tbuckley/cabot-search huggingface dataset:
Measuring the Improving Quality of Outpatient Care in Medical Oncology Practices in the United States
Authors: Michael N. Neuss, Jennifer L. Malin, Stephanie Chan, Pamela J. Kadlubek, John L. Adams, Joseph O. Jacobson, Douglas W. Blayney, Joseph V. Simone
Journal: Journal of Clinical Oncology (2013)

The American Society of Clinical Oncology Quality Oncology Practice Initiative (QOPI) has provided a method for measuring process-based practice quality since 2006. We sought to determine whether QOPI scores showed improvement in measured quality over time and, if change was demonstrated, which factors in either the measures or participants were associated with improvement.The analysis included 156 practice groups from a larger group of 308 that submitted data from 2006 to 2010. One hundred fifty-two otherwise eligible practices were excluded, most commonly for insufficient data submission. A linear regression model that controlled for varied initial performance was used to estimate the effect of participation over time and evaluate participant and measure characteristics of improvement.Participants completed a mean of 5.06 (standard deviation, 1.94) rounds of data collection. Adjusted mean quality scores improved from 0.71 (95% CI, 0.42 to 0.91) to 0.85 (95% CI, 0.60 to 0.95). Overall odds ratio of improvement over time was 1.09 (P < .001). The greatest improvement was seen in measures that assessed newly introduced clinical information, in which the mean scores improved from 0.05 (95% CI, 0.01 to 0.17) to 0.69 (95% CI, 0.33 to 0.91; P < .001). Many measures showed no change over time.Many US oncologists have participated in QOPI over the past 6 years. Participation over time was highly correlated with improvement in measured performance. Greater and faster improvement was seen in measures concerning newly introduced clinical information. Some measures showed no change despite opportunity for improvement.
Cyclin D1 Guanine/Adenine 870 Polymorphism With Altered Protein Expression Is Associated With Genomic Instability and Aggressive Clinical Biology of Esophageal Adenocarcinoma
Authors: Julie G. Izzo, Tsung-Teh Wu, Xifeng Wu, Joe Ensor, Rajyalakshmi Luthra, Jennifer Pan, Arlene Correa, Stephen G. Swisher, Clifford K.S. Chao, Walter N. Hittelman, Jaffer A. Ajani
Journal: Journal of Clinical Oncology (2007)

Purpose Altered cyclin D1 (CD1), a cell cycle regulator, may play an important role in imparting aggressive nature to esophageal adenocarcinoma (EAC). CD1 gene single nucleotide polymorphism G/A870 results in two alternatively spliced transcripts, CD1a and CD1b. CD1b, preferentially encoded by the A870 allele, is putatively oncogenic. We hypothesized that CD1 A870 allele would be associated with higher CD1 protein expression, and increased genomic instability during EAC evolution, leading to more aggressive phenotype. Patients and Methods One hundred twenty-four archival specimens of EAC, and 39 associated Barrett's esophagus (BE) specimens were examined for CD1 genotype, CD1 protein expression, and chromosome 9 polysomy (representing genomic instability). We correlated CD1 genotypes with CD1 protein expression, genomic instability, age at diagnosis of EAC, and overall survival (OS). Results The A870 allele was associated with higher levels of CD1 protein expression in EAC (P = .032); in BE (P = .01) where it was associated with concomitant increased chromosome 9 polysomy (P = .002); and with a younger age at diagnosis (P &lt; .001) and poor OS (P = .0003) of EAC patients. Conclusion Our data suggest that CD1 A870 background may be imparting aggressive phenotype to EAC. It provides a molecular basis to explain the clinical biology associated with CD1 polymorphism whereas aberrant nuclear accumulation of CD1 protein enhances the acquisition of genomic instability (ie, clonal diversity), thus leading to early age of EAC diagnosis and poor OS. CD1 genotyping with other biomarkers may help create a biomarker-based prognostic model for EAC and CD1 may also serve as a therapeutic target.
Helodermatine, a kallikrein-like, hypotensive enzyme from the venom of Heloderma horridum horridum (Mexican beaded lizard).
Authors: A Alagon, L D Possani, J Smart, W D Schleuning
Journal: The Journal of Experimental Medicine (1986)

