tbuckley/cabot-search huggingface dataset:
The retrotransposon Osvaldo from Drosophila buzzatii displays all structural features of a functional retrovirus
Authors: A. Pantazidis, M. Labrador, A. Fontdevila
Journal: Molecular Biology and Evolution (1999)

The Osvaldo retrotransposon has shown a high transposition rate in some strains of Drosophila buzzatii and in hybrids between D. buzzatii and its sibling D. koepferae. In order to understand the molecular basis of this phenomenon, we developed a procedure to clone a recently transposed copy with the aim of characterizing an active, full- length Osvaldo element. The complete nucleotide sequence of Osvaldo, obtained from a recent insertion site, was determined. Osvaldo is 9,045 bp long and is composed of a central coding region flanked by identical long terminal repeats (LTRs) of 1,196 bp each. Sequences homologous to the polypurine tract and tRNA-primer-binding site of retroviruses are located adjacent to the 3' and 5' LTRs, respectively. The internal region of Osvaldo contains three long open reading frames (ORFs 1, 2, and 3), comparable in size and location to gag, pol, and env retroviral genes. The conceptual translation of Osvaldo ORF1 exhibits sequence homology to HIV1 and SIV capsid (p24) and nucleocapsid (p7) mature proteins. ORF2 encodes the putative protease (PR), reverse transcriptase/ribonuclease H (RT/RH), integrase (IN), and a significant portion of the surface envelope (ENV) protein that is interrupted by a putative intron. A third ORF encodes the remaining part of the ENV protein. The predicted 62-kDa ENV protein shares several general features with membrane glycoproteins, including a potential signal peptide, a transmembrane domain near the C-terminus that could function as a membrane anchor, four consensus N-linked glycosylation motifs, and, finally, a potential protease cleavage site. The phylogenetic relationships of Osvaldo are explored, and they suggest that Osvaldo may constitute a new family of retroviruses in insects, distantly related to the previously described group of gypsy retroviruses.
Minimally Invasive Pharmacokinetic and Pharmacodynamic Technologies in Hypothesis-Testing Clinical Trials of Innovative Therapies
Authors: Paul Workman, Eric O. Aboagye, Yuen-Li Chung, John R. Griffiths, Rachel Hart, Martin O. Leach, Ross J. Maxwell, Paul M. J. McSheehy, Pat M. Price, Jamal Zweit
Journal: JNCI Journal of the National Cancer Institute (2006)

Clinical trials of new cancer drugs should ideally include measurements of parameters such as molecular target expression, pharmacokinetic (PK) behavior, and pharmacodynamic (PD) endpoints that can be linked to measures of clinical effect. Appropriate PK/PD biomarkers facilitate proof-of-concept demonstrations for target modulation; enhance the rational selection of an optimal drug dose and schedule; aid decision-making, such as whether to continue or close a drug development project; and may explain or predict clinical outcomes. In addition, measurement of PK/PD biomarkers can minimize uncertainty associated with predicting drug safety and efficacy, reduce the high levels of drug attrition during development, accelerate drug approval, and decrease the overall costs of drug development. However, there are many challenges in the development and implementation of biomarkers that probably explain their disappointingly low implementation in phase I trials. The Pharmacodynamic/Pharmacokinetic Technologies Advisory committee of Cancer Research UK has found that submissions for phase I trials of new cancer drugs in the United Kingdom often lack detailed information about PK and/or PD endpoints, which leads to suboptimal information being obtained in those trials or to delays in starting the trials while PK/PD methods are developed and validated. Minimally invasive PK/PD technologies have logistic and ethical advantages over more invasive technologies. Here we review these technologies, emphasizing magnetic resonance spectroscopy and positron emission tomography, which provide detailed functional and metabolic information. Assays that measure effects of drugs on important biologic pathways and processes are likely to be more cost-effective than those that measure specific molecular targets. Development, validation, and implementation of minimally invasive PK/PD methods are encouraged.
Causes and risk factors for death in systemic sclerosis: a study from the EULAR Scleroderma Trials and Research (EUSTAR) database
Authors: A. J. Tyndall, B. Bannert, M. Vonk, P. Airo, F. Cozzi, P. E. Carreira, D. F. Bancel, Y. Allanore, U. Muller-Ladner, O. Distler, F. Iannone, R. Pellerito, M. Pileckyte, I. Miniati, L. Ananieva, A. B. Gurman, N. Damjanov, A. Mueller, G. Valentini, G. Riemekasten, M. Tikly, L. Hummers, M. J. Henriques, P. Caramaschi, A. Scheja, B. Rozman, E. Ton, G. Kumanovics, B. Coleiro, E. Feierl, G. Szucs, C. A. Von Muhlen, V. Riccieri, S. Novak, C. Chizzolini, A. Kotulska, C. Denton, P. C. Coelho, I. Kotter, I. Simsek, P. G. de la Pena Lefebvre, E. Hachulla, J. R. Seibold, S. Rednic, J. Stork, J. Morovic-Vergles, U. A. Walker
Journal: Annals of the Rheumatic Diseases (2010)

