tbuckley/cabot-search huggingface dataset:
The Fundamental Role of the p53 Pathway in Tumor Metabolism and Its Implication in Tumor Therapy
Authors: Lan Shen, Xiang Sun, Zhenhong Fu, Guodong Yang, Jianying Li, Libo Yao
Journal: Clinical Cancer Research (2012)

It is well established that the altered metabolism exhibited by cancer cells, including high rates of glycolysis, lactate production, and biosynthesis of lipids, nucleotides, and other macromolecules, and which may occur either as a consequence or as a cause of tumorigenesis, plays an essential role in cancer progression. Recently, the tumor suppressor p53 was found to play a central role in this process. Here, we review the role of p53 in modulating tumor metabolism. Specifically, we focus on the functions of p53 in regulating aerobic glycolysis, oxidative phosphorylation, the pentose phosphate pathway, fatty acid synthesis and oxidation, and glutamine metabolism, and we discuss the therapeutic strategy whereby p53 helps to prevent malignant progression.
Improving surgical resection rates in lung cancer without a two stop service
Authors: E F Bowen
Journal: Thorax (2003)

The prevalence and clinical correlates of extrapyramidal signs in a consecutive series of 78 patients with Alzheimer9s disease attending a neurology clinic, and 20 age comparable normal controls, were examined. Based on the unified Parkinson9s disease rating scale (UPDRS) findings, 18 patients (23%) met criteria for parkinsonism, 44 (56%) had isolated extrapyramidal signs, and 16 (21%) had no extrapyramidal signs. Whereas the control group showed a similar prevalence of isolated extrapyramidal signs (57%), none of them showed parkinsonism. No significant differences were found for age, sex, duration of illness, and severity of dementia among the three Alzheimer9s disease groups. Patients with Alzheimer9s disease-parkinsonism, however, showed a significantly higher frequency of major depression and dysthymia and significantly higher Hamilton depression scores than patients with isolated or no extrapyramidal signs. Patients with Alzheimer9s disease-parkinsonism also showed significantly more deficits on frontal lobe related tasks such as the Wisconsin card sorting test, trail making test, and verbal fluency, as well as on tests of constructional praxis and abstract reasoning than patients with Alzheimer9s disease but no extrapyramidal signs. In conclusion, the study showed a specific association between Alzheimer9s disease and parkinsonism, as well as significant relations between parkinsonism, deficits in executive functions, and depression among patients with Alzheimer9s disease.
Estimated steps from motion detectors worn at the wrist, waist and ankle in COPD patients
Authors: Anasua Chakraborty, Richard ZuWallack, Bimalin Lahiri
Journal: European Respiratory Journal (2012)

Increased walking activity is desirable in COPD patients, but its direct measurement presents a problem in slow-moving individuals. Accordingly, we tested the effectiveness of a tri-axial accelerometer in estimating steps in patients with COPD. Devices were simultaneously worn on the dominant side on the wrist, waist, and ankle. Estimated steps were compared to visually-counted steps in 14 patients (FEV1 52 ± 22%). Step counting was performed at three walk speeds during endurance shuttle testing: 1) at the lowest shuttle walk speed [1.78 km/hr], 2) at 85% of maximal [3.18 ± 0.53 km/hr], and 3) at mid-way between these extremes [2.50 ± 0.33 km/hr]. The graphs (3 observations per patient) demonstrate the relationships between estimated steps from the 3 locations and visually counted steps. The diagonal line is the line of identity.  The devices significantly predicted counted steps (r²= 0.57, 0.46 and 0.65 for wrist, waist and ankle locations, respectively, p
Strong Epistatic Interactions within a Single Protein
Authors: Mariona Parera, Miguel Angel Martinez
Journal: Molecular Biology and Evolution (2014)

