tbuckley/cabot-search huggingface dataset:
Frequent Alterations and Epigenetic Silencing of Differentiation Pathway Genes in Structurally Rearranged Liposarcomas
Authors: Barry S. Taylor, Penelope L. DeCarolis, Christina V. Angeles, Fabienne Brenet, Nikolaus Schultz, Cristina R. Antonescu, Joseph M. Scandura, Chris Sander, Agnes J. Viale, Nicholas D. Socci, Samuel Singer
Journal: Cancer Discovery (2011)

We explored diverse alterations contributing to liposarcomagenesis by sequencing the genome, exome, transcriptome, and cytosine methylome of a primary and recurrent dedifferentiated liposarcoma (DLPS) from distinct chemotherapy/radiotherapy-naïve patients. The liposarcoma genomes had complex structural rearrangements, but in different patterns, and with varied effects on the structure and expression of affected genes. While the point mutation rate was modest, integrative analyses and additional screening identified somatic mutations in HDAC1 in 8.3% of DLPS. Liposarcoma methylomes revealed alterations in differentiation pathway genes, including CEBPA methylation in 24% of DLPS. Treatment with demethylating agents, which restored CEBPA expression in DLPS cells, was anti-proliferative and pro-apoptotic in vitro and reduced tumor growth in vivo. Both genetic and epigenetic abnormalities established a role for small RNAs in liposarcomagenesis, typified by methylation-induced silencing of microRNA-193b in DLPS but not its well-differentiated counterpart. These findings reveal an unanticipated role for epigenetic abnormalities in DLPS tumors and suggest demethylating agents as potential therapeutics.Multimodality sequence analysis of DLPS revealed recurrent mutations and epigenetic abnormalities critical to liposarcomagenesis and to the suppression of adipocyte differentiation. Pharmacologic inhibition of DNA methylation promoted apoptosis and differentiated DLPS cells in vitro and inhibited tumor growth in vivo, providing a rationale for investigating methylation inhibitors in this disease.
Physiological Differences Between Interstitial Glucose and Blood Glucose Measured in Human Subjects
Authors: Eray Kulcu, Janet A. Tamada, Gerard Reach, Russell O. Potts, Matthew J. Lesho
Journal: Diabetes Care (2003)

OBJECTIVE—This study investigated whether glucose readings from a sensor sampling in interstitial fluid differ substantially from blood glucose (BG) values measured at the same time. RESEARCH DESIGN AND METHODS—We have evaluated the relationship between BG and glucose extracted from interstitial fluid using the GlucoWatch (Cygnus, Redwood City, CA) biographer, a device that collects glucose from subcutaneous interstitial space through intact skin by application of a low electric current. We evaluated the relative change in the interstitial glucose (IG) signal (IGS) as measured by the biographer versus BG using a normalized two-point sensitivity index (NSI). RESULTS—The results show that biographer measures of IG differ in time and magnitude from the corresponding BG values. In particular, the biographer values were shifted in time due to instrumental and physiological lag. Results show an average total lag of 17.2 ± 7.2 min for all subjects evaluated. The instrumental lag was 13.5 min, suggesting that physiological lag is ∼5 min. In addition, when glucose was increasing, the change in IGS was less than that in BG, while when BG was decreasing, the change in IGS was greater than that in BG. CONCLUSIONS—Similar results have been reported for other measures of IG, suggesting that differences reflect physiological variation in glucose uptake, utilization, and elimination in blood and interstitial space. This further evidence of the difference between IG and BG should be considered when interpreting glucose measurements from devices that sample interstitial fluid.
Echinacea for Treating the Common Cold
Authors: Bruce Barrett, Roger Brown, Dave Rakel, Marlon Mundt, Kerry Bone, Shari Barlow, Tola Ewers
Journal: Annals of Internal Medicine (2010)

