tbuckley/cabot-search huggingface dataset:
Prognostic Significance of Promoter DNA Methylation in Patients with Childhood Neuroblastoma
Authors: Diana T. Lau, Luke B. Hesson, Murray D. Norris, Glenn M. Marshall, Michelle Haber, Lesley J. Ashton
Journal: Clinical Cancer Research (2012)

Abstract Purpose: To characterize the clinical significance of promoter methylation in a cohort of primary neuroblastoma tumors and investigate the association between DNA methylation and clinical outcome. Experimental Design: A customized Illumina GoldenGate methylation assay was used to assess methylation status of 96 CpG sites within 48 candidate genes in primary neuroblastoma tumors obtained from 131 children diagnosed in Australia. Genes were selected on the basis of previous reports of altered DNA methylation in embryonal cancers. Levels of DNA methylation were validated in a subset of 48 patient samples using combined bisulfite restriction analysis (CoBRA) and bisulfite sequencing. A Cox proportional hazards model was used to investigate the association between promoter hypermethylation and the risk of relapse/death within 5 years of diagnosis, while adjusting for known prognostic factors including MYCN amplification, age, and stage at diagnosis. Results: Levels of promoter methylation of DNAJC15, neurotrophic tyrosine kinase receptor 1 or TrkA (NTRK1), and tumor necrosis factor receptor superfamily, member 10D (TNFRSF10D), were higher in older patients at diagnosis (P &amp;lt; 0.01), whereas higher levels of methylation of DNAJC15, NTRK1, and PYCARD were observed in patients with MYCN amplification (P &amp;lt; 0.001). In multivariate analysis, hypermethylation of folate hydrolase (FOLH1), myogenic differentiation-1 (MYOD1), and thrombospondin-1 (THBS1) remained significant independent predictors of poorer clinical outcome after adjusting for known prognostic factors (P ≤ 0.017). Moreover, more than 30% of patients displayed hypermethylation in 2 genes or more and were at least 2 times more likely to relapse or die (HR = 2.72, 95% confidence interval = 1.55–4.78, P = 0.001), independent of MYCN status, age, and stage at diagnosis. Conclusions: Our findings highlight the potential use of methylation profiling to identify additional prognostic markers and detect new therapeutic targets for selected patient subsets. Clin Cancer Res; 18(20); 5690–700. ©2012 AACR.
Cancer Trial Enrollment After State-Mandated Reimbursement
Authors: C. P. Gross, V. Murthy, Y. Li, A. D. Kaluzny, H. M. Krumholz
Journal: JNCI Journal of the National Cancer Institute (2004)

Background: Recruitment of patients into cancer research studies is exceedingly difficult, particularly for early phase trials. Payer reimbursement policies are a frequently cited barrier. We examined whether state policies that ensure coverage of routine medical care costs for cancer trial participants are associated with an increase in clinical trial enrollment. Methods: We used logistic Poisson regressions to analyze enrollment in National Cancer Institute phase II and phase III Clinical Trials Cooperative Group trials and compared changes in trial enrollment rates between 1996 and 2001 of privately insured cancer patients who resided in the four states that enacted coverage policies in 1999 with enrollment rates in states without such policies. All statistical tests were two-sided. Results: Trial enrollment rates increased in the coverage and noncoverage states by 24.9% (95% confidence interval [CI] = 22.8% to 27.0%) and 28.8% (95% CI = 27.7% to 29.8%) per year, respectively, from 1996 through 2001. After implementation of the coverage policies in 1999 in four states, there was a 21.7% (95% CI = 3.8% to 42.6%) annual increase in phase II trial enrollment in coverage states, compared with a 15.6% (95% CI = 8.8% to 21.8%) annual decrease in noncoverage states ( P <.001). After accounting for secular trend, cancer type, and race in multivariable analyses, the odds ratio (OR) for a phase II trial participant residing in a coverage versus a noncoverage state after 1999 was 1.59 per year (95% CI = 1.22 to 2.07; P = .001). In a multivariable analysis of phase III trial participation, there was a decrease in the odds of residing in a coverage state after 1999 (OR = 0.90, 95% CI = 0.84 to 0.98; P = .011). Conclusion: State coverage policies were associated with a statistically significant increase in phase II cancer trial participation and did not increase phase III cancer trial enrollment.
Predictive genomics profiling in athletics and sports performance
Authors: Marios Kambouris
Journal: British Journal of Sports Medicine (2011)