A central question in protein molecular evolution is whether an amino acid that occurs at a given site makes an independent contribution to fitness or whether its contribution depends on other amino acid sites in the protein sequence, a phenomenon known as intragenic epistasis. In the absence of intragenic epistasis, natural selection acts on a protein mutation independent of its genetic background, and the experimentally determined fitness for a mutation should be the same across all genetic backgrounds. We tested this hypothesis by using site-directed mutagenesis to introduce a well-characterized deleterious single amino acid substitution in 56 different hepatitis C virus NS3 protease variants. The catalytic efficiency of the mutated proteases was determined and compared with the corresponding wild-type protein. Fitness effects ranged from lethality to significantly beneficial. Although primarily deleterious and lethal effects were observed (41 and 5 out of 56 tested variants, respectively), deleterious effects ranged from near neutral (−26.7% reduction of fitness) to near lethal (−98.5%). Our findings demonstrate that the introduced amino acid substitution has different fitness effects in different protein variants and provide independent support for the relevant role of intragenic epistasis in protein evolution.
The Steroid Receptor Coactivator-1 Regulates Twist Expression and Promotes Breast Cancer Metastasis
Authors: Li Qin, Zhaoliang Liu, Hongwu Chen, Jianming Xu
Journal: Cancer Research (2009)

Abstract In breast cancer, steroid receptor coactivator-1 (SRC-1) expression positively correlates with HER2 expression and poor prognosis. In mouse mammary tumor virus–polyoma middle T (PyMT) breast cancer mouse model, SRC-1 strongly promotes mammary tumor metastasis. However, the molecular targets and mechanisms that mediate the role of SRC-1 in metastasis are unknown. In this study, SRC-1 wild-type (WT) and knockout (KO) cell lines were developed from the mammary tumors of WT/PyMT and KO/PyMT mice. WT cells exhibited strong migration and invasion capabilities, reduced E-cadherin and β-catenin epithelial markers, gained N-cadherin and vimentin mesenchymal markers, and formed undifferentiated invasive structures in three-dimensional culture. In contrast, KO cells showed slow migration and invasion, retained E-cadherin, had less N-cadherin and vimentin, and developed partially differentiated three-dimensional structures. Importantly, WT cells expressed Twist, a master regulator of metastasis, at significantly higher levels versus KO cells. SRC-1 knockdown in WT cells reduced Twist expression, whereas SRC-1 restoration in KO cells also rescued Twist expression. Furthermore, SRC-1 was found to coactivate Twist transcription through physical interaction with the transcription factor PEA3 at the proximal Twist promoter. Accordingly, Twist knockdown in WT cells increased E-cadherin and reduced cell invasion and metastasis, and Twist expression in KO cells decreased E-cadherin and increased cell invasion. SRC-1 knockdown in human breast cancer cells also decreased Twist, cell migration, and invasion. Therefore, SRC-1 promotes breast cancer invasiveness and metastasis by coactivating PEA3-mediated Twist expression. Intervention of SRC-1 function may provide new strategies to inhibit breast cancer metastasis. [Cancer Res 2009;69(9):3819–27]
Expression of class II transplantation antigen on vascular smooth muscle cells in human atherosclerosis.
Authors: L Jonasson, J Holm, O Skalli, G Gabbiani, G K Hansson
Journal: Journal of Clinical Investigation (1985)

A large proportion of the cells of the human atherosclerotic plaque is assumed to be derived from medial smooth muscle cells. In contrast to these, the cells of the plaque have the capacity to accumulate lipid, and they also proliferate at a higher rate than medial cells. It has therefore been suggested that smooth muscle cells undergo a change of phenotype during atherogenesis, but there has been no evidence for such a change on the molecular level. We have now analyzed carotid artery plaques using a battery of antibodies against cell surface and cytoskeletal antigens, and found that most of the cells express the class II transplantation antigen (Ia antigen) HLA-DR. Also, the beta chain of HLA-DR was detected by immunoblotting of plaque extracts with the OKIa1 monoclonal antibody. HLA-DR is normally present on cells of the immune system, but only 60% of the DR-positive cells of the plaque reacted with monoclonal antibodies specific for macrophages and lymphocytes. Many of the remaining DR-positive cells contained the muscle-specific intermediate filament protein, desmin. This indicates that smooth muscle cells of atherosclerotic plaques express DR antigen. In contrast, very few DR-positive cells were found in normal human arteries. This suggests that expression of class II antigen is part of a phenotypic change in smooth muscle cells in atherosclerosis.
Autologous Umbilical Cord Blood Transfusion in Very Young Children With Type 1 Diabetes
Authors: Michael J. Haller, Clive H. Wasserfall, Kieran M. McGrail, Miriam Cintron, Todd M. Brusko, John R. Wingard, Susan S. Kelly, Jonathan J. Shuster, Mark A. Atkinson, Desmond A. Schatz
Journal: Diabetes Care (2009)