Background: Echinacea is widely used to treat the common cold. Objective: To assess the potential benefits of echinacea as a treatment of common cold. Design: Randomized, controlled trial. (ClinicalTrials.gov registration number: NCT00065715) Setting: Dane County, Wisconsin. Patients: 719 patients, aged 12 to 80 years, with new-onset common cold. Intervention: Patients were assigned to 1 of 4 parallel groups: no pills, placebo pills (blinded), echinacea pills (blinded), or echinacea pills (unblinded, open-label). Echinacea groups received the equivalent of 10.2 g of dried echinacea root during the first 24 hours and 5.1 g during each of the next 4 days. Indistinguishable placebo tablets contained only inert ingredients. Measurements: The primary outcome was the area under the curve for global severity, with severity assessed twice daily by self-report using the Wisconsin Upper Respiratory Symptom Survey, short version. Secondary outcomes included interleukin-8 levels and neutrophil counts from nasal wash, assessed at intake and 2 days later. Results: Of the 719 patients enrolled, 713 completed the protocol. Mean age was 33.7 years, 64% were female, and 88% were white. Mean global severity was 236 and 258 for the blinded and unblinded echinacea groups, respectively; 264 for the blinded placebo group; and 286 for the no-pill group. A comparison of the 2 blinded groups showed a 28-point trend (95% CI, −69 to 13 points) toward benefit for echinacea (P = 0.089). Mean illness duration in the blinded and unblinded echinacea groups was 6.34 and 6.76 days, respectively, compared with 6.87 days in the blinded placebo group and 7.03 days in the no-pill group. A comparison of the blinded groups showed a nonsignificant 0.53-day (CI, −1.25 to 0.19 days) benefit (P = 0.075). Median change in interleukin-8 levels and neutrophil counts were also not statistically significant (30 ng/L and 1 cell/high-power field [hpf] in the no-pill group, 39 ng/L and 1 cell/hpf in the blinded placebo group, 58 ng/L and 2 cells/hpf in the blinded echinacea group, and 70 ng/L and 1 cell/hpf in the open-label echinacea group). Limitation: Higher-than-expected variability limited power to detect small benefits. Conclusion: Illness duration and severity were not statistically significant with echinacea compared with placebo. These results do not support the ability of this dose of the echinacea formulation to substantively change the course of the common cold. Primary Funding Source: National Center for Complementary and Alternative Medicine, National Institutes of Health.
Arteriovenous Fistula Placement in the Elderly
Authors: Tammy Hod, Bhanu K. Patibandla, Yael Vin, Robert S. Brown, Alexander S. Goldfarb-Rumyantzev
Journal: Journal of the American Society of Nephrology (2014)

Arteriovenous fistula (AVF) is the preferred vascular access for hemodialysis (HD). However, many AVFs fail before starting dialysis. To assess the optimal time for AVF placement in the elderly, we linked data from the US Renal Data System with Medicare claims data to identify 17,511 patients ≥67 years old on incident HD who started dialysis between January 1, 2005, and December 31, 2008, with an AVF placed as the first predialysis access. AVF success was defined as dialysis initiation using the AVF, with time between AVF placement and dialysis start as our primary variable of interest. The mean age was 76.1±6.0 years, and 58.3% of subjects were men. Overall, 54.9% of subjects initiated dialysis using an AVF, and 45.1% of subjects used a catheter or graft. The success rate increased as time from AVF creation to HD initiation increased from 1-3 months (odds ratio [OR], 0.49; 95% confidence interval [95% CI], 0.44 to 0.53) to 3-6 months (OR, 0.93; 95% CI, 0.85 to 1.02) to 6-9 months (OR, 0.99; 95% CI, 0.88 to 1.11) but stabilized after that time. Furthermore, the number of interventional access procedures increased over time starting at 1-3 months, with a mean of 0.64 procedures/patient for AVFs created 6-9 months predialysis compared with 0.72 for AVFs created >12 months predialysis (P<0.001). Although limited by the observational nature of this study, our results suggest that placing an AVF >6-9 months predialysis in the elderly may not associate with a better AVF success rate.
Direct demonstration of an HLA-DR allotypic determinant on the low molecular weight (beta) subunit using a mouse monoclonal antibody specific for DR3
Authors: JP Johnson, T Meo, G Reithmuller, DJ Schendel, R Wank
Journal: The Journal of Experimental Medicine (1982)

