tbuckley/cabot-search huggingface dataset:
Postinduction Minimal Residual Disease Monitoring by Polymerase Chain Reaction in Children With Acute Lymphoblastic Leukemia
Authors: Maddalena Paganin, Giulia Fabbri, Valentino Conter, Elena Barisone, Katia Polato, Giovanni Cazzaniga, Eugenia Giraldi, Franca Fagioli, Maurizio Aricò, Maria Grazia Valsecchi, Giuseppe Basso
Journal: Journal of Clinical Oncology (2014)

Purpose Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer. Monitoring minimal residual disease (MRD) by using real-time quantitative polymerase chain reaction (RQ-PCR) provides information for patient stratification and individual risk-directed treatment. Cooperative studies have documented that measurement of blast clearance from the bone marrow during and after induction therapy identifies patient populations with different risk of relapse. We explored the possible contribution of measurements of MRD during the course of treatment. Patients and Methods We used RQ-PCR to detect MRD in 110 unselected patients treated in Italy in the International Collaborative Treatment Protocol for Children and Adolescents With Acute Lymphoblastic Leukemia (AIEOP-BFM ALL 2000). The trial took place in AIEOP centers during postinduction chemotherapy. Results were categorized as negative, low positive (below the quantitative range [&lt; 5 × 10 −4 ]), or high positive (≥ 5 × 10 −4 ). Patients with at least one low-positive or high-positive result were assigned to the corresponding subgroup. Results Patients who tested high positive, low positive, or negative had significantly different cumulative incidences of leukemia relapse: 83.3%, 34.8%, and 8.6%, respectively (P &lt; .001). Two thirds of positive cases were identified within 4 months after induction-consolidation therapy, suggesting that this time frame may be most suitable for cost-effective MRD monitoring, particularly in patients who did not clear their disease at the end of consolidation. Conclusion These findings provide further insights into the dynamic of MRD and the ongoing effort to define molecular relapse in childhood ALL.
The Rise and Decline of Homicide—and Why
Authors: Alfred Blumstein, Frederick P. Rivara, Richard Rosenfeld
Journal: Annual Review of Public Health (2000)

▪ Abstract A dramatic rise in homicide in the latter half of the 1980s peaked during the 1990s and then declined at an equally dramatic rate. Such trends in homicide rates can be understood only by examining rates in specific age, sex, and racial groups. The increase primarily involved young males, especially black males, occurred first in the big cities, and was related to the sudden appearance of crack cocaine in the drug markets of the big cities around 1985. This development led to an increased need for and use of guns and was accompanied by a general diffusion of guns into the larger community. The decline in homicide since the early 1990s has been caused by changes in the drug markets, police response to gun carrying by young males, especially those under 18 years old, the economic expansion, and efforts to decrease general access to guns, as well as an increase in the prison population and a continued decline in homicide among those over age 24. The lessons learned from the recent homicide trends and the factors associated with them have important implications for public health and the criminal justice system.
The significance of a mycobacterial isolate in a low tuberculosis prevalence setting
Authors: Guy Hagan, Andrew Fairfax
Journal: European Respiratory Journal (2012)

Introduction : The incidence of tuberculosis in semi-rural Staffordshire is very low, around 2.8/100,000/year (1). We reviewed the significance of identifying mycobacteria in this population.

Methods : Retrospective analysis of patients from our institution with mycobacterium isolated from 1st Jan 2007 to 31st July 2011, with follow up until 1st Nov 2011. For patients with multiple isolates, the first species isolated was recorded.

Results : 67 patients were identified. Demographics of the M. tuberculosis(MTB) and non-tuberculous mycobacteria(NTM) patient groups are in Table 1. 22/43(51%) of the NTM samples were considered significant and treated. Patients with NTM were older and more likely to die (p<0.001). Chronic lung disease was present in 11(50%) of the treated NTM patients, and none of the MTB patients. 3 skin biopsies and 1 urine sample were +ve for NTM. Mycobacterial species isolated included 22 M. avium intracellularae, 6 gordonae, 4 chelonae, 3 kansassii, 3 malmoense, 2 xenopi and 1 each of shimoidei, marinum and interjectum.

