tbuckley/cabot-search huggingface dataset:
Autologous stem-cell transplant after conventional dose adjuvant chemotherapy for high-risk breast cancer: Impact on the delivery of local-regional radiation therapy
Authors: H.C.F. Moore, R. Mick, L.J. Solin, C. Sickles, P.A. Mangan, S.M. Luger, K.R. Fox, L.M. Schuchter, E. Loh, D.L. Porter, S. Schuster, G.P. Buzby, E. Glatstein, L.E. Silberstein, E.A. Stadtmauer
Journal: Annals of Oncology (1999)

Background: High-dose chemotherapy with autologous stemcell transplantation is used increasingly in the treatment of poor-prognosis primary breast cancer.Because these patients may be cured with standard multimodality therapy, it is important to address both the efficacy of transplantation, and its effect on the delivery of standard treatments including local radiation therapy.Patients and methods: Patients with high risk primary breast cancer were treated with high-dose cyclophosphamide and thiotepa and stem-cell transplant following surgery and conventional-dose adjuvant chemotherapy.Outcome, including sites of failure and delivery of local radiation therapy, was assessed for 103 patients.Results: Overall and disease-free survival rates at 18 months were 83% (± 4%) and 77% (± 4%) respectively.Twenty patients (19.4%) received radiation therapy prior to transplant.Of the remaining 83, 77 received radiation therapy after transplant.Overall, 5 (19.2%) of 26 first sites of recurrence were local alone.For patients receiving radiation prior to transplant, 3 of 7 (43%, 95% CI: 6%-80%) sites of first recurrence were local, while 2 of 19 (10.5%, 95% CI: 0%-24.5%)sites of first recurrence were local alone in patients receiving post-transplant radiation or no radiation.Conclusion: Transplantation does not appear to significantly compromise the delivery or outcome of local radiation therapy for primary breast cancer.
Genetic Variations in Tibetan Populations and High-Altitude Adaptation at the Himalayas
Authors: Y. Peng, Z. Yang, H. Zhang, C. Cui, X. Qi, X. Luo, X. Tao, T. Wu, None Ouzhuluobu, None Basang, None Ciwangsangbu, None Danzengduojie, H. Chen, H. Shi, B. Su
Journal: Molecular Biology and Evolution (2010)

Modern humans have occupied almost all possible environments globally since exiting Africa about 100,000 years ago. Both behavioral and biological adaptations have contributed to their success in surviving the rigors of climatic extremes, including cold, strong ultraviolet radiation, and high altitude. Among these environmental stresses, high-altitude hypoxia is the only condition in which traditional technology is incapable of mediating its effects. Inhabiting at >3,000-m high plateau, the Tibetan population provides a widely studied example of high-altitude adaptation. Yet, the genetic mechanisms underpinning long-term survival in this environmental extreme remain unknown. We performed an analysis of genome-wide sequence variations in Tibetans. In combination with the reported data, we identified strong signals of selective sweep in two hypoxia-related genes, EPAS1 and EGLN1. For these two genes, Tibetans show unusually high divergence from the non-Tibetan lowlanders (Han Chinese and Japanese) and possess high frequencies of many linked sequence variations as reflected by the Tibetan-specific haplotypes. Further analysis in seven Tibetan populations (1,334 individuals) indicates the prevalence of selective sweep across the Himalayan region. The observed indicators of natural selection on EPAS1 and EGLN1 suggest that during the long-term occupation of high-altitude areas, the functional sequence variations for acquiring biological adaptation to high-altitude hypoxia have been enriched in Tibetan populations.
Angelo Celli and research on the prevention of malaria in Italy a century ago
Authors: Eliana Ferroni, Tom Jefferson, Gabriel Gachelin
Journal: Journal of the Royal Society of Medicine (2012)