Lecture 27 Genes control biological systems such as muscle, cartilage and bone formation, muscle energy production and metabolism (mitochondriogenesis, lactic acid removal), blood and tissue oxygenation (erythropoiesis, angiogenesis, vasodilatation) all essential in Athletics and Sports. DNA sequence variations in these genes confer genetic advantages that can be exploited and genetic ‘barriers’ that could be overcome to achieve optimal athletic performance. The four ‘P's of Predictive Genomics (Personalization, Prediction, Prevention, Participation) are not only applicable but rather essential in athletics. Predictive genomic profiling for athletics reveals genetic variations that determine suitability for sports requiring either endurance or strength and speed, determine vulnerability to sports-related traumas as well as individualised nutritional requirements. Knowledge of genetic ‘suitability’ in respect to endurance capacity or strength and speed would lead to appropriate sport and athletic activity selection. Knowledge of genetic advantages and barriers would ‘direct’ an individualised training programme and nutritional plan and supplementation to achieving optimal performance, overcome the ‘pain barriers’ that results from intense exercise and pressure under competition with minimum waste of time and energy and avoidance of health risks (hypertension, cardiovascular disease, inflammation and injuries in tendons and bones) related to exercise, training and competition. Genetic ‘profiling’ for Athletics and Sports performance is an essential tool for proper Athletic activity and Sport selection as well as for the formulation of Individualized and Personalized training and nutritional programmes for optimising health and performance for the athlete.
Only high disease activity and positive rheumatoid factor indicate poor prognosis in patients with early rheumatoid arthritis treated with "sawtooth" strategy
Authors: T Mottonen, L Paimela, M Leirisalo-Repo, H Kautiainen, J Ilonen, P Hannonen
Journal: Annals of the Rheumatic Diseases (1998)

<h3>OBJECTIVES</h3> To investigate the prognostic significance of clinical and genetic markers on the outcome of patients with recent-onset rheumatoid arthritis (RA) treated actively with slow acting antirheumatic drugs (SAARDs). <h3>METHODS</h3> A total of 142 consecutive patients with early RA (median disease duration of 7 months) were treated according to the "sawtooth" strategy and prospectively followed up for an average of 6.2 years. Several clinical parameters at start as well as genetic markers were related to the functional outcome (ARA Functional class and HAQ disability score) and radiographic joint damage (Larsen's score) at the latest visit. <h3>RESULTS</h3> In logistic regression analysis only Mallya score (including morning stiffness, pain scale, grip strength, Ritchie's articular index, haemoglobin, and erythrocyte sedimentation rate) at baseline, and Mallya score and rheumatoid factor (RF) positivity at one year were found to be of significance with respect to the radiographic outcome of the patients. Furthermore, at the latest visit HAQ score was related to radiographic score. At baseline the mean ages of the DR4 positive patients and the patients with RA associated DR alleles were statistically significantly lower than those without the above mentioned risk factors (44 <i>v</i> 49, p=0.03 and 41<i> v</i> 53, p=0.04, respectively). However, these genetic markers had no prognostic significance on the functional or radiographic outcome of the patients. <h3>CONCLUSION</h3> High clinical disease activity at baseline and RF positivity especially at one year after the institution of SAARD treatment are the best predictors of poor prognosis in early RA. However, from the clinical point of view, the disease outcome of an individual patient with early RA, cannot be predicted accurately enough by present means.
A 53-year-old female with haemoptysis following breast cancer resection
Authors: R. S. Morehead
Journal: European Respiratory Journal (2006)

A 53-yr-old female presented with a 1-month history of cough productive of blood-flecked white sputum and right-sided chest pain.She had undergone a mastectomy 11 months previously for breast cancer.At surgery, the resection margins were free of tumour, lymph node sampling was negative, and no additional therapy was given.A chest radiograph at that time was normal.The patient's medical history was otherwise remarkable for a remote seizure disorder, migraine headaches, and a 15 pack-yr smoking history without known lung disease.There was no history of fever or chills, weight loss, dyspnoea, sinus complaints, voice change, renal disease, distant travel or other provocative exposures.
Longitudinal studies of the association between peripheral CD27++ plasma cells and systemic lupus erythematosus disease activity: preliminary results
Authors: E. T. Boekel, M. Prins, G.-J. Vrielink, W. de Kieviet, C. E. H. Siegert
Journal: Annals of the Rheumatic Diseases (2010)

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with a wide spectrum of clinical manifestations and immunological abnormalities. Because of its heterogeneous presentation and unpredictable course, clinical management of SLE remains difficult.1 High numbers of CD27++ CD20− B lymphocytes, identified as plasma cells (PCs), in peripheral blood have been reported in patients with increased SLE disease activity.2 3 This is the first prospective study to evaluate PCs as a biomarker for SLE disease activity.