A murine monoclonal antibody directed against a human B cell surface antigen with the characteristics of HLA-DR is described. The antigen detected is tightly linked to HLA and is correlated with the alloantigen HLA-Dw/DR3. Reactivity with a fraction of Dw/DRw6 cells is also observed. The determinant recognized by this antibody has been shown to be present on the smaller molecular weight β subunit of the HLA-DR antigen.
1279 NON-INVASIVE DIAGNOSIS OF NON-ALCOHOLIC STEATOHEPATITIS BY COMBINED CYTOKERATIN-18 APOPTOTIC FRAGMENT AND ELASTOMETRY
Authors: S. Carenzi, C. Rosso, L. Mezzabotta, G.P. Caviglia, F. Salamone, M. Rizzetto, A. Smedile, M.L. Abate, E. Bugianesi
Journal: Journal of Hepatology (2012)
A Glycolytic Mechanism Regulating an Angiogenic Switch in Prostate Cancer
Authors: Jianhua Wang, Jincheng Wang, Jinlu Dai, Younghun Jung, Chuen-Long Wei, Yu Wang, Aaron M. Havens, Phillip J. Hogg, Evan T. Keller, Kenneth J. Pienta, Jacques E. Nor, Cun-Yu Wang, Russell S. Taichman
Journal: Cancer Research (2007)

Abstract The generation of an ‘angiogenic switch’ is essential for tumor growth, yet its regulation is poorly understood. In this investigation, we explored the linkage between metastasis and angiogenesis through CXCL12/CXCR4 signaling. We found that CXCR4 regulates the expression and secretion of the glycolytic enzyme phosphoglycerate kinase 1 (PGK1). Overexpression of PGK1 reduced the secretion of vascular endothelial growth factor and interleukin-8 and increased the generation of angiostatin. At metastatic sites, however, high levels of CXCL12 signaling through CXCR4 reduced PGK1 expression, releasing the angiogenic response for metastastic growth. These data suggest that PGK1 is a critical downstream target of the chemokine axis and an important regulator of an ‘angiogenic switch’ that is essential for tumor and metastatic growth. [Cancer Res 2007;67(1):149–59]
Advanced Stage, Increased Lactate Dehydrogenase, and Primary Site, but Not Adolescent Age (≥ 15 Years), Are Associated With an Increased Risk of Treatment Failure in Children and Adolescents With Mature B-Cell Non-Hodgkin's Lymphoma: Results of the FAB LMB 96 Study
Authors: Mitchell S. Cairo, Richard Sposto, Mary Gerrard, Anne Auperin, Stanton C. Goldman, Lauren Harrison, Ross Pinkerton, Martine Raphael, Keith McCarthy, Sherrie L. Perkins, Catherine Patte
Journal: Journal of Clinical Oncology (2012)

Adolescents (age 15 to 21 years) compared with younger children with mature B-cell non-Hodgkin's lymphoma (NHL) have been historically considered to have an inferior prognosis. We therefore analyzed the impact of age and other diagnostic factors on the risk of treatment failure in children and adolescents treated on the French-American-British Mature B-Cell Lymphoma 96 (FAB LMB 96) trial.Patients were divided by risk: group A (limited), group B (intermediate), and group C (advanced), as previously described. Prognostic factors analyzed for event-free survival (EFS) included age (< 15 v ≥ 15 years), stage (I/II v III/IV), primary site, lactate dehydrogenase (LDH), bone marrow/CNS (BM/CNS) involvement, and histology (diffuse large B-cell lymphoma v mediastinal B-cell lymphoma v Burkitt lymphoma or Burkitt-like lymphoma).The 3-year EFS for the whole cohort was 88% ± 1%. Age was not associated as a risk factor for increased treatment failure in either univariate analysis (P = .15) or multivariate analysis (P = .58). Increased LDH (≥ 2 × upper limit of normal [ULN] v < 2 × ULN), primary site, and BM-positive/CNS-positive disease were all independent risk factors associated with a significant increase in treatment failure rate (relative risk, 2.0; P < .001, P < .012, and P < .001, respectively).LDH level at diagnosis, mediastinal disease, and combined BM-positive/CNS-positive involvement are independent risk factors in children with mature B-cell NHL. Future studies should be developed to identify specific therapeutic strategies (immunotherapy) to overcome these risk factors and to identify the biologic basis associated with these prognostic factors in children with mature B-cell NHL.
Inherited Mitochondrial Diseases of DNA Replication
Authors: William C. Copeland
Journal: Annual Review of Medicine (2007)