View this table:

Table 1





Conclusions : Isolates of NTM were nearly twice as common as MTB. The diagnosis should particularly be considered in older patients with underlying lung disease. Isolation of a NTM requires careful assessment of its significance and pathogenicity. The incidence of NTM infection seems to be increasing(2).

1. www.hpa.org.uk, accessed Dec 2012.

2. Martin-Casabona N et al, Int J Tuberc Lung Dis 8(10):1186-1193 (2004).
Sustained platelet GP IIb/IIIa blockade with oral orbofiban: interim phamacodynamic results of the SOAR study
Authors: J.J. Ferguson, P.C. Deedwania, D.J. Kereiakes, D. Fitzgerald, R.J. Anders, D.M. Burns, B.S. Bryzinski
Journal: Journal of the American College of Cardiology (1998)
Dementia before Death in Ageing Societies— The Promise of Prevention and the Reality
Authors: Carol Brayne, Lu Gao, Michael Dewey, Fiona E Matthews
Journal: PLoS Medicine (2006)

Background Dementia and severe cognitive impairment are very closely linked to ageing. The longer we live the more likely we are to suffer from these conditions. Given population increases in longevity it is important to understand not only risk and protective factors for dementia and severe cognitive impairment at given ages but also whether protection affects cumulative risk. This can be explored by examining the effect on cumulative risk by time of death of factors found consistently to reduce risk at particular ages, such as education and social status. Methods and Findings In this analysis we report the prevalence of dementia and severe cognitive impairment in the year before death in a large population sample. In the Medical Research Council Cognitive Function and Ageing Study (a 10-y population-based cohort study of individuals 65 and over in England and Wales), these prevalences have been estimated by age, sex, social class, and education. Differences have been explored using logistic regression. The overall prevalence of dementia at death was 30%. There was a strong increasing trend for dementia with age from 6% for those aged 65–69 y at time of death to 58% for those aged 95 y and above at time of death. Higher prevalences were seen for severe cognitive impairment, with similar patterns. People with higher education and social class had significantly reduced dementia and severe cognitive impairment before death, but the absolute difference was small (under 10%). Conclusions Reducing risk for dementia at a given age will lead to further extension of life, thus cumulative risk (even in populations at lower risk for given ages) remains high. Ageing of populations is likely to result in an increase in the number of people dying with dementia and severe cognitive impairment even in the presence of preventative programmes. Policy development and research for dementia must address the needs of individuals who will continue to experience these conditions before death.
Is Prostate-Specific Antigen a Valid Surrogate End Point for Survival in Hormonally Treated Patients With Metastatic Prostate Cancer? Joint Research of the European Organisation for Research and Treatment of Cancer, the Limburgs Universitair Centrum, and AstraZeneca Pharmaceuticals
Authors: Laurence Collette, Tomasz Burzykowski, Kevin J. Carroll, Don Newling, Tom Morris, Fritz H. Schröder
Journal: Journal of Clinical Oncology (2005)

The long duration of phase III clinical trials of overall survival (OS) slows down the treatment-development process. It could be shortened by using surrogate end points. Prostate-specific antigen (PSA) is the most studied biomarker in prostate cancer (PCa). This study attempts to validate PSA end points as surrogates for OS in advanced PCa.Individual data from 2,161 advanced PCa patients treated in studies comparing bicalutamide to castration were used in a meta-analytic approach to surrogate end-point validation. PSA response, PSA normalization, time to PSA progression, and longitudinal PSA measurements were considered.The known association between PSA and OS at the individual patient level was confirmed. The association between the effect of intervention on any PSA end point and on OS was generally low (determination coefficient, < 0.69).It is a common misconception that high correlation between biomarkers and true end point justify the use of the former as surrogates. To statistically validate surrogate end points, a high correlation between the treatment effects on the surrogate and true end point needs to be established across groups of patients treated with two alternative interventions. The levels of association observed in this study indicate that the effect of hormonal treatment on OS cannot be predicted with a high degree of precision from observed treatment effects on PSA end points, and thus statistical validity is unproven. In practice, non-null treatment effects on OS can be predicted only from precisely estimated large effects on time to PSA progression (TTPP; hazard ratio, < 0.50).
Inhibition of Orthotopic Human Bladder Tumor Growth by Lentiviral Gene Transfer of Endostatin
Authors: Eiji Kikuchi, Silvia Menendez, Makoto Ohori, Carlos Cordon-Cardo, Noriyuki Kasahara, Bernard H. Bochner
Journal: Clinical Cancer Research (2004)

