cellular metabolism of serine, folate, and glycine are overexpressed in a subset of human cancers and that their expression is required for tumor maintenance. In this Perspective article, we propose that the expression of mitochondrial enzymes in the metabolism of serine and glycine, in addition to those involved in folate metabolism, are determinants of the response to methotrexate. Furthermore, we show that myc activation in tumors is associated with upregulation of these enzymes. We propose that patients whose tumors show this phenotype will be sensitive to folate antagonists targeting thymidylate or purine biosynthesis.
Phase III Study of Gefitinib Compared With Intravenous Methotrexate for Recurrent Squamous Cell Carcinoma of the Head and Neck
Authors: J. Simon W. Stewart, Ezra E.W. Cohen, Lisa Licitra, Carla M.L. Van Herpen, Chonlakiet Khorprasert, Denis Soulieres, Pavel Vodvarka, Danny Rischin, Avgust M. Garin, Fred R. Hirsch, Marileila Varella-Garcia, Serban Ghiorghiu, Laura Hargreaves, Alison Armour, Georgina Speake, Alan Swaisland, Everett E. Vokes
Journal: Journal of Clinical Oncology (2009)

Purpose To compare survival in patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) treated with gefitinib 250 or 500 mg/day or standard methotrexate. Patients and Methods Four hundred eighty-six patients with recurrent SCCHN were randomly assigned to oral gefitinib 250 mg/day, gefitinib 500 mg/day, or methotrexate 40 mg/m 2 intravenously weekly. Primary end point was overall survival, secondary end points were objective response rate (ORR), safety, symptom improvement, and quality of life (QOL). Exploratory end points included association of efficacy with epidermal growth factor receptor gene copy number and other biomarkers. Results Neither gefitinib 250 nor 500 mg/day improved overall survival compared with methotrexate (hazard ratio [HR], 1.22; 95% CI, 0.95 to 1.57; P = .12; and HR, 1.12; 95% CI, 0.87 to 1.43; P = .39, respectively). In the gefitinib 250 mg/day, 500 mg/day, and methotrexate groups, respectively, median overall survival was 5.6, 6.0, and 6.7 months; ORRs (Response Evaluation Criteria in Solid Tumors) were 2.7%, 7.6% and 3.9%, with no statistically significant difference between either gefitinib arm and methotrexate. No unexpected adverse events were observed, except for tumor hemorrhage-type events with gefitinib (8.9%, gefitinib 250 mg/day; 11.4%, gefitinib 500 mg/day; 1.9%, methotrexate). QOL improvement rates (Functional Assessment of Cancer Therapy-Head &amp; Neck total score) were 13.4%, 18.0%, and 6.0% for gefitinib 250 mg/day, 500 mg/day, and methotrexate, respectively. Conclusion In patients with recurrent or metastatic SCCHN, while responses with gefitinib were seen, neither gefitinib 250 nor 500 mg/day improved overall survival compared with methotrexate. With the exception of tumor hemorrhage–type events with gefitinib, the adverse event profiles were generally consistent with those previously observed.
Communicating and Understanding the Purpose of Pediatric Phase I Cancer Trials
Authors: Melissa K. Cousino, Stephen J. Zyzanski, Amy D. Yamokoski, Rebecca A. Hazen, Justin N. Baker, Robert B. Noll, Susan R. Rheingold, J. Russell Geyer, Stewart C. Alexander, Dennis Drotar, Eric D. Kodish
Journal: Journal of Clinical Oncology (2012)

Quality informed consent should provide a clear understanding of the purpose of the research. Given the ethical challenges of pediatric phase I cancer trials, it is important to investigate physician-parent communication during informed consent conferences (ICCs) and parental understanding of the purpose of these studies.In the multisite Informed Consent in Pediatric Phase I Cancer Trials study, 85 ICCs for phase I research between June 2008 and May 2011 were directly observed, and 60 parents were subsequently interviewed. The scientific purpose was defined as composite understanding of drug safety, dose finding, and dose escalation. We determined the frequency with which physicians explained these and other phase I-related concepts during the ICC. Parent interviews were analyzed to determine understanding.The child was present at 83 of 85 ICCs. Only 32% of parents demonstrated substantial understanding of the scientific purpose of phase I cancer trials; 35% demonstrated little or no understanding. Parents of higher socioeconomic status and racial majority status were more likely to understand the scientific purpose. Factors associated with understanding included physician explanation of the goal of the applicable phase I protocol offered (explained in 85% of ICCs) and explanation of the dose cohorts (explained in 43% of ICCs). Physicians explained drug safety in 23% of ICCs, dose finding in 52% of ICCs, and dose escalation in 53% of ICCs.Many parents of children participating in phase I trials do not understand the purpose of these trials. Physician-parent communication about the purpose of phase I research is lacking during ICCs.
Effect of Intracardiac Blood on the Spatial Vectorcardiogram
Authors: Clifford V. Nelson, Peter W. Rand, Evangelakos T. Angelakos, Paul G. Hugenholtz
Journal: Circulation Research (1972)