We have purified and characterized the major N-benzoyl-L-arginine ethyl ester hydrolase from the venom of Heloderma horridum horridum. The enzyme belongs to the serine proteinase family, and its activity vs. peptide amide substrates and human high-molecular-weight kininogen suggests a similarity to the family of kallikreins. This interpretation is corroborated by its reactivity with the natural inhibitors soybean trypsin inhibitor and Kunitz-type bovine pancreatic trypsin inhibitor (aprotinin). Injection of the enzyme (2-16 micrograms/kg) into anesthetized rabbits leads to a rapid dose-dependent transient decrease of the arterial blood pressure. Like glandular kallikrein it specifically converts single-chain tissue type plasminogen activator into its double chain form. In contrast to other kallikrein-like enzymes from snake venoms it shows no thrombin-like or plasminogen activator activity. The enzyme is a single-chain glycoprotein (Mr 63,000). The N-terminal sequence revealed significant homology to pig pancreatic kallikrein and to kallikrein like enzymes from Crotalus atrox and Crotalus adamanteus venom. This enzyme, which we name Helodermatine, is the first purified from Sauria with kallikrein-like properties.
Autologous stimulation of human lymphocyte subpopulation.
Authors: G Opelz, M Kiuchi, M Takasugi, P I Terasaki
Journal: The Journal of Experimental Medicine (1975)

The background stimulation universally seen when lymphocytes are cultured in vitro has been shown to be markedly lowered by reducing the proportion of B lymphocytes. B-rich fractions of lymphocytes had extremely high background stimulation. It is concluded that stimulation of T cells, probably by autologous B cells, provides the most probable explanation for the findings described.
Allele *2 of the HS1,2A enhancer of the Ig regulatory region associates with rheumatoid arthritis
Authors: B Tolusso, D Frezza, C Mattioli, A L Fedele, S Bosello, F Faustini, G Peluso, V Giambra, D Pietrapertosa, A Morelli, E Gremese, M De Santis, G F Ferraccioli
Journal: Annals of the Rheumatic Diseases (2008)

Objective: To investigate the role of the HS1,2 enhancer polymorphisms as a new candidate marker for rheumatoid arthritis (RA) and to define the possible association with autoantibody positivity and clinical outcome. Methods: Genomic DNA was obtained from two cohorts of patients with RA (100 with early RA (ERA) and 114 with longstanding RA (LSRA)) and from 248 gender-matched controls from the same geographical area. Clinical and immunological characteristics were recorded for all the patients. Results: The percentage of the 2/2 genotype was higher in patients with ERA (27.0%), and in patients with LSRA (34.2%), than in controls (14.9%) (ERA: OR = 2.11 (95% CI 1.20 to 3.70) vs controls; LSRA: OR = 2.96 (95% CI 1.76 to 5.00) vs controls). A lower representation of allele *3 was present in patients with ERA (2.0%) than in controls (6.0%; OR = 0.32 (95% CI 0.11 to 0.91)). No significant associations were found between polymorphisms and autoantibodies positivity. Conclusion: The HS1,2A allele *2 associates with early and longstanding RA.
AIDS vaccine trial begins in Uganda
Authors: S. Mayor
Journal: BMJ (2003)

Researchers working at the Uganda Virus Research Institute have begun a trial of an AIDS vaccine with the aim of vaccinating 50 volunteers not infected with HIV, it was announced last week.

The vaccine has been developed to prevent infection with the A strain of HIV, the subtype that is prevalent in Uganda and other parts of east Africa. It represents a major step forward in efforts to prevent the spread of AIDS in Africa, as other vaccines currently being investigated are designed to combat the B strain of HIV, found in the United States and …
Cost-Effectiveness of Sirolimus-Eluting Stents for Treatment of Complex Coronary Stenoses
Authors: David J. Cohen, Ameet Bakhai, Chunxue Shi, Louise Githiora, Tara Lavelle, Ronna H. Berezin, Martin B. Leon, Jeffrey W. Moses, Joseph P. Carrozza, James P. Zidar, Richard E. Kuntz
Journal: Circulation (2004)