Inhibitors of endothelial cell proliferation, such as endostatin, result in suppression of tumor-associated angiogenesis and can achieve growth-inhibitory effects depending on the type of tumor treated. The purpose of this study was to investigate whether local overexpression of endostatin could serve to diminish tumor growth of bladder cancer in vivo.We examined the capability of lentiviral-mediated gene transfer in vitro and therapeutic effects of lentivirus-based vectors expressing endostatin on tumor growth using an orthotopic human bladder tumor model.We found that self-inactivating lentivirus vectors containing green fluorescent protein, alone or in combination with endostatin, were capable of efficient and stable gene transfer to a variety of human bladder tumor cell lines. The production and secretion of endostatin from lentivirus-transduced KU-7 human bladder cancer cells was confirmed by Western blot and competitive enzyme immunoassay. Intravesical instillation of untransduced, green fluorescent protein control lentivirus-transduced, and endostatin-transduced KU-7 cells was performed in murine models to establish orthotopic tumors. Sustained long-term expression of endostatin was achieved in lentivirus-transduced orthotopic bladder tumors, and it was associated with decreased vascularization and inhibition of tumor growth. Lentivirus vector-mediated overexpression of endostatin did not affect the intrinsic production of basic fibroblast growth factor and vascular endothelial growth factor.These findings suggest that lentivirus-mediated gene transfer might represent an effective strategy for expression of angioinhibitory peptides to achieve inhibition of human bladder cancer proliferation and tumor progression.
Mitogen-initiated synthesis and secretion of T cell growth factor(s) by a T-lymphoma cell line.
Authors: S Shimizu, Y Konaka, R T Smith
Journal: The Journal of Experimental Medicine (1980)

Of 12 T-lymphoma cell lines investigated, one line, EL-4 azgr (Thy-1+, Lyt-1+, Lyt-2-3-,Ia-, T-200+, sIg-, and FcR-) and, to a lesser extent, the parental cell line, EL-4, produced T cell growth factor(s) (TCGF) when stimulated by the T-cell mitogen concanavalin A (Con A). Induced production of TCGF-E was detected by 6 h and maximal at 18-24 h. Purified TCGF-E from this source had an approximately 30,000 mol wt and the biological activity of TCGF produced by whole spleen cells, including: augmentation of T cell-mitogen responses, cytotoxic T lymphocyte (CTL) proliferation support dependence, augmented generation of CTL, lack of strain specificity, and failure to stimulate resting T cells. TCGF-E is neither synthesized or secreted by this lymphoma cell line unless stimulated by Con A. X-irradiation up to 7,000 rad failed to inhibit synthesis and secretion. These observations have a practical application in providing a relatively homogeneous clonal cell product for T cell culture support and for structural and functional studies of the TCGF molecule(s). They suggest also a model for examining mechanisms of triggering production and secretion of a regulatory molecule that controls T cell functions.
SKUP<sup>3</sup>trial: comment
Authors: John Stradling, Malcolm Kohler
Journal: Thorax (2013)

In contrast, the Canadian data related to arrhythmias requiring hospital admission in the last 6 months. 1 Third, the cardiovascular and renal comorbidity exclusion criteria in UPLIFT were not used in major longterm COPD trials evaluating LABAS±ICS, such as the landmark TOwards a Revolution in COPD Health study, which had no specific cardiovascular or renal comorbidity exclusion criteria. 4 In our view, the efficacy/safety profile of a COPD medication can only be determined if those patients who are at greatest risk of serious adverse events are studied.If this has not been done, then failing to list the characteristics of patients who were excluded from trial participation in the medication data sheet is unsatisfactory.We propose that the tiotropium data sheet 5 is amended to state that the favourable efficacy/safety profile of
P-Selectin Glycoprotein Ligand-1 Regulates Adhesive Properties of the Endothelium and Leukocyte Trafficking Into Adipose Tissue
Authors: Hana M. Russo, Kevin J. Wickenheiser, Wei Luo, Miina K. Öhman, Luigi Franchi, Andrew P. Wright, Peter F. Bodary, Gabriel Núñez, Daniel T. Eitzman
Journal: Circulation Research (2010)