The parasite responsible for severe malaria (Plasmodium falciparum) has recently been demonstrated to have been transmitted to humans from gorillas, a finding that substantiates an earlier hypothesis that malaria spread from monkeys to early neolithic peasants at the dawn of land cultivation. The first written records of seasonal and/ or intermittent fevers – which arewidely assumed to be malaria – are found in Sumerian, Babylonian, Assyrian, Chinese, Egyptian and Indian texts. In the fifth century BCE, these fevers became widespread in ancient Greece, prompting Hippocrates to investigate them and to attempt a detailed description. He tried to understand the relationship between the timing and frequency of intermittent fevers and the swelling of the spleen, as well as their relationship to where patients lived, identifying swampy areas as particularly inhospitable. These intermittent fevers affected the inhabitants of wetlands in and around ancient Rome, a situation most probably aggravated by population flows from North Africa around the time of the Punic wars. Some classical civilizations – for example, the Etruscans – channeled water flows and drained marshes, although this may have been primarily for land reclamation. In 1717, the Italian physician Giovanni Lancisi described factors associated with intermittent fevers and postulated that mosquitoes might have a role in transmitting them. Lancisi gave the word malaria its present medical meaning. The word began to be adopted in Italian and English medical texts in the eighteenth century, the word itself reflecting the popular belief that malaria was caused by stagnant air (‘mal’aria’) rising from swampy areas.
SIRT1 protects against emphysema via FOXO3-mediated reduction of premature senescence in mice
Authors: Hongwei Yao, Sangwoon Chung, Jae-woong Hwang, Saravanan Rajendrasozhan, Isaac K. Sundar, David A. Dean, Michael W. McBurney, Leonard Guarente, Wei Gu, Mikko Rönty, Vuokko L. Kinnula, Irfan Rahman
Journal: Journal of Clinical Investigation (2012)

Chronic obstructive pulmonary disease/emphysema (COPD/emphysema) is characterized by chronic inflammation and premature lung aging. Anti-aging sirtuin 1 (SIRT1), a NAD+-dependent protein/histone deacetylase, is reduced in lungs of patients with COPD. However, the molecular signals underlying the premature aging in lungs, and whether SIRT1 protects against cellular senescence and various pathophysiological alterations in emphysema, remain unknown. Here, we showed increased cellular senescence in lungs of COPD patients. SIRT1 activation by both genetic overexpression and a selective pharmacological activator, SRT1720, attenuated stress-induced premature cellular senescence and protected against emphysema induced by cigarette smoke and elastase in mice. Ablation of Sirt1 in airway epithelium, but not in myeloid cells, aggravated airspace enlargement, impaired lung function, and reduced exercise tolerance. These effects were due to the ability of SIRT1 to deacetylate the FOXO3 transcription factor, since Foxo3 deficiency diminished the protective effect of SRT1720 on cellular senescence and emphysematous changes. Inhibition of lung inflammation by an NF-κB/IKK2 inhibitor did not have any beneficial effect on emphysema. Thus, SIRT1 protects against emphysema through FOXO3-mediated reduction of cellular senescence, independently of inflammation. Activation of SIRT1 may be an attractive therapeutic strategy in COPD/emphysema.
Disclosing Individual Genetic Results to Research Participants
Authors: Vardit Ravitsky, Benjamin S. Wilfond
Journal: The American Journal of Bioethics (2006)

Investigators and institutional review boards should integrate plans about the appropriate disclosure of individual genetic results when designing research studies. The ethical principles of beneficence, respect, reciprocity, and justice provide justification for routinely offering certain results to research participants. We propose a result-evaluation approach that assesses the expected information and the context of the study in order to decide whether results should be offered. According to this approach, the analytic validity and the clinical utility of a specific result determine whether it should be offered routinely. Different results may therefore require different decisions even within the same study. We argue that the threshold of clinical utility for disclosing a result in a research study should be lower than the threshold used for clinical use of the same result. The personal meaning of a result provides additional criteria for evaluation. Finally, the context of the study allows for a more nuanced analysis by addressing the investigators' capabilities for appropriate disclosure, participants' alternative access to the result, and their relationship with the investigators. This analysis shows that the same result may require different decisions in different contexts.
Increased mediastinal fat and impaired left ventricular energy metabolism in young men with newly found fatty liver
Authors: Gianluca Perseghin, Guido Lattuada, Francesco De Cobelli, Antonio Esposito, Elena Belloni, Georgia Ntali, Francesca Ragogna, Tamara Canu, Paola Scifo, Alessandro Del Maschio, Livio Luzi
Journal: Hepatology (2007)