<h3>Objectives</h3> To determine the causes and predictors of mortality in systemic sclerosis (SSc). <h3>Methods</h3> Patients with SSc (n=5860) fulfilling the American College of Rheumatology criteria and prospectively followed in the EULAR Scleroderma Trials and Research (EUSTAR) cohort were analysed. EUSTAR centres completed a structured questionnaire on cause of death and comorbidities. Kaplan–Meier and Cox proportional hazards models were used to analyse survival in SSc subgroups and to identify predictors of mortality. <h3>Results</h3> Questionnaires were obtained on 234 of 284 fatalities. 55% of deaths were attributed directly to SSc and 41% to non-SSc causes; in 4% the cause of death was not assigned. Of the SSc-related deaths, 35% were attributed to pulmonary fibrosis, 26% to pulmonary arterial hypertension (PAH) and 26% to cardiac causes (mainly heart failure and arrhythmias). Among the non-SSc-related causes, infections (33%) and malignancies (31%) were followed by cardiovascular causes (29%). Of the non-SSc-related fatalities, 25% died of causes in which SSc-related complications may have participated (pneumonia, sepsis and gastrointestinal haemorrhage). Independent risk factors for mortality and their HR were: proteinuria (HR 3.34), the presence of PAH based on echocardiography (HR 2.02), pulmonary restriction (forced vital capacity below 80% of normal, HR 1.64), dyspnoea above New York Heart Association class II (HR 1.61), diffusing capacity of the lung (HR 1.20 per 10% decrease), patient age at onset of Raynaud9s phenomenon (HR 1.30 per 10 years) and the modified Rodnan skin score (HR 1.20 per 10 score points). <h3>Conclusion</h3> Disease-related causes, in particular pulmonary fibrosis, PAH and cardiac causes, accounted for the majority of deaths in SSc.
BAX and p16INK4Aare independent positive prognostic markers for advanced tumour stage of nonsmall cell lung cancer
Authors: C. Gessner, U. Liebers, H. Kuhn, P. Stiehl, C. Witt, J. Schauer, G. Wolff
Journal: European Respiratory Journal (2002)

Clinical studies suggest prognostic relevance of p16 INK4A in nonsmall cell lung cancer (NSCLC) while conflicting results for p53 have been published. However, the importance of the apoptosis regulating gene BAX, a downstream regulator of p53, on the prognosis of NSCLC is unknown. The present study investigated the prognostic relevance of BAX with respect to the status of p53 and p16 INK4A in 61 patients with advanced NSCLC. Protein expression of BAX, p53 and p16 INK4A was investigated retrospectively by immunohistochemistry. Tumour deoxyribonucleic acid (DNA) was screened for p53 mutations by single strand-conformation polymorphism polymerase chain reaction (PCR) and BAX frameshift mutations by fragment length analysis. Patients with positive BAX protein expression had a significantly longer median survival (14 months) than those patients without BAX expression (6 months, p=0.0004). In contrast, p53 status did not influence prognosis. Patients with p16 INK4A negative tumours had a significantly shorter survival (4 months) than those with p16 INK4A protein expression (15 months, p=0.0001). Furthermore, the loss of p16 INK4A protein expression correlated strongly with the pressure of distant and advanced lymph-node metastases. The best survival was seen in a subgroup of 20 patients with positive p16 INK4A expression and intact BAX (p=0.0002). The results of the present study suggest that the loss of BAX and p16 INK4A expression are independent markers for poor prognosis in nonsmall cell lung cancer. The study suggests that multimarker analysis of genes involved in apoptosis may be useful for determining individual therapy and for identifying targets for gene-replacement therapy. This should be assessed in a prospective study with a larger cohort of patients.
Serum Uric Acid Predicts Progression of Subclinical Coronary Atherosclerosis in Individuals Without Renal Disease
Authors: Ticiana C. Rodrigues, David M. Maahs, Richard J. Johnson, Diana I. Jalal, Gregory L. Kinney, Christopher Rivard, Marian Rewers, Janet K. Snell-Bergeon
Journal: Diabetes Care (2010)