Recently, sirolimus-eluting stents (SESs) have been shown to dramatically reduce the risk of angiographic and clinical restenosis compared with bare metal stent (BMS) implantation. However, the overall cost-effectiveness of this strategy is unknown.Between February and August 2001, 1058 patients with complex coronary stenoses were enrolled in the SIRIUS trial and randomized to percutaneous coronary revascularization with either a SES or BMS. Clinical outcomes, resource use, and costs were assessed prospectively for all patients over a 1-year follow-up period. Initial hospital costs were increased by 2881 dollars per patient with SESs. Over the 1-year follow-up period, use of SESs led to substantial reductions in the need for repeat revascularization, including repeat percutaneous coronary intervention and bypass surgery. Although follow-up costs were reduced by 2571 dollars per patient with SESs, aggregate 1-year costs remained 309 dollars per patient higher. The incremental cost-effectiveness ratio for SES was 1650 dollars per repeat revascularization event avoided or 27,540 dollars per quality-adjusted year of life gained, values that compare reasonably with other accepted medical interventions. Under updated treatment assumptions regarding available stent lengths and duration of antiplatelet therapy, use of SESs was projected to reduce total 1-year costs compared with BMSs.Although use of SESs was not cost-saving compared with BMS implantation, for patients undergoing percutaneous coronary intervention of complex coronary stenoses, their use appears to be reasonably cost-effective within the context of the US healthcare system.
Effect of Hyperhomocysteinemia on Plasma or Tissue Adenosine Levels and Renal Function
Authors: Ya-Fei Chen, Pin-Lan Li, Ai-Ping Zou
Journal: Circulation (2002)

Hyperhomocysteinemia (hHcys) is considered an independent risk factor of cardiovascular diseases. Recent studies in our laboratory have shown that hHcys produced glomerular dysfunction and sclerosis independently of hypertension. However, the mechanism mediating these pathogenic effects of homocysteine (Hcys) is poorly understood. Because Hcys and adenosine (Ado) are simultaneously produced via hydrolysis of S-adenosylhomocysteine (SAH), we hypothesized that hHcys may produce its pathogenic effects by decrease in plasma or tissue Ado concentrations.L-Hcys (1.5 micromol/min per kilogram) was infused intravenously for 60 minutes to produce acute hHcys in Sprague-Dawley rats. Plasma Hcys levels increased from 6.7+/-0.4 to 14.7+/-0.5 micromol/L, but Ado decreased from 141.7+/-15.1 to 52.4+/-6.8 nmol/L in these rats with acute hHcys. This hHcys-induced reduction of Ado was also observed in the kidney dialysate. In rats with chronic hHcys, plasma Ado levels were also significantly decreased. By kinetic analysis of the enzyme activities, decrease in renal Ado levels in hHcys was shown to be associated with inhibition of SAH hydrolase but not 5'-nucleotidase. Functionally, intravenous infusion of Hcys was found to decrease renal blood flow, glomerular filtration rate, and sodium and water excretion, which could be blocked by the Ado receptor antagonist 8-SPT.These results strongly suggest that hHcys decreases plasma and tissue Ado concentrations associated with inhibition of SAH hydrolase. Decrease in plasma and tissue Ado may be an important mechanism mediating the pathogenic effects of Hcys.
Interaction between Selection and Biased Gene Conversion in Mammalian Protein-Coding Sequence Evolution Revealed by a Phylogenetic Covariance Analysis
Authors: N. Lartillot
Journal: Molecular Biology and Evolution (2012)

According to the nearly-neutral model, variation in long-term effective population size among species should result in correlated variation in the ratio of nonsynonymous over synonymous substitution rates (dN/dS). Previous empirical investigations in mammals have been consistent with this prediction, suggesting an important role for nearly-neutral effects on protein-coding sequence evolution. GC-biased gene conversion (gBGC), on the other hand, is increasingly recognized as a major evolutionary force shaping genome nucleotide composition. When sufficiently strong compared with random drift, gBGC may significantly interfere with a nearly-neutral regime and impact dN/dS in a complex manner. Here, we investigate the phylogenetic correlations between dN/dS, the equilibrium GC composition (GC*), and several life-history and karyotypic traits in placental mammals. We show that the equilibrium GC composition decreases with body mass and increases with the number of chromosomes, suggesting a modulation of the strength of biased gene conversion due to changes in effective population size and genome-wide recombination rate. The variation in dN/dS is complex and only partially fits the prediction of the nearly-neutral theory. However, specifically restricting estimation of the dN/dS ratio on GC-conservative transversions, which are immune from gBGC, results in correlations that are more compatible with a nearly-neutral interpretation. Our investigation indicates the presence of complex interactions between selection and biased gene conversion and suggests that further mechanistic development is warranted, to tease out mutation, selection, drift, and conversion.
Incidence of primary carcinoma of the liver in the west of Scotland between 1949 and 1965.
Authors: W G Manderson, R S Patrick, E E Peters
Journal: Gut (1968)