A heterogeneous population of patients with SLE (n=17) were followed up for a period of 2–7 years (172 total clinic visits). The cohort included 14 clinically quiescent patients with previously diagnosed SLE treated with immunosuppressive drugs and three patients with newly diagnosed SLE admitted to our hospital with active disease (SLE disease activity index (SLEDAI) 16–32).4

Thirty-one peaks, defined as a PC value >3.6×106 …
Phenomenology of Rapid-Cycling Bipolar Disorder: Data From the First 500 Participants in the Systematic Treatment Enhancement Program
Authors: Christopher D. Schneck, David J. Miklowitz, Joseph R. Calabrese, Michael H. Allen, Marshall R. Thomas, Stephen R. Wisniewski, Sachiko Miyahara, Melvin D. Shelton, Terence A. Ketter, Joseph F. Goldberg, Charles L. Bowden, Gary S. Sachs
Journal: American Journal of Psychiatry (2004)

OBJECTIVE: This study compared demographic and phenomenological variables between bipolar patients with and without rapid cycling as a function of bipolar I versus bipolar II status. METHOD: The authors examined demographic, historical, and symptomatic features of patients with and without rapid cycling in a cross-sectional study of the first 500 patients with bipolar I or bipolar II disorder enrolled in the Systematic Treatment Enhancement Program for Bipolar Disorder, a multicenter project funded by the National Institute of Mental Health designed to evaluate the longitudinal outcome of patients with bipolar disorder. RESULTS: Rapid-cycling bipolar disorder occurred in 20% of the study group. Rapid-cycling patients were more likely to be women, although the effect was somewhat more pronounced among bipolar I patients than bipolar II patients. In addition, rapid-cycling bipolar patients experienced onset of their illness at a younger age, were more often depressed at study entry, and had poorer global functioning in the year before study entry than nonrapid-cycling patients. Rapid-cycling patients also experienced a significantly greater number of depressive and hypomanic/manic episodes in the prior year. A lifetime history of psychosis did not distinguish between rapid and nonrapid-cycling patients, although bipolar I patients were more likely to have experienced psychosis than bipolar II patients. CONCLUSIONS: Patients with rapid-cycling bipolar disorder demonstrate a greater severity of illness than nonrapid-cycling patients on a number of clinical measures. This study highlights the need to refine treatments for rapid cycling to reduce the overall morbidity and mortality of patients with this illness course modifier.
Quiescent Sox2+ Cells Drive Hierarchical Growth and Relapse in Sonic Hedgehog Subgroup Medulloblastoma
Authors: Robert J. Vanner, Marc Remke, Marco Gallo, Hayden J. Selvadurai, Fiona Coutinho, Lilian Lee, Michelle Kushida, Renee Head, Sorana Morrissy, Xueming Zhu, Tzvi Aviv, Veronique Voisin, Ian D. Clarke, Yisu Li, Andrew J. Mungall, Richard A. Moore, Yussanne Ma, Steven J.M. Jones, Marco A. Marra, David Malkin, Paul A. Northcott, Marcel Kool, Stefan M. Pfister, Gary Bader, Konrad Hochedlinger, Andrey Korshunov, Michael D. Taylor, Peter B. Dirks
Journal: Cancer Cell (2014)
Safety of Celecoxib in Patients With Ulcerative Colitis in Remission: A Randomized, Placebo-Controlled, Pilot Study
Authors: William J. Sandborn, William F. Stenson, Jørn Brynskov, Robin G. Lorenz, Gina M. Steidle, Jeffery L. Robbins, Jeffery D. Kent, Bradley J. Bloom
Journal: Clinical Gastroenterology and Hepatology (2006)
Junctophilin-2 is necessary for T-tubule maturation during mouse heart development
Authors: Julia O. Reynolds, David Y. Chiang, Wei Wang, David L. Beavers, Sayali S. Dixit, Darlene G. Skapura, Andrew P. Landstrom, Long-Sheng Song, Michael J. Ackerman, Xander H.T. Wehrens
Journal: Cardiovascular Research (2013)