To examine uric acid (UA) as a possible predictor of the progression of coronary artery calcification (CAC) using data from the prospective Coronary Artery Calcification in Type 1 Diabetes (CACTI) Study.CAC was measured by electron beam tomography at the baseline and at a follow-up 6.0±0.5 years later. The study population included 443 participants with type 1 diabetes and 526 control subjects who were free of diagnosed coronary artery disease at baseline. The presence of renal disease was defined by the presence of albuminuria and/or low glomerular filtration rate.In subjects without renal disease, serum UA predicted CAC progression (odds ratio 1.30 [95% CI 1.07-1.58], P=0.007) independent of conventional cardiovascular risk factors including diabetes and the presence of metabolic syndrome.Serum UA levels predict the progression of coronary atherosclerosis and may be useful in identifying who is at risk for vascular disease in the absence of significant chronic kidney disease.
Antitumor Activity of Metal-Chelating Compound Dp44mT Is Mediated by Formation of a Redox-Active Copper Complex That Accumulates in Lysosomes
Authors: David B. Lovejoy, Patric J. Jansson, Ulf T. Brunk, Jacky Wong, Prem Ponka, Des R. Richardson
Journal: Cancer Research (2011)

The metal-chelating compound Dp44mT is a di-2-pyridylketone thiosemicarbazone (DpT) which displays potent and selective antitumor activity. This compound is receiving translational attention, but its mechanism is poorly understood. Here, we report that Dp44mT targets lysosome integrity through copper binding. Studies using the lysosomotropic fluorochrome acridine orange established that the copper-Dp44mT complex (Cu[Dp44mT]) disrupted lysosomes. This targeting was confirmed with pepstatin A-BODIPY FL, which showed redistribution of cathepsin D to the cytosol with ensuing cleavage of the proapoptotic BH3 protein Bid. Redox activity of Cu[Dp44mT] caused cellular depletion of glutathione, and lysosomal damage was prevented by cotreatment with the glutathione precursor N-acetylcysteine. Copper binding was essential for the potent antitumor activity of Dp44mT, as coincubation with nontoxic copper chelators markedly attenuated its cytotoxicity. Taken together, our studies show how the lysosomal apoptotic pathway can be selectively activated in cancer cells by sequestration of redox-active copper. Our findings define a novel generalized strategy to selectively target lysosome function for chemotherapeutic intervention against cancer.
Lipoprotein(a) as a Risk Factor for Cardiovascular Mortality in Type 2 Diabetic Patients
Authors: Cristina Hernández, Gemma Francisco, Pilar Chacón, Rafael Simó
Journal: Diabetes Care (2005)

Although patients with type 2 diabetes have a high risk of death from cardiovascular disease (CVD), the traditional risk factors do not fully explain this excess of mortality. In this regard, it would be of great interest to assess the role of nontraditional risk factors such as lipoprotein(a) in cardiovascular mortality in diabetic patients.

Danesh et al. (1), in a meta-analysis including the prospective studies published before 2000, concluded that there was a clear association between lipoprotein(a) and CVD in the general population. Further prospective reports have demonstrated that lipoprotein(a) is an independent predictor of the development of CVD (2–5). However, little data exist on the clinical importance of lipoprotein(a) in the diabetic population. We herein report a prospective study to evaluate the relationship between lipoprotein(a) levels and cardiovascular mortality in type 2 diabetic patients of Caucasian origin.

One hundred twenty-two consecutive type 2 diabetic outpatients of Caucasian origin attending the outpatient diabetic unit of a university hospital between April and May of 1993 were enrolled for a 10-year prospective study. To avoid the possible transient increase of lipoprotein(a) after starting insulin treatment (6), all patients in whom insulin treatment was initiated in the months before the study were excluded. Patients with renal failure were also excluded. To assess evidence of macroangiopathy, we used the World Health Organization (WHO) protocol, which includes a detailed questionnaire and a 12-lead electrocardiogram (7,8). By the end of the study, data were available from 100 patients. Of these, 29 had died (23 from CVD).

