tbuckley/cabot-search huggingface dataset:
Age-Related DNA Methylation Changes in Normal Human Prostate Tissues
Authors: Bernard Kwabi-Addo, Woonbok Chung, Lanlan Shen, Michael Ittmann, Thomas Wheeler, Jaroslav Jelinek, Jean-Pierre J. Issa
Journal: Clinical Cancer Research (2007)

Abstract Purpose: Prostate cancer is a leading cause of cancer death among the aging male population but the mechanism underlying this association is unclear. Aberrant methylation of promoter CpG islands is associated with silencing of genes and age-dependent methylation of several genes has been proposed as a risk factor for sporadic cancer. We examined the extent of gene methylation in pathologically normal human prostate as a function of age. Experimental Design: We used pyrosequencing to quantitatively analyze the methylation status of nine CpG islands in normal prostate tissue DNA from 45 organ donors and 45 patients who had undergone cystoprostatectomy for bladder cancer. We also analyzed 12 pairs of matched benign and prostate cancer tissue DNA from patients with prostate cancer. Results: Linear regression analysis revealed a significant increase in promoter methylation levels correlating with age for CpG islands at RARβ2 (r = 0.4; P &amp;lt; 0.0001), RASSF1A (r = 0.27; P = 0.01), GSTP1 (r = 0.59; P &amp;lt; 0.0001), NKX2-5 (r = 0.27; P = 0.008), and ESR1 (r = 0.244; P = 0.023) in the normal prostate tissue samples studied. A calculated average methylation (z score) at all nine CpG loci analyzed in the normal prostate tissues showed a strong correlation with age (r = 0.6; P &amp;lt; 0.001). Comparison of the methylation level for the matched benign and prostate cancer tissues from individual patients with prostate cancer showed significantly higher methylation in the prostate cancer tissue samples for RARβ2 (P &amp;lt; 0.001), RASSF1A (P = 0.005), GSTP1 (P &amp;lt; 0.001), NKX2-5 (P = 0.003), ESR1 (P = 0.016), and CLSTN1 (P = 0.01). Conclusions: Our findings show aberrant hypermethylation as a function of age in the normal prostate tissues. Such age-related methylation may precede and predispose to full-blown malignancy.
Mutant<i>PIK3CA</i>-Bearing Colon Cancer Cells Display Increased Metastasis in an Orthotopic Model
Authors: Xiao-Ning Guo, Ashwani Rajput, Rebecca Rose, Jennie Hauser, Alexander Beko, Karen Kuropatwinski, Charles LeVea, Robert M. Hoffman, Michael G. Brattain, Jing Wang
Journal: Cancer Research (2007)

Abstract Mutations in the PIK3CA gene are common in human cancers, including colon cancer. We compared two pairs of colon cancer cells (HCT116 and DLD1) bearing only the wild-type (WT) or mutant (MUT) PIK3CA allele for their survival capacity under stress conditions in vitro as well as their metastatic properties in an in vivo orthotopic model. When subjected to growth factor deprivation stress (GFDS), the MUT PIK3CA cells displayed resistance to GFDS-induced apoptosis relative to the WT cells. Phosphatidylinositol 3-kinase (PI3K) and its downstream effector AKT were constitutively activated during stress conditions in the MUT PIK3CA cells but not in the WT cells. The MUT cells showed hypersensitivity to PI3K inhibition. Moreover, the proapoptotic protein Bax was expressed at a very high level in the WT PIK3CA cells, whereas it was almost undetectable in the MUT cells. Inhibition of Bax expression by small interfering RNA protected the WT PIK3CA cells from GFDS-induced apoptosis, suggesting an important role of Bax in GFDS-induced apoptosis. These results indicated that the MUT PI3K confers resistance to GFDS-induced apoptosis and that the MUT cells are more dependent on the PI3K pathway for survival. In vivo studies showed that the MUT PIK3CA-bearing cells were more metastatic than the WT cells in an orthotopic model of colon cancer. Taken together, these results suggest that MUT PI3K imparts a more aggressive phenotype in colon cancer cells and could be a potential therapeutic target for treatment of colon cancer patients bearing PIK3CA mutations. [Cancer Res 2007;67(12):5851–8]
Management of Human Immunodeficiency Virus Infection in Advanced Age
Authors: Meredith Greene, Amy C. Justice, Harry W. Lampiris, Victor Valcour
Journal: JAMA (2013)