Interest continues to grow regarding the therapeutic potential for umbilical cord blood therapies to modulate autoimmune disease. We conducted an open-label phase I study using autologous umbilical cord blood infusion to ameliorate type 1 diabetes.Fifteen patients diagnosed with type 1 diabetes and for whom autologous umbilical cord blood was stored underwent a single intravenous infusion of autologous cells and completed 1 year of postinfusion follow-up. Intensive insulin regimens were used to optimize glycemic control. Metabolic and immunologic assessments were performed before infusion and at established time periods thereafter.Median (interquartile range [IQR]) age at infusion was 5.25 (3.1-7.3) years, with a median postdiagnosis time to infusion of 17.7 (10.9-26.5) weeks. No infusion-related adverse events were observed. Metabolic indexes 1 year postinfusion were peak C-peptide median 0.50 ng/ml (IQR 0.26-1.30), P = 0.002; A1C 7.0% (IQR 6.5-7.7), P = 0.97; and insulin dose 0.67 units * kg(-1) * day(-1) (IQR 0.55-0.77), P = 0.009. One year postinfusion, no changes were observed in autoantibody titers, regulatory T-cell numbers, CD4-to-CD8 ratio, or other T-cell phenotypes.Autologous umbilical cord blood transfusion in children with type 1 diabetes is safe but has yet to demonstrate efficacy in preserving C-peptide. Larger randomized studies as well as 2-year postinfusion follow-up of this cohort are needed to determine whether autologous cord blood-based approaches can be used to slow the decline of endogenous insulin production in children with type 1 diabetes.
Stereotactic Body Radiation Therapy for Inoperable Early Stage Lung Cancer
Authors: Robert Timmerman
Journal: JAMA (2010)

<h3>Context</h3>Patients with early stage but medically inoperable lung cancer have a poor rate of primary tumor control (30%-40%) and a high rate of mortality (3-year survival, 20%-35%) with current management.<h3>Objective</h3>To evaluate the toxicity and efficacy of stereotactic body radiation therapy in a high-risk population of patients with early stage but medically inoperable lung cancer.<h3>Design, Setting, and Patients</h3>Phase 2 North American multicenter study of patients aged 18 years or older with biopsy-proven peripheral T1-T2N0M0 non–small cell tumors (measuring &lt;5 cm in diameter) and medical conditions precluding surgical treatment. The prescription dose was 18 Gy per fraction × 3 fractions (54 Gy total) with entire treatment lasting between 1½ and 2 weeks. The study opened May 26, 2004, and closed October 13, 2006; data were analyzed through August 31, 2009.<h3>Main Outcome Measures</h3>The primary end point was 2-year actuarial primary tumor control; secondary end points were disease-free survival (ie, primary tumor, involved lobe, regional, and disseminated recurrence), treatment-related toxicity, and overall survival.<h3>Results</h3>A total of 59 patients accrued, of which 55 were evaluable (44 patients with T1 tumors and 11 patients with T2 tumors) with a median follow-up of 34.4 months (range, 4.8-49.9 months). Only 1 patient had a primary tumor failure; the estimated 3-year primary tumor control rate was 97.6% (95% confidence interval [CI], 84.3%-99.7%). Three patients had recurrence within the involved lobe; the 3-year primary tumor and involved lobe (local) control rate was 90.6% (95% CI, 76.0%-96.5%). Two patients experienced regional failure; the local-regional control rate was 87.2% (95% CI, 71.0%-94.7%). Eleven patients experienced disseminated recurrence; the 3-year rate of disseminated failure was 22.1% (95% CI, 12.3%-37.8%). The rates for disease-free survival and overall survival at 3 years were 48.3% (95% CI, 34.4%-60.8%) and 55.8% (95% CI, 41.6%-67.9%), respectively. The median overall survival was 48.1 months (95% CI, 29.6 months to not reached). Protocol-specified treatment-related grade 3 adverse events were reported in 7 patients (12.7%; 95% CI, 9.6%-15.8%); grade 4 adverse events were reported in 2 patients (3.6%; 95% CI, 2.7%-4.5%). No grade 5 adverse events were reported.<h3>Conclusion</h3>Patients with inoperable non–small cell lung cancer who received stereotactic body radiation therapy had a survival rate of 55.8% at 3 years, high rates of local tumor control, and moderate treatment-related morbidity.
von Hippel-Lindau: A Tumor Suppressor Links Microtubules to Ciliogenesis and Cancer Development
Authors: E. Wolfgang Kuehn, Gerd Walz, Thomas Benzing
Journal: Cancer Research (2007)