Fatty liver is characterized by metabolic abnormalities at the liver, but also at skeletal muscle and adipose tissue sites. It is hypothesized that the heart may be suffering metabolic alterations, and this study was undertaken to ascertain whether individuals with fatty liver have left ventricular (LV) alterations of energy metabolism, structure, and function and abnormal amounts of epicardial fat as a specific marker of visceral fat accumulation. To this end we studied young, nondiabetic men matched for anthropometric features with (n = 21) or without (n = 21) fatty liver by means of (1) cardiac magnetic resonance imaging (MRI); (2) cardiac 31P-MR spectroscopy (MRS); and (3) hepatic 1H-MRS to assess quantitatively the intrahepatic fat (IHF) content. Insulin sensitivity was determined by the updated HOMA-2 computer model. Individuals with fatty liver showed reduced insulin sensitivity, increased serum free fatty acid (FFA), and E-selectin, abnormal adipokine concentrations, and higher blood pressure. LV morphology and systolic and diastolic functions were not different; however, in the scanned intrathoracic region, the intrapericardial (7.8 ± 3.1 versus 5.9 ± 2.5 cm2; P &lt; 0.05) and extrapericardial (11.7 ± 6.1 versus 7.8 ± 3.2 cm2; P &lt; 0.03) fat was increased in men with fatty liver compared with those without fatty liver. The phosphocreatine (PCr)/adenosine triphosphate (ATP) ratio, a recognized in vivo marker of myocardial energy metabolism, was reduced in men with fatty liver in comparison with normals (1.85 ± 0.35 versus 2.11 ± 0.31; P &lt; 0.016). In conclusion, in newly found individuals with fatty liver, fat was accumulated in the epicardial area and despite normal LV morphological features and systolic and diastolic functions, they had abnormal LV energy metabolism. (Hepatology 2008.)
Bile salt secretion in cirrhosis of the liver
Authors: L. A. Turnberg, G. Grahame
Journal: Gut (1970)

Secretion of bile salts into the duodenum was studied in eight normal subjects, in 10 patients with cirrhosis, and in two cholecystectomized subjects. Duodenal juice was aspirated continuously through a double-lumen tube during an unstimulated period, after an intravenous injection of pancreozymin/cholecystokinin, and during a continuous intravenous infusion of secretin given at a rate of 3 units per kilogram body weight per hour. Precautions were taken to try to ensure quantitative recovery during the studies, and recovery of an infused nonabsorbable marker was greater than 80% in all subjects. Secretin induced a flow of a greater volume of juice in the cirrhotic patients than in the normal group (49 to 57 ml per 10 minutes compared with 28 to 49 ml per 10 minutes). This change may have resulted from a higher effective dose of secretin if it is assumed that the cirrhotic liver fails to catabolize secretin. The bile acid response to pancreozymin/cholecystokinin followed by secretin in the cirrhotic subjects resembled that seen in patients after cholecystectomy in whom pancreozymin/cholecystokinin induces only a slight increase in bile salt output but in whom the output of bile salts during rest and secretin stimulation is markedly greater than normal. This response in cirrhosis is probably best interpreted as due to impaired function of the gallbladder. The total amount of bile salt liberated over the two hours of the test in the cirrhotic patients was similar to normal The concentration of bile salt after pancreozymin/cholecystokinin was less than in normal subjects, but similar to that in cholecystectomized patients. It is unlikely therefore that deficient output or concentration of bile salt can be held responsible for steatorrhea in cirrhosis. There was a marked decrease in the deoxycholate conjugates and a reduction in the glycine: taurine ratio in the bile of cirrhotic patients. The former change may reflect a change in bacterial flora and the latter a defect in hepatic conjugating mechanisms.
Cardiac Dysfunction in Hypertrophic Cardiomyopathy Mutant Tropomyosin Mice Is Transgene-Dependent, Hypertrophy-Independent, and Improved by β-Blockade
Authors: Daniel E. Michele, Carlen A. Gomez, Katie E. Hong, Margaret V. Westfall, Joseph M. Metzger
Journal: Circulation Research (2002)

Familial hypertrophic cardiomyopathy (FHC) has been linked to mutations in proteins of the cardiac contractile apparatus, including α-tropomyosin (Tm). Mice expressing αTm in the heart were developed to determine the effects of FHC mutant Tm on cardiac structure and function from single cardiac myocytes to whole organ function in vivo. Expression of E180G mutant Tm did not produce cardiac hypertrophy or detectable changes in cardiac muscle morphology. However, E180G mutant Tm expression increased the Ca 2+ sensitivity of force production in single cardiac myocytes in a transgene expression–dependent manner. Contractile dysfunction in single myocytes manifested organ level dysfunction, as conductance-micromanometry showed E180G Tm mice had significantly slowed relaxation (diastolic dysfunction) under physiological conditions. The diastolic dysfunction in E180G Tm mice was no longer evident during β-blockade because propranolol eliminated the effect of E180G Tm to slow myocardial relaxation. Cellular and organ level dysfunction were evident in E180G Tm mice in the absence of significant cardiac structural abnormalities normally associated with FHC. These findings therefore suggest that diastolic dysfunction in FHC may be a direct consequence of FHC mutant protein expression. In addition, because diastolic dysfunction in E180G Tm mice is dependent on inotropic status, cardiovascular stress may play an important role in FHC pathogenesis.
Computerized Tomography of the Musculoskeletal System
Authors: E. Mark Levinsohn
Journal: JAMA (1980)