Adhesive interactions between endothelial cells and leukocytes affect leukocyte trafficking in adipose tissue. The role of P-selectin glycoprotein ligand-1 (Psgl-1) in this process is unclear.The goal of this study was to determine the effect of Psgl-1 deficiency on adhesive properties of the endothelium and on leukocyte recruitment into obese adipose depots.A genetic model of obesity was generated to study the effects of Psgl-1 deficiency on leukocyte trafficking. Leukocyte-endothelial interactions were increased in obese leptin receptor mutant mice (Lepr(db/db),Psgl-1(+/+)) but not obese Psgl-1-deficient mice (Lepr(db/db),Psgl-1(-/-)), when compared with lean mice (Lepr(+/+),Psgl-1(+/+)). This effect of Psgl-1 deficiency was due to indirect effects of Psgl-1, because Psgl-1(+/+) adoptively transferred leukocytes did not exhibit enhanced rolling in Lepr (db/db),Psgl-1(-/-) mice. Additionally, circulating levels of P-selectin, E-selectin, monocyte chemoattractant protein-1, and macrophage content of visceral adipose tissue were reduced in Lepr(db/db),Psgl-1(-/-) compared with Lepr(db/db),Psgl-1(+/+) mice. Reduced leukocyte-endothelial interactions and macrophage content of visceral adipose tissue due to Psgl-1 deficiency was also observed in a diet-induced obese mouse model. Psgl-1(-/-) mice were resistant to the endothelial effects of exogenous IL-1beta, suggesting that defective cytokine signaling contributes to the effect of Psgl-1 deficiency on leukocyte-endothelial interactions. Mice deficient in the IL-1 receptor also had reduced levels of circulating P-selectin, similar to those observed in Psgl-1(-/-) mice.Deficiency of Psgl-1 is associated with reduced IL-1 receptor-mediated adhesive properties of the endothelium and is protective against visceral fat inflammation in obese mice.
The Position of the Polycystic Kidney Disease 1 (PKD1) Gene Mutation Correlates with the Severity of Renal Disease
Authors: Sandro Rossetti, Sarah Burton, Lana Strmecki, Gregory R. Pond, Jośe L. San Millán, Klaus Zerres, T. Martin Barratt, Seza Ozen, Vicente E. Torres, Erik J. Bergstralh, Christopher G. Winearls, Peter C. Harris
Journal: Journal of the American Society of Nephrology (2002)

ABSTRACT. The severity of renal cystic disease in the major form of autosomal dominant polycystic kidney disease (PKD1) is highly variable. Clinical data was analyzed from 324 mutation-characterized PKD1 patients (80 families) to document factors associated with the renal outcome. The mean age to end-stage renal disease (ESRD) was 54 yr, with no significant difference between men and women and no association with the angiotensin-converting enzyme polymorphism. Considerable intrafamilial variability was observed, reflecting the influences of genetic modifiers and environmental factors. However, significant differences in outcome were also found among families, with rare examples of unusually late-onset PKD1. Possible phenotype/genotype correlations were evaluated by estimating the effects of covariants on the time to ESRD using proportional hazards models. In the total population, the location of the mutation (in relation to the median position; nucleotide 7812), but not the type, was associated with the age at onset of ESRD. Patients with mutations in the 5′ region had significantly more severe disease than the 3′ group; median time to ESRD was 53 and 56 yr, respectively ( P = 0.025), with less than half the chance of adequate renal function at 60 yr (18.9% and 39.7%, respectively). This study has shown that the position of the PKD1 mutation is significantly associated with earlier ESRD and questions whether PKD1 mutations simply inactivate all products of the gene.
An analysis of myocardial infarction. The effect of regional changes in contractility.
Authors: D K Bogen, A Needleman, T A McMahon
Journal: Circulation Research (1984)