Importance-Human immunodeficiency virus (HIV)-positive patients treated with antiretroviral therapy now have increased life expectancy and develop chronic illnesses that are often seen in older HIV-negative patients.Objective-To address emerging issues related to aging with HIV.Screening older adults for HIV, diagnosis of concomitant diseases, management of multiple comorbid medical illnesses, social isolation, polypharmacy, and factors associated with end-of-life care are reviewed.Evidence Acquisition-Published guidelines and consensus statements were reviewed.PubMed and PsycINFO were searched between January 2000 and February 2013.Articles not appearing in the search that were referenced by reviewed articles were also evaluated.Findings-The population of older HIV-positive patients is rapidly expanding.It is estimated that by 2015 one-half of the individuals in the United States with HIV will be older than age 50.Older HIV-infected patients are prone to having similar chronic diseases as their HIV-negative counterparts, as well as illnesses associated with co-infections.Medical treatments associated with these conditions, when added to an antiretroviral regimen, increase risk for polypharmacy.Care of aging HIV-infected patients involves a need to balance a number of concurrent comorbid medical conditions.
Influence of Serotonin-Transporter-Linked Promoter Region Polymorphism on Platelet Activation in Geriatric Depression
Authors: E M Whyte, B G Pollock, W R Wagner, B H Mulsant, R E Ferrell, S Mazumdar, C F Reynolds
Journal: American Journal of Psychiatry (2001)

OBJECTIVE: Depression has been associated with increased platelet activation. Variations in the serotonin-transporter-linked promoter region (5-HTTLPR) polymorphism may influence the degree of activation. The authors examined the association among depression, platelet activation, and 5-HTTLPR genotype. METHOD: Elderly subjects with (N=61) and without (N=12) major depression were assessed for cognitive impairment, cardiovascular disease, and two indices of platelet activation. The depressed subjects were genotyped for the 5-HTTLPR polymorphism. RESULTS: The depressed subjects were older, were more cognitively impaired, and had higher platelet factor 4 and β-thromboglobulin levels; cardiovascular disease was minimal in both groups. In the depressed group, subjects with the 5-HTTLPR l/l genotype had significantly higher platelet factor 4 and β-thromboglobulin levels. CONCLUSIONS: Platelet activation is increased in elderly depressed patients, especially those with the 5-HTTLPR l/l genotype. This finding suggests how genetic differences may influence cardiovascular mortality in depressed patients with ischemic heart disease.
Multiple Viral Strategies of HTLV-1 for Dysregulation of Cell Growth Control
Authors: Mitsuaki Yoshida
Journal: Annual Review of Immunology (2001)

The human T cell leukemia virus-1 (HTLV-1) is a retrovirus that causes adult T cell leukemia (ATL) and neurological disorder, the tropical spastic paraparesis (HAM/TSP). The pathogenesis apparently results from the pleiotropic function of Tax protein, which is a key regulator of viral replication. Tax exerts (a) trans-activation and -repression of transcription of different sets of cellular genes through binding to groups of transcription factors and coactivators, (b) dysregulation of cell cycle through binding to inhibitors of CDK4/6, and (c) inhibition of some tumor suppressor proteins. These effects on a wide variety of cellular targets seem to cooperate in promoting cell proliferation. This is an effective viral strategy to amplify its proviral genome through replication of infected cells; ultimately it results in cell transformation and leukemogenesis.
Cortisone in Ulcerative Colitis
Authors: S. C. Truelove, L. J. Witts
Journal: BMJ (1955)

In a preliminary report (Truelove and Witts, 1954) we have given the immediate results of a controlled trial of cortisone in the treatment of chronic ulcerative colitis.In the present paper it is intended to fill in some of the details about the immediate results and to report on the subsequent progress of the patients.The trial was con- fined to typical cases of chronic ulcerative colitis which would normally be expected to require at least six weeks' treatment in hospital, and patients with regional colitis, ileitis, or proctitis were not included.A total of 213 patients received treatment.Of these, three have been rejected from the analysis of results for the following reasons: one patient proved to be suffering from carcinoma of the colon, one had had a colostomy, and in the third the records were inadequate.Of the remain- ing 210 patietts, 109 received cortisone and 101 received the dummy preparation.Diagnosis.-Thediagnosis was established by the following criteria: (1) History. (2)Character of stools.(3) Sigmoidoscopy (in very ill patients, proctoscopy was regarded as sufficient). (4)Barium enema, except when the patient was gravely ill.(5) Absence of known pathogens in the stools.
Interaction of verapamil and other calcium channel blockers with alpha 1- and alpha 2-adrenergic receptors.
Authors: H J Motulsky, M D Snavely, R J Hughes, P A Insel
Journal: Circulation Research (1983)