Metabolic parameters …
Correction of acidosis in hemodialysis patients increases the sensitivity of the parathyroid glands to calcium.
Authors: K A Graham, N A Hoenich, M Tarbit, M K Ward, T H Goodship
Journal: Journal of the American Society of Nephrology (1997)

Correction of acidosis in hemodialysis patients increases the sensitivity of the parathyroid glands to calcium. In this study, the parathyroid response to the correction of acidosis in eight hemodialysis patients was determined by performing dynamic assessment of parathyroid function before and after the correction of acidosis. The parathyroid response to intravenous calcitriol before and after the correction of acidosis was also assessed. After optimal correction of acidosis, there were no significant changes in blood pH, ionized calcium, phosphate, or alkaline phosphatase values, but the level of venous total CO2 increased significantly. Parathyroid hormone/ionized calcium curves were displaced downward after correction of acidosis, but not after the administration of intravenous calcitriol. The correction of metabolic acidosis in hemodialysis patients with secondary hyperparathyroidism can suppress parathyroid hormone secretion by increasing the sensitivity of the parathyroid glands to ionized calcium.
Lifetime Events and Posttraumatic Stress Disorder in 4 Postconflict Settings
Authors: J T de Jong, I H Komproe, M Van Ommeren, M El Masri, M Araya, N Khaled, W van De Put, D Somasundaram
Journal: JAMA (2001)

ContextLittle is known about the impact of trauma in postconflict, low-income countries where people have survived multiple traumatic experiences.ObjectiveTo establish the prevalence rates of and risk factors for posttraumatic stress disorder (PTSD) in 4 postconflict, low-income countries.Design, Setting, and ParticipantsEpidemiological survey conducted between 1997 and 1999 among survivors of war or mass violence (aged ≥16 years) who were randomly selected from community populations in Algeria (n = 653), Cambodia (n = 610), Ethiopia (n = 1200), and Gaza (n = 585).Main Outcome MeasurePrevalence rates of PTSD, assessed using the PTSD module of the Composite International Diagnostic Interview version 2.1 and evaluated in relation to traumatic events, assessed using an adapted version of the Life Events and Social History Questionnaire.ResultsThe prevalence rate of assessed PTSD was 37.4% in Algeria, 28.4% in Cambodia, 15.8% in Ethiopia, and 17.8% in Gaza. Conflict-related trauma after age 12 years was the only risk factor for PTSD that was present in all 4 samples. Torture was a risk factor in all samples except Cambodia. Psychiatric history and current illness were risk factors in Cambodia (adjusted odds ratio [OR], 3.6; 95% confidence interval [CI], 2.3-5.4 and adjusted OR,1.6; 95% CI, 1.0-2.7, respectively) and Ethiopia (adjusted OR, 3.9; 95% CI, 2.0-7.4 and adjusted OR, 1.8; 95% CI, 1.1-2.7, respectively). Poor quality of camp was associated with PTSD in Algeria (adjusted OR, 1.8; 95% CI, 1.3-2.5) and in Gaza (adjusted OR, 1.7; 95% CI, 1.1-2.8). Daily hassles were associated with PTSD in Algeria (adjusted OR, 1.6; 95% CI, 1.1-2.4). Youth domestic stress, death or separation in the family, and alcohol abuse in parents were associated with PTSD in Cambodia (adjusted OR, 1.7; 95% CI, 1.1-2.6; adjusted OR, 1.7; 95% CI, 1.0-2.8; and adjusted OR, 2.2; 95% CI, 1.1-4.4, respectively).ConclusionsUsing the same assessment methods, a wide range of rates of symptoms of PTSD were found among 4 low-income populations who have experienced war, conflict, or mass violence. We identified specific patterns of risk factors per country. Our findings indicate the importance of contextual differences in the study of traumatic stress and human rights violations.
Adjuvant Ovarian Suppression in Premenopausal Breast Cancer
Authors: Prudence A. Francis, Meredith M. Regan, Gini F. Fleming, István Láng, Eva Ciruelos, Meritxell Bellet, Hervé R. Bonnefoi, Miguel A. Climent, Gian Antonio Da Prada, Harold J. Burstein, Silvana Martino, Nancy E. Davidson, Charles E. Geyer, Barbara A. Walley, Robert Coleman, Pierre Kerbrat, Stefan Buchholz, James N. Ingle, Eric P. Winer, Manuela Rabaglio-Poretti, Rudolf Maibach, Barbara Ruepp, Anita Giobbie-Hurder, Karen N. Price, Marco Colleoni, Giuseppe Viale, Alan S. Coates, Aron Goldhirsch, Richard D. Gelber
Journal: New England Journal of Medicine (2014)