THE VALUE of computerized tomography (CT) in evaluating cranial, thoracic, abdominal, and pelvic abnormalities is well accepted.<sup>1</sup>The use of CT in diagnosing disorders of the musculoskeletal system is similar to its application to other regions of the body. In those anatomic areas where muscles and neurovascular structures are relatively large, CT provides an accurate tool in assessing anteroposterior relationships. The availability of the opposite extremity to serve as a control is an added advantage. The axial plane is particularly useful in assessing orthopedic disorders of the hip, thigh, shoulder, and sternoclavicular joint. Around joints, where a curving plane may not be optimally visualized on either the anteroposterior or lateral roentgenogram, the axial projection is particularly valuable.<sup>2</sup>Although plain roentgenograms provide better bony detail than CT, the medullary space is better seen with CT. Computerized tomography is more sensitive to small differences in x-ray absorption than conventional films.
Endocytic pathways mediating oligomeric Aβ42 neurotoxicity
Authors: Chunjiang Yu, Evelyn Nwabuisi-Heath, Kevin Laxton, Mary Jo LaDu
Journal: Molecular Neurodegeneration (2010)

One pathological hallmark of Alzheimer's disease (AD) is amyloid plaques, composed primarily of amyloid-beta peptide (Abeta). Over-production or diminished clearance of the 42 amino acid form of Abeta (Abeta42) in the brain leads to accumulation of soluble Abeta and plaque formation. Soluble oligomeric Abeta (oAbeta) has recently emerged to be as a likely proximal cause of AD.Here we demonstrate that endocytosis is critical in mediating oAbeta42-induced neurotoxicity and intraneuronal accumulation of Abeta. Inhibition of clathrin function either with a pharmacological inhibitor, knock-down of clathrin heavy chain expression, or expression of the dominant-negative mutant of clathrin-assembly protein AP180 did not block oAbeta42-induced neurotoxicity or intraneuronal accumulation of Abeta. However, inhibition of dynamin and RhoA by expression of dominant negative mutants reduced neurotoxicity and intraneuronal Abeta accumulation. Pharmacologic inhibition of the dynamin-mediated endocytic pathway by genistein also reduced neurotoxicity.These data suggest that dynamin-mediated and RhoA-regulated endocytosis are integral steps for oligomeric Abeta42-induced neurotoxicity and intraneuronal Abeta accumulation.
Rapamycin for Treatment of Chronic Allograft Nephropathy in Renal Transplant Patients
Authors: Giovanni Stallone, Barbara Infante, Antonio Schena, Michele Battaglia, Pasquale Ditonno, Antonia Loverre, Loreto Gesualdo, Francesco Paolo Schena, Giuseppe Grandaliano
Journal: Journal of the American Society of Nephrology (2005)

Chronic allograft nephropathy (CAN) represents the main cause of renal allograft loss after 1 yr of transplantation. Calcineurin inhibitor (CNI) use is associated with increased graft expression of profibrotic cytokines, whereas rapamycin inhibits fibroblast proliferation. The aim of this randomized, prospective, open-label, single-center study was to evaluate the histologic and clinical effect of rapamycin on biopsy-proven CAN. Eighty-four consecutive patients who had biopsy-proven CAN and received a transplant were randomized to receive either a 40% CNI reduction plus mycophenolate mofetil (group 1; 50 patients) or immediate CNI withdrawal and rapamycin introduction with a loading dose of 0.1 mg/kg per d and a maintaining dose aiming at through levels of 6 to 10 ng/ml (group 2; 34 patients). The follow-up period was 24 mo. At the end of follow-up, 25 patients (group 1, 10 patients; group 2, 15 patients) underwent a second biopsy. CAN lesions were graded according to Banff criteria. alpha-Smooth muscle actin (alpha-SMA) protein expression was evaluated in all biopsies as a marker of fibroblast activation. Graft function and Banff grading were superimposable at randomization. Graft survival was significantly better in group 2 (P = 0.0376, chi2 = 4.323). CAN grading worsened significantly in group 1, whereas it remained stable in group 2. After 24 mo, all group 1 biopsies showed an increase of alpha-SMA expression at the interstitial and vascular levels (P < 0.001); on the contrary, alpha-SMA expression was dramatically reduced in group 2 biopsies (P = 0.005). This study demonstrates that rapamycin introduction/CNI withdrawal improves graft survival and reduces interstitial and vascular alpha-SMA expression, slowing down the progression of allograft injury in patients with CAN.
Preventing adolescents' uptake of smoking
Authors: T. Coleman, L. Bauld
Journal: Thorax (2011)