In a preceding paper, we employed an initially spherical, modified membrane model of the infarcted ventricle to investigate the relation between ventricular function and both infarct size and infarct stiffness. In the present paper, we have applied the same model to a set of different questions, namely, the consequences of enhanced or depressed inotropic state within the noninfarcted myocardium. When infarcted ventricles containing up to 41% infarction are examined, stroke volume appears to be relatively insensitive to increases in inotropic state. However, stroke volume falls rapidly when inotropic state is depressed below 80% of normal. For the case of a ventricle with a large, weakly contracting segment which is not totally infarcted, stroke volume is impaired only when the contractility of the weak region is diminished below 50% of normal. Finally, the stress concentration around a region of infarction appears to be dependent more strongly on the inotropic state of the noninfarcted tissue than on the infarct size.
Pulse oximetry with clinical assessment to screen for congenital heart disease in neonates in China: a prospective study
Authors: Qu-ming Zhao, Xiao-jing Ma, Xiao-ling Ge, Fang Liu, Wei-li Yan, Lin Wu, Ming Ye, Xue-cun Liang, Jing Zhang, Yan Gao, Bing Jia, Guo-ying Huang
Journal: The Lancet (2014)
Interleukin-6 Prevents the Initiation but Enhances the Progression of Lung Cancer
Authors: Zhaoxia Qu, Fan Sun, Jingjiao Zhou, Liwen Li, Steven D. Shapiro, Gutian Xiao
Journal: Cancer Research (2015)

Recent studies suggest that high expression of the proinflammatory cytokine IL6 is associated with poor survival of lung cancer patients. Accordingly, IL6 has been a target of great interest for lung cancer therapy. However, the role of IL6 in lung cancer has not been determined yet. Here, we demonstrate that IL6 plays opposite roles in the initiation and growth of lung cancer in a mouse model of lung cancer induced by the K-Ras oncogene. We find that compared with wild-type mice, IL6-deficient mice developed much more lung tumors after an activating mutant of K-Ras was induced in the lungs. However, lung tumors developed in IL6-deficient mice were significantly smaller. Notably, both the lung tumor-suppressing and -promoting functions of IL6 involve its ability in activating the transcription factor STAT3. IL6/STAT3 signaling suppressed lung cancer initiation through maintaining lung homeostasis, regulating lung macrophages, and activating cytotoxic CD8 T cells under K-Ras oncogenic stress, whereas it promoted lung cancer cell growth through inducing the cell proliferation regulator cyclin D1. These studies reveal a previously unexplored role of IL6/STAT3 signaling in maintaining lung homeostasis and suppressing lung cancer induction. These studies also significantly improve our understanding of lung cancer and provide a molecular basis for designing IL6/STAT3-targeted therapies for this deadliest human cancer.
Detection of HBSAG in fixed liver tissue - use of a modified immunofluorescent technique and comparison with histochemical methods.
Authors: B Portmann, R M Galbraith, A L Eddleston, A J Zuckerman, R Williams
Journal: Gut (1976)

Spontaneously occurring mutations are of great relevance in diverse fields including biochemistry, oncology, evolutionary biology, and human genetics. Studies in experimental systems have identified a multitude of mutational mechanisms including DNA replication infidelity as well as many forms of DNA damage followed by inefficient repair or replicative bypass. However, the relative contributions of these mechanisms to human germline mutations remain completely unknown. Here, based on the mutational asymmetry with respect to the direction of replication and transcription, we suggest that error-prone damage bypass on the lagging strand plays a major role in human mutagenesis. Asymmetry with respect to transcription is believed to be mediated by the action of transcription-coupled DNA repair (TC-NER). TC-NER selectively repairs DNA lesions on the transcribed strand; as a result, lesions on the non-transcribed strand are preferentially converted into mutations. In human polymorphism we detect a striking similarity between transcriptional asymmetry and asymmetry with respect to replication fork direction. This parallels the observation that damage-induced mutations in human cancers accumulate asymmetrically with respect to the direction of replication, suggesting that DNA lesions are asymmetrically resolved during replication. Re-analysis of XR-seq data, Damage-seq data and cancers with defective NER corroborate the preferential error-prone bypass of DNA lesions on the lagging strand. We experimentally demonstrate that replication delay greatly attenuates the mutagenic effect of UV-irradiation, in line with the key role of replication in conversion of DNA damage to mutations. We conservatively estimate that at least 10% of human germline mutations arise due to DNA damage rather than replication infidelity. The number of these damage-induced mutations is expected to scale with the number of replications and, consequently, paternal age.