Transverse tubules (TTs) provide the basic subcellular structures that facilitate excitation–contraction (EC) coupling, the essential process that underlies normal cardiac contractility. Previous studies have shown that TTs develop within the first few weeks of life in mammals but the molecular determinants of this development have remained elusive. This study aims to elucidate the role of junctophilin-2 (JPH2), a junctional membrane complex protein, in the maturation of TTs in cardiomyocytes. Using a novel cardiac-specific short-hairpin-RNA-mediated JPH2 knockdown mouse model (Mus musculus; αMHC-shJPH2), we assessed the effects of the loss of JPH2 on the maturation of the ventricular TT structure. Between embryonic day (E) 10.5 and postnatal day (P) 10, JPH2 mRNA and protein levels were reduced by >70% in αMHC-shJPH2 mice. At P8 and P10, knockdown of JPH2 significantly inhibited the maturation of TTs, while expression levels of other genes implicated in TT development remained mostly unchanged. At the same time, intracellular Ca2+ handling was disrupted in ventricular myocytes from αMHC- shJPH2 mice, which developed heart failure by P10 marked by reduced ejection fraction, ventricular dilation, and premature death. In contrast, JPH2 transgenic mice exhibited accelerated TT maturation by P8. Our findings suggest that JPH2 is necessary for TT maturation during postnatal cardiac development in mice. In particular, JPH2 may be critical in anchoring the invaginating sarcolemma to the sarcoplasmic reticulum, thereby enabling the maturation of the TT network.
Should Adjuvant Weekly Paclitaxel Be Considered Less Efficacious Than Anthracyclines Plus Cyclophosphamide for Lower-Risk Patients With Early-Stage Breast Cancer?
Authors: Vito Amoroso, Rebecca Pedersini, Phoebe Sharratt, Lucia Vassalli, Laura Ferrari, Sandra Sigala, Edda Simoncini, Alfredo Berruti
Journal: Journal of Clinical Oncology (2014)

TO THE EDITOR: The report of the Cancer and Leukemia Group B (CALGB) 40101 trial has shown that doxorubicin plus cyclophosphamide (AC) is potentially superior to weekly paclitaxel (T) suggesting that anthracyclines should not be abandoned in the management of early-stage breast cancer, even in subsets with a low/moderate risk of relapse as seen in those included in this study. Besides the methodological issues of all trials with a factorial design discussed in the accompanying editorial, we have noticed that patients with either human epidermal growth factor receptor 2 (HER2) -positive or HER2-negative breast cancer were recruited in the CALGB 40101 trial without prior stratification. In our opinion, HER2 status may be a potential confounder in the analysis testing the noninferiority of T compared with AC. The prognosis of HER2-positive breast cancers in the absence of trastuzumab is notoriously worse compared with HER2-negative tumors, but HER2 positivity may also have a predictive value of efficacy of anthracyclines. A published meta-analysis of adjuvant trials with individual patient data demonstrated a quantitative interaction between anthracycline activity and HER2 status. Furthermore, in relation to taxanes, a retrospective analysis of the CALGB 9344/INT0148 trial showed a significant benefit with the addition of paclitaxel after adjuvant therapy with doxorubicin and cyclophosphamide only in patients with tumors that had HER2 overexpression or amplification. To our knowledge, no data on the relative efficacy of anthracyclines over paclitaxel according to HER2 status are available up to now. The CALGB 40101 trial initiated in the early 2000s, and at that time HER2 status was not considered a stratification variable. As a consequence, only 48% of the 3,871 patients enrolled onto this study had their HER2 status available. This limitation notwithstanding, we believe that it would be clinically relevant to explore the hypothesis that the relative efficacy of AC compared with T might be different according to HER2 status in the CALGB 40101 data set. This single subgroup-specific analysis would involve approximately 1,800 women and might potentially have adequate statistical power. Treatment-associated toxicities are an important concern, particularly when adjuvant therapy is prescribed in a patient with breast cancer with low risk of relapse, as Shulman et al pointed out in their article. If the advantage of AC over T is mainly confined to HER2positive tumors, then there would be a rationale for reconsidering the less toxic regimen with single-agent T as a possible option for HER2negative patients, which should be tested in a future prospective randomized trial.
Inflammatory cells and activation markers in BAL during acute rejection and infection in lung transplant recipients: a prospective, longitudinal study
Authors: GC Riise, C Kjellstrom, W Ryd, H Schersten, F Nilsson, G Martensson, BA Andersson
Journal: European Respiratory Journal (1997)