Abstract Loss of von Hippel-Lindau (VHL) tumor suppressor gene function occurs in familial and most sporadic renal cell carcinoma. The tumor suppressor role of the protein pVHL is based on its ability to target transcription factors of the hypoxia-inducible factor family for degradation, but other functions of pVHL are less clearly defined. New findings show that pVHL is necessary for cilia formation. pVHL interacts with PAR proteins, a complex that specifies the membrane domains of polarized epithelial cells, and directs the orientation of growing microtubules. Loss of pVHL results in aberrant orientation of newly formed microtubules and prevents ciliogenesis. These results add to a growing body of evidence linking cilia and the cell cycle and suggest that the tumor suppressor role of pVHL may involve previously unrecognized pathways. [Cancer Res 2007;67(10):4537–40]
Do steroids increase lymphoma risk? A case-control study of lymphoma risk in polymyalgia rheumatica/giant cell arteritis
Authors: Johan Askling, Lars Klareskog, Henrik Hjalgrim, Eva Baecklund, Magnus Björkholm, Anders Ekbom
Journal: Annals of the Rheumatic Diseases (2005)

Recent studies indicate increased risks of malignant lymphomas among individuals treated with corticosteroids, but have not taken into account the underlying reasons for steroid use, so the increased risks might be attributable to the underlying disease or concomitant treatments other than steroids. Polymyalgia rheumatica (PMR) and temporal arteritis (giant cell arteritis, GCA) are common inflammatory conditions treated with steroids as single immunosuppressive therapy, but data on lymphoma risk in GCA/PMR are limited.To assess the risk of lymphoma associated with steroid treatment of GCA/PMR.The association between GCA/PMR and malignant lymphomas (overall, and separately for non-Hodgkin lymphoma, Hodgkin lymphoma, and chronic lymphatic leukaemia) was examined in a nationwide, population based, case-control study of 42,676 lymphoma cases and 78,487 matched population controls, using prospectively recorded data on lymphomas from the Swedish cancer register 1964-2000 and data on pre-lymphoma hospital admissions for GCA/PMR from the Swedish inpatient register 1964-2000. Odds ratios (OR) associated with a pre-lymphoma hospital admission for GCA/PMR were calculated using conditional logistic regression.153 lymphoma cases and 345 population controls had a history of GCA/PMR, resulting in an overall OR for malignant lymphomas of 0.81 (95% confidence interval, 0.67 to 0.98). The OR varied little with lymphoma type, sex, age, and calendar period. The OR for GCA was 0.67 (0.48 to 0.98) and for PMR, 0.83 (0.67 to 1.04).Treated GCA is not associated with increased lymphoma risks, which suggests that even at considerable cumulative doses, steroids may not appreciably increase lymphoma risk.
Pulse oximetry to assess sleep disordered breathing (SDB)
Authors: Sara Neale, Adrian H. Kendrick
Journal: European Respiratory Journal (2012)

Pulse oximetry is a simple tool used to assess suspected SDB. Currently focus is mainly on using 4% hypoxic dips/hr, although other indices exist.   Aim : To determine the use of pulse oximetry in the assessment of SDB using 4 indices and the value of using 2 nights of assessment   Methods : 150 consecutively referred patients had 2 nights of oximetry at home (Minolta 300i). Data was analysed (Download 2001; Stowood Scientific, UK), by experienced Physiologists and artefact removed. The 4% and 3% dips/hr, cumulative %time at SpO 2  90 ; Olson et al, J Sleep Res 1999;8:51-55) and Δindex>0.6 (Levy et al, Chest 1996;109:395-99) were obtained for each night.  Results : 132 patients gave usable data, 39F and 93M, aged 50 yrs (19 - 79).  The median(range) differences between the two nights (N1 - N2) for the group were: 4% dips/hr: -0.78 (-29.5 to 19.9), 3% dips/hr: -1.2 (-15.6 to 20.2), CT 90 : -0.12 (-21.9 to 29.7) and Δindex: -0.04 (-10.4 to 1.2). Using a combination of these indices, 26/132 (20%) were negative for all 4, 66 (50%) positive for all 4, 10 for any 3, 12 for any 2 and 18 for any one.   Conclusions : To use pulse oximetry  1) requires analysis by experienced practitioners to ensure accuracy of data;  2) requires two nights, resulting in a > 23% increase in a positive diagnosis from the second night;  3) with a combination of the 4 indices, all of which have good sensitivity and specificity for SDB, gives an indication of the likelihood of SDB being present. Using a combination of any 3 or all 4 accounts for 77% of the patients assessed.
The Association Between A1C and Subclinical Cardiovascular Disease
Authors: Marguerite J. McNeely, Robyn L. McClelland, Diane E. Bild, David R. Jacobs, Russell P. Tracy, Mary Cushman, David C. Goff, Brad C. Astor, Steven Shea, David S. Siscovick
Journal: Diabetes Care (2009)