Mitochondrial genetic diseases can result from defects in mitochondrial DNA (mtDNA) in the form of deletions, point mutations, or depletion, which ultimately cause loss of oxidative phosphorylation. These mutations may be spontaneous, maternally inherited, or a result of inherited nuclear defects in genes that maintain mtDNA. This review focuses on our current understanding of nuclear gene mutations that produce mtDNA alterations and cause mitochondrial depletion syndrome (MDS), progressive external ophthalmoplegia (PEO), ataxia-neuropathy, or mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). To date, all of these etiologic nuclear genes fall into one of two categories: genes whose products function directly at the mtDNA replication fork, such as POLG, POLG2, and TWINKLE, or genes whose products supply the mitochondria with deoxynucleotide triphosphate pools needed for DNA replication, such as TK2, DGUOK, TP, SUCLA2, ANT1, and possibly the newly identified MPV17.
Segmental Ostial Ablation to Isolate the Pulmonary Veins During Atrial Fibrillation
Authors: Hakan Oral, Bradley P. Knight, Mehmet Özaydın, Aman Chugh, Steve W.K. Lai, Christoph Scharf, Sohail Hassan, Radmira Greenstein, Jihn D. Han, Frank Pelosi, S. Adam Strickberger, Fred Morady
Journal: Circulation (2002)

Background— The purpose of this study was to determine the feasibility and mechanistic implications of segmental pulmonary vein (PV) ostial ablation during atrial fibrillation (AF). Methods and Results— Forty consecutive patients underwent PV isolation for AF. Among 125 PVs targeted for isolation, ablation was performed during AF in 70 veins and during sinus rhythm in 55 veins. A decapolar Lasso catheter was positioned near the ostium. During AF, ostial ablation was performed near the Lasso catheter electrodes that recorded a tachycardia with a cycle length shorter than in the adjacent left atrium. During sinus rhythm, ostial ablation was guided by PV potentials. Complete PV isolation was achieved in 70 PVs (100%) ablated during AF and in 53 PVs (96%) ablated during sinus rhythm ( P =0.4). The mean durations of radiofrequency energy needed for isolation were 7.4±4.4 and 5.2±3.9 minutes during AF and sinus rhythm, respectively ( P &lt;0.01). Before ablation, an immediate recurrence of AF (IRAF), occurred after cardioversion in 18 of 40 patients, and IRAF was consistently abolished by PV isolation. The probability of AF termination during isolation of a PV was directly related to the extent of tachycardia in that vein. As more PVs were isolated, induction of persistent AF by rapid pacing became less likely. Conclusions— Segmental ostial ablation guided by PV tachycardia during AF is feasible and as efficacious as during sinus rhythm. The responses to cardioversion, ablation, and rapid pacing observed in this study imply that IRAF is triggered by the PVs and that PV tachycardias may play an important role in the perpetuation of AF.
Studies of cloned Friend erythroleukemia tumor cells. Modulation of the tumor-specific cytologic T lymphocyte response by infectious Friend virus production in vitro.
Authors: F Plata, M M Goodenow, F Lilly
Journal: The Journal of Experimental Medicine (1980)

The HFL/b tumor cell line, induced by Friend erythroleukemia virus in BALB.B mice, was used to study the relation between virus production or nonproduction and the antigens recognized by Friend virus-specific cytolytic T lymphocytes (CTL). Analysis of clones and subclones of these tumor cells revealed a high degree of heterogeneity with respect to the production and release into culture fluids of infectious Friend virus in vitro, ranging from high levels to low or undetectable levels of virus production. Although no major differences could be detected among the antibody-defined serotypes of the various clones, the susceptibility of cells of individual HFL/b clones to attack by Friend virus-specific CTL varied widely, and those clones which produced large amounts of infectious virus provided the most sensitive target cells. It was also apparent that production of infectious Friend virus was inhibitory to CTL generation in syngeneic mixed leukocyte-tumor cell cultures. Friend erythroleukemia virus-producing cells thus appeared to interact in a complex manner with the host CTL response by modulating their production of infectious Friend virus.
De novo purine synthesis inhibition and antileukemic effects of mercaptopurine alone or in combination with methotrexate in vivo
Authors: Thierry Dervieux, Timothy L. Brenner, Yuen Y. Hon, Yinmei Zhou, Michael L. Hancock, John T. Sandlund, Gaston K. Rivera, Raul C. Ribeiro, James M. Boyett, Ching-Hon Pui, Mary V. Relling, William E. Evans
Journal: Blood (2002)
Transcriptome-Wide Studies of Merkel Cell Carcinoma and Validation of Intratumoral CD8+ Lymphocyte Invasion As an Independent Predictor of Survival
Authors: Kelly G. Paulson, Jayasri G. Iyer, Andrew R. Tegeder, Renee Thibodeau, Janell Schelter, Shinichi Koba, David Schrama, William T. Simonson, Bianca D. Lemos, David R. Byrd, David M. Koelle, Denise A. Galloway, J. Helen Leonard, Margaret M. Madeleine, Zsolt B. Argenyi, Mary L. Disis, Juergen C. Becker, Michele A. Cleary, Paul Nghiem
Journal: Journal of Clinical Oncology (2011)