Studies were done on dogs in vivo to determine the effect of intracardiac blood on the electrocardiogram. By exchange transfusions of packed cells or of Rheomacrodex, hematocrit was raised to over 70% or lowered to 16%. The electrical resistivity of the blood changed accordingly from control values of 150 ohm-cm to over 500 ohm-cm or to as low as 67 ohm-cm. The x-, y-, and z- vector leads were processed by analog computer. Computer output signals were: spatial dipole moment, M, vertical angle, V°, and horizontal angle, H°. Three peaks of M (M 1 ; M 2 , and M 3 ) were found at mean times of 29%, 42%, and 64% of QRS duration. Increases in blood resistivity to values near that of the myocardium caused M 1 to decrease to 33% and M 2 to 40% of control values, but M 3 rose to 125% of control values. These results are in accord with radial excitation for M 1 and M 2 and tangential excitation for M 3 . Decreases in hematocrit below control values caused opposite changes. Normal intracardiac blood causes an apparent increase of M 1 by a factor of 3 and of M 2 by 2.5 and a decrease in M 3 of about 25%.
Slower Treatment Response in Bipolar Depression Predicted by Lower Pretreatment Thyroid Function
Authors: Daniel P. Cole, Michael E. Thase, Alan G. Mallinger, Jair C. Soares, James F. Luther, David J. Kupfer, Ellen Frank
Journal: American Journal of Psychiatry (2002)

OBJECTIVE: Because treatment of the depressed phase of bipolar disorder is a clinical challenge and hypothyroidism is known to be associated with depression, the authors examined the relationship between pretreatment thyroid values and response to antidepressant treatment. It was hypothesized that subjects with lower thyroid function, even within the normal range, would have a poorer response to initial treatment. METHOD: The subjects were 65 patients in the depressed phase of bipolar I disorder who were enrolled in a larger ongoing study. A panel of thyroid measures, including thyroid-stimulating hormone (TSH), thyroxine, triiodothyronine resin uptake, and free thyroxine index (FTI), were determined before initiation of algorithm-guided treatment. The effect of each thyroid measurement on time to remission was estimated by using the Cox proportional hazards model. RESULTS: Both lower values of FTI and higher values of TSH were significantly associated with longer times to remission, i.e., slower response to treatment. Outcomes were relatively poor unless patients had FTI values above the median and TSH values below the median. Patients with this optimal profile experienced remission 4 months faster than the remainder of the study group. CONCLUSIONS: This study provides further evidence that patients with bipolar disorder are particularly sensitive to variations in thyroid function within the normal range. Our results suggest that nearly three-quarters of patients with bipolar disorder have a thyroid profile that may be suboptimal for antidepressant response. It remains to be seen whether pharmacological enhancement of thyroid function will facilitate recovery from bipolar depression.
SKELETAL DYNAMICS IN MAN MEASURED BY NONRADIOACTIVE STRONTIUM*
Authors: Eugene Eisenberg, Gilbert S. Gordan
Journal: Journal of Clinical Investigation (1961)

Skeletal dynamics were calculated by usual dilution formulas, using stable strontium as a tracer, in 25 normal subjects, 14 athletes, 26 patients with postmenopausal osteoporosis, 28 with primary hyperparathyroidism, 3 with hyperadrenocorticism 8 with acromegaly, 7 with thyrotoxicosis, 11 with urclithiasis, 5 with Paget's disease of bone. and 1 with vitamin D poisoning. The technic requires that 10 mEq of strontium gluconate be injected intravenously and blood and urine concentrations be measured for 4 to 6 days. In normal subjects the rapidly miscible pool was equivalent to 42.7 + 1.1 L of serum, turning over at a rate of 13.5 plus or minus 0.6 L daily, of which 3.9 + 0.2 L was excreted by the kidney and 9.6 + 0.4 L went to bone. Since only approximately 2.5% of the pool is excreted in the feces daily, fecal excretion was not measured routinely. Good reproducibility was found in 21 duplicate studies. Intense muscular exercise (athletes) was found to expand the pool greatly and to accelerate the rate of deposition in bone. Kinetically, two divergent types of osteoporosis were differentiated. A small pool and low rate of bone deposition were found in postmenopausal osteoporosis and Cushing's disease of long duration.more » The large pool and rapid rate of bone deposition in thyrotoxicosis was confirmed and also found in acromegaly. In these two, excessive bone resorption is postulated. Urinary excretion rate was excessive in Cushing's disease, thyrotoxicosis, and acromegaly. In hyperparathyroidism with clinically evident osteitis, expanded pools, greatly increased turnover, urinary excretion, and bone deposition rates were confirmed. In patients with normal roentgenographic appearance and phosphatase, bone involvement was shown by slight increase in bone deposition rate and microscopic foci of resorption on iliac crest biopsy. In seven patients without histological foci of resorption, the bone deposition rate was not increased. (auth)« less