Changes in the incidence of tumours are worthy of note as these may draw attention to factors concerned with aetiology.In recent years our attention has been drawn to the increasing frequency of primary carcinoma of liver in the west of Scotland.This change has been particularly notable in Glasgow Royal Infirmary where a marked rise in the number of fatal cases has been maintained since 1959.The cause is not apparent, but it is not associ- ated with any corresponding increase in the pre- valence of hepatic cirrhosis.Our original investiga- tions were concerned only with necropsies carried out in Glasgow Royal Infirmary and a few associ- ated hospitals in the east end of Glasgow from 1949 to 1963 (Manderson, Patrick, and Peters, 1965).This communication reports the findings of an extension of the study by two years, and to most of the general hospitals in the Scottish western region.
STAT4 and STAT6 regulate systemic inflammation and protect against lethal endotoxemia
Authors: Alex B. Lentsch, Atsushi Kato, Brian Davis, Warner Wang, Celia Chao, Michael J. Edwards
Journal: Journal of Clinical Investigation (2001)

Members of the signal transducer and activator of transcription (STAT) family are transcription factors that mediate many of the effects of pro- and anti-inflammatory cytokines. The progressive systemic inflammatory response induced by endotoxin is mediated by overzealous cytokine production. Here we identify STAT4 and STAT6 as critical regulators of the systemic inflammatory response to endotoxin. Mice deficient for STAT4 or STAT6 were highly susceptible to lethal endotoxemia. In STAT4–/– mice, antibody blockade of IL-12 prevented mortality, suggesting that STAT4 confers protection, while another signaling pathway mediates the detrimental effects of IL-12. In STAT6–/– mice we observed dysregulated activation of the transcription factor NF-κB, resulting in augmented production of proinflammatory cytokines and chemokines. Furthermore, STAT6–/– mice displayed increased organ accumulation of leukocytes and significant hepatocellular injury. These findings demonstrate that STAT4 and STAT6 confer protection against endotoxin-induced death and that for STAT6 these protective effects occur through the regulation of NF-κB activation and subsequent production of proinflammatory cytokines and chemokines.
Limited Durability of Viral Control following Treated Acute HIV Infection
Authors: Daniel E Kaufmann, Mathias Lichterfeld, Marcus Altfeld, Marylyn M Addo, Mary N Johnston, Paul K Lee, Bradford S Wagner, Elizabeth T Kalife, Daryld Strick, Eric S Rosenberg, Bruce D Walker
Journal: PLoS Medicine (2004)

Early treatment of acute HIV infection with highly active antiretroviral therapy, followed by supervised treatment interruption (STI), has been associated with at least transient control of viremia. However, the durability of such control remains unclear. Here we present longitudinal follow-up of a single-arm, open-label study assessing the impact of STI in the setting of acute HIV-1 infection.Fourteen patients were treated during acute HIV-1 infection and subsequently subjected to an STI protocol that required retreatment if viral load exceeded 50,000 RNA copies/ml plasma or remained above 5,000 copies/ml for more than three consecutive weeks. Eleven of 14 (79%) patients were able to achieve viral loads of less than 5,000 RNA copies/ml for at least 90 d following one, two, or three interruptions of treatment. However, a gradual increase in viremia and decline in CD4+ T cell counts was observed in most individuals. By an intention-to-treat analysis, eight (57%), six (43%), and three (21%) of 14 patients achieved a maximal period of control of 180, 360, and 720 d, respectively, despite augmentation of HIV-specific CD4+ and CD8+ T cell responses. The magnitude of HIV-1-specific cellular immune responses before treatment interruption did not predict duration of viremia control. The small sample size and lack of concurrent untreated controls preclude assessment of possible clinical benefit despite failure to control viremia by study criteria.These data indicate that despite initial control of viremia, durable viral control to less than 5,000 RNA copies/ml plasma in patients following treated acute HIV-1 infection occurs infrequently. Determination of whether early treatment leads to overall clinical benefit will require a larger and randomized clinical trial. These data may be relevant to current efforts to develop an HIV-1 vaccine designed to retard disease progression rather than prevent infection since they indicate that durable maintenance of low-level viremia may be difficult to achieve.
Prognostic Significance of Tryptophan Catabolism in Adult T-cell Leukemia/Lymphoma
Authors: Ayako Masaki, Takashi Ishida, Yasuhiro Maeda, Susumu Suzuki, Asahi Ito, Hisashi Takino, Hiroka Ogura, Haruhito Totani, Takashi Yoshida, Shiori Kinoshita, Tomoko Narita, Masaki Ri, Shigeru Kusumoto, Atsushi Inagaki, Hirokazu Komatsu, Akio Niimi, Ryuzo Ueda, Atae Utsunomiya, Hiroshi Inagaki, Shinsuke Iida
Journal: Clinical Cancer Research (2015)