Purpose Merkel cell carcinoma (MCC) is a polyomavirus-associated skin cancer that is frequently lethal and lacks established prognostic biomarkers. This study sought to identify biomarkers that improve prognostic accuracy and provide insight into MCC biology. Patients and Methods Gene expression profiles of 35 MCC tumors were clustered based on prognosis. The cluster of genes overexpressed in good-prognosis tumors was tested for biologic process enrichment. Relevant mRNA expression differences were confirmed by quantitative polymerase chain reaction and immunohistochemistry. An independent set of 146 nonoverlapping MCC tumors (median follow-up, 25 months among 116 living patients) was employed for biomarker validation. Univariate and multivariate Cox regression analyses were performed. Results Immune response gene signatures were prominent in patients with good prognoses. In particular, genes associated with cytotoxic CD8+ lymphocytes were overexpressed in tumors from patients with favorable prognoses. In the independent validation set, cases with robust intratumoral CD8+ lymphocyte infiltration had improved outcomes (100% MCC-specific survival, n = 26) compared with instances characterized by sparse infiltration (60% survival, n = 120). Only stage and intratumoral CD8 infiltration (but not age, sex, or CD8+ lymphocytes localized to the tumor-stroma interface) were significant in both univariate and multivariate Cox regression analyses. Notably, traditional histologic identification of tumor-infiltrating lymphocytes was not a significant independent predictor of survival. Conclusion Intratumoral CD8+ lymphocyte infiltration can be readily assessed on paraffin-embedded tissue, is independently associated with improved MCC-specific survival, and therefore, may provide prognostic information that enhances established MCC staging protocols.
Serum and urine cystatin C are poor biomarkers for acute kidney injury and renal replacement therapy
Authors: Annick A. N. M. Royakkers, Johanna C. Korevaar, Jeroen D. E. van Suijlen, Lieuwe S. Hofstra, Michael A. Kuiper, Peter E. Spronk, Marcus J. Schultz, Catherine S. C. Bouman
Journal: Intensive Care Medicine (2010)

To evaluate whether cystatin C in serum (sCyC) and urine (uCyC) can predict early acute kidney injury (AKI) in a mixed heterogeneous intensive care unit (ICU), and also whether these biomarkers can predict the need for renal replacement therapy (RRT).Multicenter prospective observational cohort study in patients ≥18 years old and with expected ICU stay ≥72 h. The RIFLE class for AKI was calculated daily, while sCyC and uCyC were determined on days 0, 1, and alternate days until ICU discharge. Test characteristics were calculated to assess the diagnostic performance of CyC.One hundred fifty-one patients were studied, and three groups were defined: group 0 (N = 60), non-AKI; group 1 (N = 35), AKI after admission; and group 2 (N = 56), AKI at admission. We compared the two days prior to developing AKI from group 1 with the first two study days from group 0. On Day -2, median sCyC was significantly higher (0.93 versus 0.80 mg/L, P = 0.01), but not on Day -1 (0.98 versus 0.86 mg/L, P = 0.08). The diagnostic performance for sCyC was fair on Day -2 [area under the curve (AUC) 0.72] and poor on Day -1 (AUC 0.62). Urinary CyC had no diagnostic value on either of the two days prior to AKI (AUC <0.50). RRT was started in 14 patients with AKI; sCyC and uCyC determined on Day 0 were poor predictors for the need for RRT (AUC ≤0.66).In this study, sCyC and uCyC were poor biomarkers for prediction of AKI and the need for RRT.
Polyethylene Glycol for Hepatic Encephalopathy
Authors: Amy E. Doran, Neeral L. Shah
Journal: JAMA Internal Medicine (2014)

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