To determine the specificity of the previously demonstrated competition of verapamil with radioligand binding to alpha-adrenergic receptors, we examined the interaction of calcium channel blockers with alpha 1- and alpha 2-adrenergic receptors on several tissues. Verapamil competed for [3H] prazosin binding to alpha 1-adrenergic receptors and for [3H]yohimbine binding to alpha 2-adrenergic receptors in several tissues (human platelets, rat kidney and heart, and cultured muscle cells) with dissociation constants of 0.6-6 microM. The calcium channel blockers D600, D591, fendiline, and prenylamine--which are structural analogues of verapamil--also competed for [3H]yohimbine binding to human platelets. Two other calcium channel blockers, diltiazem and nifedipine, did not compete for [3H] yohimbine binding to human platelets or [3H]prazosin binding to membranes prepared from rat ventricles. We used [3H]nitrendipine binding to identify putative calcium channels on rat myocardial membranes. Nifedipine and verapamil blocked these [3H]nitrendipine-binding sites on ventricular membranes, but epinephrine and prazosin did not, indicating that the ventricular alpha 1 receptors and calcium channels are distinct. We found no specific [3H]nitrendipine binding to human platelets. We conclude that the interaction of verapamil with alpha-adrenergic receptors is not receptor subtype or tissue specific, that interaction with alpha-adrenergic receptors is not a property of all calcium channel blockers, and that the interaction of verapamil with alpha-adrenergic receptors and its interaction with calcium channels occur at at least two distinct sites.
Biased alternative polyadenylation in human tissues
Authors: Haibo Zhang, Ju Youn Lee, Bin Tian
Journal: Genome biology (2005)

Abstract Background Alternative polyadenylation is one of the mechanisms in human cells that give rise to a variety of transcripts from a single gene. More than half of the human genes have multiple polyadenylation sites (poly(A) sites), leading to variable mRNA and protein products. Previous studies of individual genes have indicated that alternative polyadenylation could occur in a tissue-specific manner. Results We set out to systematically investigate the occurrence and mechanism of alternative polyadenylation in different human tissues using bioinformatic approaches. Using expressed sequence tag (EST) data, we investigated 42 distinct tissue types. We found that several tissues tend to use poly(A) sites that are biased toward certain locations of a gene, such as sites located in introns or internal exons, and various sites in the exon located closest to the 3' end. We also identified several tissues, including eye, retina and placenta, that tend to use poly(A) sites not frequently used in other tissues. By exploring microarray expression data, we analyzed over 20 genes whose protein products are involved in the process or regulation of mRNA polyadenylation. Several brain tissues showed high concordance of gene expression of these genes with each other, but low concordance with other tissue types. By comparing genomic regions surrounding poly(A) sites preferentially used in brain tissues with those in other tissues, we identified several cis -regulatory elements that were significantly associated with brain-specific poly(A) sites. Conclusion Our results indicate that there are systematic differences in poly(A) site usage among human tissues, and both trans -acting factors and cis -regulatory elements may be involved in regulating alternative polyadenylation in different tissues.
The limits to exercise performance and the future of fatigue research
Authors: F E Marino, M Gard, E J Drinkwater
Journal: British Journal of Sports Medicine (2009)

The study of human fatigue stretches back centuries and remains a significant part of medical and social discourse. In the exercise sciences fatigue is routinely related to the ability to produce muscle force or to the recovery from force decrements. However, the study of fatigue has by virtue of the experimental paradigm excluded the subjective sense a person attributes to an event or experience, thus reducing our overall understanding of the fatigue process. Modern studies report the causes of fatigue as either central or peripheral in origin. Although useful, this dichotomy can also exclude the individual subjective assessment. Furthermore, adhering dogmatically to set parameters is likely limiting the advancement of our understanding. A more realistic paradigm would permit the individual to use the sensory cues to adjust the effort along with the fatigue process rather than rely purely on feedback mechanisms. Therefore, bringing feedforward mechanisms of the brain into fatigue research perhaps represents the next phase in the unravelling of the fatigue process.
Diabetic Charcot Neuroarthropathy of the Hand: Clinical Course, Diagnosis, and Treatment Options
Authors: Ulrich Illgner, Jaap van Netten, Carolin Droste, Thomas Meiners, Klaas Postema, Hans H. Wetz
Journal: Diabetes Care (2014)

During the treatment of diabetic Charcot neuroarthropathy (CN) of the foot in two young patients, we discovered atypical alterations of their hands with loss of strength and paresthesia combined with atypical and nonhealing bone alterations and instability. Whereas CN of the foot is a serious and well-known complication of diabetes, CN of the hand is only mentioned in four articles (1–4).