Indoleamine 2,3-dioxygenase 1 (IDO1: IDO), an enzyme catabolizing tryptophan (Trp) into the kynurenine (Kyn) pathway, is increasingly being recognized as an important microenvironmental factor suppressing antitumor immune responses. The purpose of the present study was to determine the prognostic significance of Trp catabolism in adult T-cell leukemia/lymphoma (ATL).We quantified serum Trp and Kyn in 96 ATL patients, 38 human T-cell lymphotropic virus type-1 asymptomatic carriers (HTLV-1 ACs), and 40 healthy adult volunteer controls. The relationships between various clinical parameters including overall survival were analyzed. IDO expression was evaluated in the affected lymph nodes of ATL patients.Serum Kyn concentrations and Kyn/Trp ratios were significantly higher in HTLV-1 ACs than healthy controls. Both increased significantly with progression from HTLV-1 AC to ATL. However, there were no significant differences in the serum Trp concentrations between ATL patients, HTLV-1 ACs, and controls. IDO was possibly produced by ATL and/or cells of the microenvironment. Multivariate analyses demonstrated that a high serum Kyn/Trp ratio and high Kyn level, but not a high Trp level, were significantly independent detrimental prognostic factors in ATL, as well as in that subset of patients with aggressive variant ATL.Quantification of serum Kyn and Trp is useful for predicting prognosis of an individual ATL patient. Furthermore, ATL, especially in patients with a high serum Kyn/Trp ratio, is an appropriate disease for testing novel cancer immunotherapies targeting IDO.
Cytoplasmic Sequestration of p27 via AKT Phosphorylation in Renal Cell Carcinoma
Authors: Jinhee Kim, Eric Jonasch, Angela Alexander, John D. Short, Shengli Cai, Sijin Wen, Dimitra Tsavachidou, Pheroze Tamboli, Bogdan A. Czerniak, Kim Anh Do, Kevin J. Wu, Laura A. Marlow, Christopher G. Wood, John A. Copland, Cheryl Lyn Walker
Journal: Clinical Cancer Research (2008)

Abstract Purpose: p27 localization and expression has prognostic and predictive value in cancer. Little is known regarding expression patterns of p27 in renal cell carcinoma (RCC) or how p27 participates in disease progression or response to therapy. Experimental Design: RCC-derived cell lines, primary tumors, and normal renal epithelial cells were analyzed for p27 expression, phosphorylation (T157 of the NLS), and subcellular localization. RCC-derived cell lines were treated with phosphatidylinositol 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) inhibitors and effects on p27 localization were assessed. The potential contribution of cytoplasmic p27 to resistance to apoptosis was also evaluated. Results: p27 was elevated in tumors compared with matched controls, and cytoplasmic mislocalization of p27 was associated with increasing tumor grade. Cytoplasmic localization of p27 correlated with phosphorylation at T157, an AKT phosphorylation site in the p27 NLS. In RCC cell lines, activated PI3K/AKT signaling was accompanied by mislocalization of p27. AKT activation and phosphorylation of p27 was associated with resistance to apoptosis, and small interfering RNA knockdown of p27 or relocalization to the nucleus increased apoptosis in RCC cells. Treatment with the PI3K inhibitors LY294002 or wortmannin resulted in nuclear relocalization of p27, whereas mTOR inhibition by rapamycin did not. Conclusions: In RCC, p27 is phosphorylated at T157 of the NLS, with increasing tumor grade associated with cytoplasmic p27. PI3K inhibition (which reduces AKT activity) reduces T157 phosphorylation and induces nuclear relocalization of p27, whereas mTOR inhibition does not. Clinical testing of these findings may provide a rational approach for use of mTOR and PI3K/AKT pathway inhibitors in patients with RCC.