OBJECTIVE To test the hypothesis that A1C is associated with subclinical cardiovascular disease (CVD) in a population without evident diabetes, after adjusting for traditional CVD risk factors and BMI. RESEARCH DESIGN AND METHODS This was a cross-sectional study of 5,121 participants without clinically evident CVD or diabetes (fasting glucose ≥7.0 mmol/l or use of diabetes medication), aged 47–86 years, enrolled in the Multi-Ethnic Study of Atherosclerosis (MESA). Measurements included carotid intimal-medial wall thickness (CIMT) and coronary artery calcification (CAC). Results were adjusted for age, sex, ethnicity, smoking, systolic blood pressure, LDL cholesterol, HDL cholesterol, antihypertensive medication use, lipid-lowering medication use, and BMI. RESULTS Compared with those in the lowest quartile for A1C ([mean ± SD] 5.0 ± 0.2%), participants in the highest quartile (6.0 ± 0.3%) had higher adjusted mean values for common CIMT (0.85 vs. 0.87 mm, P = 0.003) and internal CIMT (1.01 vs. 1.08 mm, P = 0.003). A1C quartile was not associated with prevalence of CAC in the entire cohort (P = 0.27); however, the association was statistically significant in women (adjusted prevalence of CAC in lowest and highest A1C quartiles 37.5 vs. 43.0%, P = 0.01). Among those with some CAC, higher A1C quartile tended to be associated with higher CAC score, but the results were not statistically significant (adjusted P = 0.11). CONCLUSIONS In this multiethnic cohort, there were small, positive associations between A1C, common CIMT, and internal CIMT in the absence of clinically evident diabetes. An association between higher A1C and CAC prevalence was evident only in women.
Prevention of sports injury I: a systematic review of applied biomechanics and physiology outcomes research
Authors: Kellen McBain, Ian Shrier, Rebecca Shultz, Willem H Meeuwisse, Martin Klügl, Daniel Garza, Gordon O Matheson
Journal: British Journal of Sports Medicine (2011)

To analyse published articles that used interventions aimed at investigating biomechanical/physiological outcomes (ie, intermediate risk factors) for sport injury prevention in order to characterise the state of the field and identify important areas not covered in the literature.PubMed, Cinahl, Web of Science and Embase were searched using a broad search strategy.Only 144 of 2525 articles retrieved by the search strategy met the inclusion criteria. Crossover study designs increased by 175% in the late 1980s until 2005 but have declined 32% since then. Randomised controlled trial (RCT) study designs increased by 650% since the early 1980s. Protective equipment studies (61.8% of all studies) declined by 35% since 2000, and training studies (35.4% of all studies) increased by 213%. Equipment research studied stability devices (83.1%) and attenuating devices (13.5%) whereas training research studied balance and coordination (54.9%), strength and power (43.1%) and stretching (15.7%). Almost all (92.1%) studies investigated the lower extremity and 78.1% were of the joint (non-bone)-ligament type. Finally, 57.5% of the reports studied contact sports, 24.2% collision and 25.8% non-contact sports.The decrease in crossover study design and increase in RCTs over time suggest a shift in study design for injury prevention articles. Another notable finding was the change in research focus from equipment interventions, which have been decreasing since 2000 (35% decline), to training interventions, which have been increasing (213% increase). Finally, there is very little research on overuse or upper extremity injuries.