Smoking is the principal preventable cause of ill health worldwide.1 It not only affects smokers themselves but is also extremely harmful to non-smokers who inhale environmental tobacco smoke (ETS).2 In non-smoking adults, ETS exposure causes lung and other cancers, ischaemic heart disease, stroke, chronic obstructive pulmonary disease, asthma and other respiratory illnesses.3 Perhaps less well known by the general public is the threat that ETS inhalation poses for infants and children; there are strong associations with children's asthma, lower respiratory tract infection, sudden infant death syndrome, middle ear infection and bacterial meningitis.3 4 Knowledge of the health risks of ETS exposure have led many countries, including the UK, to introduce laws that prohibit smoking in indoor public spaces like bars and pubs (smoke-free legislation).5 Advocates of smoke-free laws successfully argued for these on the basis of protecting non-smokers who might work in or visit smoky environments. Consequently, as tobacco smoke has been completely eliminated from most situations in which adult non-smokers might encounter it, they are well protected from ETS. No similar protection exists for the children of smokers. Most of children's exposure to tobacco smoke occurs domestically3 4 but, internationally, there are no smoke-free laws which forbid smokers from ‘lighting up’ in their homes when children are present. Children's domestic ETS exposure therefore remains an important public health concern which, as Leonardi-Bee and colleagues6 show in this issue of Thorax , is even more harmful than was previously thought. The authors show that children's exposure to ETS from parental smoking has a pervasive inter-generational behaviour-modelling effect such that the children of smokers are much more likely to become smokers themselves. Their systematic review and meta-analysis collated findings from 58 epidemiological studies investigating associations between parental smoking and the subsequent development of …
Diseases of the Small Intestine in Childhood
Authors: R TRONCONE
Journal: Gut (2000)

Diseases of the Small Intestine in Childhood . 4th edn. By Walker-Smith J, Murch S. (Pp 424; illustrated; £99.50.) UK: Isis Medical Media Ltd, 1999. ISBN: 1 90186 503 7.

Pediatric gastroenterology, and our knowledge about diseases of the small intestine in children, has grown rapidly over the last few years, owing to advances in the basic sciences, such as molecular genetics and, particularly, gut immunology. The …
Critical Review of Published Microarray Studies for Cancer Outcome and Guidelines on Statistical Analysis and Reporting
Authors: Alain Dupuy, Richard M. Simon
Journal: JNCI Journal of the National Cancer Institute (2007)

Both the validity and the reproducibility of microarray-based clinical research have been challenged. There is a need for critical review of the statistical analysis and reporting in published microarray studies that focus on cancer-related clinical outcomes. Studies published through 2004 in which microarray-based gene expression profiles were analyzed for their relation to a clinical cancer outcome were identified through a Medline search followed by hand screening of abstracts and full text articles. Studies that were eligible for our analysis addressed one or more outcomes that were either an event occurring during follow-up, such as death or relapse, or a therapeutic response. We recorded descriptive characteristics for all the selected studies. A critical review of outcome-related statistical analyses was undertaken for the articles published in 2004. Ninety studies were identified, and their descriptive characteristics are presented. Sixty-eight (76%) were published in journals of impact factor greater than 6. A detailed account of the 42 studies (47%) published in 2004 is reported. Twenty-one (50%) of them contained at least one of the following three basic flaws: 1) in outcome-related gene finding, an unstated, unclear, or inadequate control for multiple testing; 2) in class discovery, a spurious claim of correlation between clusters and clinical outcome, made after clustering samples using a selection of outcome-related differentially expressed genes; or 3) in supervised prediction, a biased estimation of the prediction accuracy through an incorrect cross-validation procedure. The most common and serious mistakes and misunderstandings recorded in published studies are described and illustrated. Based on this analysis, a proposal of guidelines for statistical analysis and reporting for clinical microarray studies, presented as a checklist of "Do's and Don'ts," is provided.