We reviewed all patients who had been treated in our clinic for CN of the foot ( N = 281) from 1998 to 2010. We scanned all patient reports for X-rays or complaints of the hand and visible alterations. Photo documentation and X-rays of the affected joints were obtained after the patients had given formal consent and all demands of the Declaration of Helsinki were fulfilled.

Three patients with CN …
Beneficial Effect of Oral Sildenafil Therapy on Childhood Pulmonary Arterial Hypertension
Authors: Tilman Humpl, Janette T. Reyes, Helen Holtby, Derek Stephens, Ian Adatia
Journal: Circulation (2005)

Pulmonary arterial hypertension (PAH) is a progressive and fatal disease. Sildenafil is a type 5 phosphodiesterase inhibitor and pulmonary vasodilator. Therefore, we hypothesized that sildenafil would improve distance walked in 6 minutes and hemodynamics in children with PAH.After baseline assessment of hemodynamics by cardiac catheterization and distance walked in 6 minutes, we administered oral sildenafil at 0.25 to 1 mg/kg 4 times daily to 14 children (median age, 9.8 years; range, 5.3 to 18). Diagnoses were primary (n=4) and secondary (n=10) PAH. We repeated the 6-minute walk test at 6 weeks and at 3, 6, and 12 months (n=14) and cardiac catheterization (n=9) after a median follow-up of 10.8 months (range, 6 to 15.3). During sildenafil therapy, the mean distance walked in 6 minutes increased from 278+/-114 to 443+/-107 m over 6 months (P=0.02), and at 12 months, the distance walked was 432+/-156 m (P=0.005). A plateau was reached between 6 and 12 months (P=0.48). Mean pulmonary artery pressure decreased from a median of 60 mm Hg (range, 50 to 105) to 50 mm Hg (range, 38 to 84) mm Hg (P=0.014). Median pulmonary vascular resistance decreased from 15 Wood units m2 (range, 9 to 42) to 12 Wood Units m2 (range, 5 to 29) (P=0.024).Oral sildenafil has the potential to improve hemodynamics and exercise capacity for up to 12 months in children with PAH. Confirmation of these results in a randomized, controlled trial is essential.
Improved Growth in Young Children with Severe Chronic Renal Insufficiency Who Use Specified Nutritional Therapy
Authors: RULAN S. PAREKH, JOSEPH T. FLYNN, WILLIAM E. SMOYER, JOAN L. MILNE, DAVID B. KERSHAW, TIMOTHY E. BUNCHMAN, AILEEN B. SEDMAN
Journal: Journal of the American Society of Nephrology (2001)

Growth in children with chronic renal failure caused by polyuric, salt-wasting diseases may be hampered if ongoing sodium and water losses are not corrected. Twenty-four children were treated with polyuric chronic renal insufficiency (CRI; creatinine clearance <65 ml/min per 1.73 m2) with low-caloric-density, high-volume, sodium-supplemented feedings. Subsequent growth was compared with that of children in two control groups: a national historic population control from the US Renal Data System database (n = 42), and a literature control (n = 12). Members of the three groups were 81 to 96% white, and 58 to 70% were boys. Obstructive uropathy and dysplasia were the cause of CRI in 92% of the treatment group, 75% of the literature control group, and 30% of the population control group. Treatment effect was assessed in a multivariate, retrospective analysis of the height standard deviation score (SDS), simultaneously controlling for the severity of disease by renal replacement therapy, primary cause of CRI, and initial height SDS. The change in SDS (ΔSDS) for height by regression analysis at 1 yr was significantly greater by +1.37 in the treatment group versus the population control (P = 0.017). The 2-yr height ΔSDS by regression analysis adjusted for creatinine clearance was significantly greater by +1.83 in the treatment group versus the literature control (P = 0.003). Nutritional support with sodium and water supplementation can maintain or improve the growth of children with polyuric, salt-wasting CRI. This inexpensive intervention may delay the need for renal replacement therapy, growth hormone treatment, or both in many of these children and may be used in any clinical setting.
Responsibility for Costs Associated With Clinical Trials
Authors: Paul J. Martin, Nancy Davenport-Ennis, Nicholas J. Petrelli, F. Marc Stewart, Frederick R. Appelbaum, Al Benson
Journal: Journal of Clinical Oncology (2014)