Acute rejection of the transplanted lung is a clinical problem, since it decreases graft survival and predisposes the patient to chronic rejection and obliterative bronchiolitis (OB). In an earlier study, we had indications that eosinophil cationic protein (ECP) from activated eosinophils and hyaluronan (HYA) from fibroblasts were associated with acute pulmonary rejection. This prospective longitudinal study was designed to investigate whether molecules from activated inflammatory cells in bronchoalveolar lavage (BAL) fluid could serve as clinically useful diagnostic markers for acute rejection. BAL fluid from 138 bronchoscopies performed in 10 single lung, four bilateral lung and five heart-lung transplant recipients were analysed. Nine patients were studied for a period of more than 1 yr (mean 13.4 months) after surgery. Differential cell counts were made from the BAL fluid. ECP, myeloperoxidase (MPO), HYA and interleukin-8 (IL-8) were used as indirect markers for activation and attraction of eosinophils, neutrophils and fibroblasts, respectively. Fifty four episodes of acute rejection were diagnosed. Two patients developed OB. Nine episodes of bacterial infection, 13 episodes of cytomegalovirus (CMV) pneumonitis, three of Pneumocystis carinii infection and one of respiratory syncytial virus (RSV) infection were diagnosed. The mean levels of ECP, MPO, HYA and IL-8 were all higher during rejection episodes, but differences were not statistically significant compared to no rejection, when the confounding factors of time, concomitant infection, and repeated measures in the same individual had been accounted for. We could not confirm that measurements of eosinophil cationic protein, myeloperoxidase, hyaluronan and interleukin-8 in bronchoalveolar lavage fluid can be used as diagnostic markers for acute rejection in the postoperative follow-up of lung transplant recipients.
Preclinical Evaluation of a Potent Novel DNA-Dependent Protein Kinase Inhibitor NU7441
Authors: Yan Zhao, Huw D. Thomas, Michael A. Batey, Ian G. Cowell, Caroline J. Richardson, Roger J. Griffin, A. Hilary Calvert, David R. Newell, Graeme C.M. Smith, Nicola J. Curtin
Journal: Cancer Research (2006)

Abstract DNA double-strand breaks (DSB) are the most cytotoxic lesions induced by ionizing radiation and topoisomerase II poisons, such as etoposide and doxorubicin. A major pathway for the repair of DSB is nonhomologous end joining, which requires DNA-dependent protein kinase (DNA-PK) activity. We investigated the therapeutic use of a potent, specific DNA-PK inhibitor (NU7441) in models of human cancer. We measured chemosensitization by NU7441 of topoisomerase II poisons and radiosensitization in cells deficient and proficient in DNA-PKCS (V3 and V3-YAC) and p53 wild type (LoVo) and p53 mutant (SW620) human colon cancer cell lines by clonogenic survival assay. Effects of NU7441 on DSB repair and cell cycle arrest were measured by γH2AX foci and flow cytometry. Tissue distribution of NU7441 and potentiation of etoposide activity were determined in mice bearing SW620 tumors. NU7441 increased the cytotoxicity of ionizing radiation and etoposide in SW620, LoVo, and V3-YAC cells but not in V3 cells, confirming that potentiation was due to DNA-PK inhibition. NU7441 substantially retarded the repair of ionizing radiation–induced and etoposide-induced DSB. NU7441 appreciably increased G2-M accumulation induced by ionizing radiation, etoposide, and doxorubicin in both SW620 and LoVo cells. In mice bearing SW620 xenografts, NU7441 concentrations in the tumor necessary for chemopotentiation in vitro were maintained for at least 4 hours at nontoxic doses. NU7441 increased etoposide-induced tumor growth delay 2-fold without exacerbating etoposide toxicity to unacceptable levels. In conclusion, NU7441 shows sufficient proof of principle through in vitro and in vivo chemosensitization and radiosensitization to justify further development of DNA-PK inhibitors for clinical use. (Cancer Res 2006; 66(10): 5354-62)