Suppression of ovarian estrogen production reduces the recurrence of hormone-receptor-positive early breast cancer in premenopausal women, but its value when added to tamoxifen is uncertain.We randomly assigned 3066 premenopausal women, stratified according to prior receipt or nonreceipt of chemotherapy, to receive 5 years of tamoxifen, tamoxifen plus ovarian suppression, or exemestane plus ovarian suppression. The primary analysis tested the hypothesis that tamoxifen plus ovarian suppression would improve disease-free survival, as compared with tamoxifen alone. In the primary analysis, 46.7% of the patients had not received chemotherapy previously, and 53.3% had received chemotherapy and remained premenopausal.After a median follow-up of 67 months, the estimated disease-free survival rate at 5 years was 86.6% in the tamoxifen-ovarian suppression group and 84.7% in the tamoxifen group (hazard ratio for disease recurrence, second invasive cancer, or death, 0.83; 95% confidence interval [CI], 0.66 to 1.04; P=0.10). Multivariable allowance for prognostic factors suggested a greater treatment effect with tamoxifen plus ovarian suppression than with tamoxifen alone (hazard ratio, 0.78; 95% CI, 0.62 to 0.98). Most recurrences occurred in patients who had received prior chemotherapy, among whom the rate of freedom from breast cancer at 5 years was 82.5% in the tamoxifen-ovarian suppression group and 78.0% in the tamoxifen group (hazard ratio for recurrence, 0.78; 95% CI, 0.60 to 1.02). At 5 years, the rate of freedom from breast cancer was 85.7% in the exemestane-ovarian suppression group (hazard ratio for recurrence vs. tamoxifen, 0.65; 95% CI, 0.49 to 0.87).Adding ovarian suppression to tamoxifen did not provide a significant benefit in the overall study population. However, for women who were at sufficient risk for recurrence to warrant adjuvant chemotherapy and who remained premenopausal, the addition of ovarian suppression improved disease outcomes. Further improvement was seen with the use of exemestane plus ovarian suppression. (Funded by Pfizer and others; SOFT ClinicalTrials.gov number, NCT00066690.).
The Emergence of Modern Neuroscience: Some Implications for Neurology and Psychiatry
Authors: W. Maxwell Cowan, Donald H. Harter, Eric R. Kandel
Journal: Annual Review of Neuroscience (2000)

One of the most significant developments in biology in the past half century was the emergence, in the late 1950s and early 1960s, of neuroscience as a distinct discipline. We review here factors that led to the convergence into a common discipline of the traditional fields of neurophysiology, neuroanatomy, neurochemistry, and behavior, and we emphasize the seminal roles played by David McKenzie Rioch, Francis O Schmitt, and especially Stephen W Kuffler in creating neuroscience as we now know it. The application of the techniques of molecular and cellular biology to the study of the nervous system has greatly accelerated our understanding of the mechanisms involved in neuronal signaling, neural development, and the function of the major sensory and motor systems of the brain. The elucidation of the underlying causes of most neurological and psychiatric disorders has proved to be more difficult; but striking progress is now being made in determining the genetic basis of such disorders as Alzheimer’s disease, amyotrophic lateral sclerosis, Parkinson’s disease, and a number of ion channel and mitochondrial disorders, and a significant start has been made in identifying genetic factors in the etiology of such disorders as manic depressive illness and schizophrenia. These developments presage the emergence in the coming decades of a new nosology, certainly in neurology and perhaps also in psychiatry, based not on symptomatology but on the dysfunction of specific genes, molecules, neuronal organelles and particular neural systems.
Deficiency of Renal Cortical EGF Increases ENaC Activity and Contributes to Salt-Sensitive Hypertension
Authors: Tengis S. Pavlov, Vladislav Levchenko, Paul M. O’Connor, Daria V. Ilatovskaya, Oleg Palygin, Takefumi Mori, David L. Mattson, Andrey Sorokin, Julian H. Lombard, Allen W. Cowley, Alexander Staruschenko
Journal: Journal of the American Society of Nephrology (2013)

Various stimuli, including hormones and growth factors, modulate epithelial sodium channels (ENaCs), which fine-tune Na(+) absorption in the kidney. Members of the EGF family are important for maintaining transepithelial Na(+) transport, but whether EGF influences ENaC, perhaps mediating salt-sensitive hypertension, is not well understood. Here, the ENaC inhibitor benzamil attenuated the development of hypertension in Dahl salt-sensitive rats. Feeding these salt-sensitive rats a high-salt diet led to lower levels of EGF in the kidney cortex and enhanced the expression and activity of ENaC compared with feeding a low-salt diet. To directly evaluate the role of EGF in the development of hypertension and its effect on ENaC activity, we infused EGF intravenously while continuously monitoring BP of the salt-sensitive rats. Infusion of EGF decreased ENaC activity, prevented the development of hypertension, and attenuated glomerular and renal tubular damage. Taken together, these findings indicate that cortical EGF levels decrease with a high-salt diet in salt-sensitive rats, promoting ENaC-mediated Na(+) reabsorption in the collecting duct and the development of hypertension.