Medicare and coverage requirements in the Patient Protection and Affordable Care Act (ACA) have improved access to clinical trials, but major obstacles persist. First, access to participation in studies can be limited if networks established by insurance plans do not include providers involved in clinical trials. Second, certain details of the relationship between the clinical trials provisions of the ACA and state laws have not been defined. Third, consensus regarding the scope of insurance coverage for costs in clinical trials has not been reached. We discuss each of these problems and offer suggestions for resolution. These obstacles must be addressed to improve access for patients and to advance medical care through research.
Production of monoclonal antibodies specific for two distinct steric portions of the glycolipid ganglio-N-triosylceramide (asialo GM2).
Authors: W W Young, E M MacDonald, R C Nowinski, S I Hakomori
Journal: The Journal of Experimental Medicine (1979)

Two hybrid cell lines were prepared by the fusion of mouse myeloma cells with the spleen cells of BALB/c mice that had been immunized with the glycolipid ganglio-N-triosylceramide (asialo GM2). The specificity of the monoclonal antibodies produced by these hybridomas, one an IgM and the other an IgG3, has been defined by hemagglutination inhibition, complement fixation, and lysis of glycolipid liposomes by antibody and complement. A major determinant recognized by the IgM antibody is the nonreducing terminal N-acetylgalactosamine including the C6 primary hydroxyl group, but excluding the C2-acetamide group of N-acetylgalactosamine, because oxidation with galactose oxidase produced a structure showing only minimal cross-reaction with the IgM but replacement of the N-acetyl group with an N-n-butyryl group produced a glycolipid that reacts with IgM antibody to the same extent as with the unmodified glycoplipd. A major determinant recognized by the IgG3 antibody is the terminal N-acetylgalactosamine including the C2-acetamido group, but excluding the C6 primary hydroxyl group of N-acetylgalactosamine, because replacement of the N-acetyl group with an N-n-butyryl group produced a glycolipid that did not react with the IgG3 antibody; in striking contrast the IgG3 antibody reacted with the C6-oxidized glycolipid as well as with the native glycolipid. Neither antibody reacted significantly with any other natural glycolipids tested including several that are structurally related to asialo GM2 such as ganglioside GM2, ganglio-N-tetraosylceramide (asialo GM1), or ceramide dihexoside. These results indicated that in addition to the fine structure specificity described above both antibodies recognize the nonreducing terminal GalNAc beta 1 leads to 4Gal structure. The strict antigenic specificity of these monoclonal anti-glycolipid antibodies indicates their great potential as specific probes for cell surface studies.
A possible role for endogenous prostaglandins in the electrophysiological effects of acetylstrophanthidin on isolated canine ventricular tissues.
Authors: M P Moffat, G R Ferrier, M Karmazyn
Journal: Circulation Research (1986)

A possible role for endogenous prostaglandins in the toxic electrophysiological effects of the aglycone acetylstrophanthidin was studied in isolated canine Purkinje fiber papillary muscle preparations by standard microelectrode techniques. Acetylstrophanthidin (5 X 10(-8) g/ml) caused a significant increase in 6-keto-prostaglandin F1 alpha release from these preparations. A significant loss of membrane potential and the development of oscillatory afterpotentials was observed, as well. Administration of either of two nonsteroidal antiinflammatory agents, indomethacin (3 X 10(-5) g/ml) or aspirin (5 X 10(-5) g/ml), in the presence of acetylstrophanthidin, abolished the stimulation of 6-keto-prostaglandin F1 alpha release and delayed and attenuated the loss of membrane potential and the development of oscillatory afterpotentials. In addition, indomethacin and aspirin appeared to preserve the electrogenic pumping capacity of Purkinje fiber cells exposed to acetylstrophanthidin. Exposure of Purkinje tissues to acetylstrophanthidin inhibited post-pacing hyperpolarization normally exhibited by these tissues. Both indomethacin and aspirin decreased this inhibition. Addition of prostacyclin (1 ng/ml) after 30 minutes of exposure to acetylstrophanthidin to preparations in which endogenous prostaglandin synthesis had been inhibited, resulted in a significant increase in the amplitude of oscillatory afterpotentials within 2 minutes. These results suggest that the presence of endogenous prostaglandins may play a role in the development of the toxic electrophysiological effects associated with acetylstrophanthidin.