tbuckley/cabot-search huggingface dataset:
Benefit of Paclitaxel in Estrogen Receptor-Negative Versus Estrogen Receptor-Positive Early Breast Cancer
Authors: Cicely Bryce, Hagen Kennecke, Stephen Chia, Joseph Ragaz
Journal: Journal of Clinical Oncology (2003)

The Art of Oncology: When the Tumor Is Not the Target is a section within the Journal of Clinical Oncology.It has attracted a series of interesting and enjoyable articles.However, the title of the section refers to the divisions between biologic and nonbiologic care, rather than their integration, and likens biologic therapy to target eradication.Should the title be reconsidered?The title Simultaneous Care: Treatment and Palliative Care Throughout Disease 1 is representative of the theme and ethos of the articles within the section.It describes the improvement of patient well-being-be it biologic, psychological, social, or spiritual-at all stages of the course of disease.The article from which this title is quoted discusses integrated therapy, the communication between patients and doctors of the uncertainties associated with treatment outcome, and the role of clinical research.Many patients and fellow health professionals see oncologists as having a key responsibility in delivering and integrating care.The oncologist is in an authoritative position because of his or her knowledge and experience.Oncologists also understand the value of collaboration by the team of caregivers, as well as the influence of the doctor-patient relationship on all the aforementioned aspects of patient well-being.The title of the section should thus emphasize integration of therapies, rather than their divisions.The metaphor of target eradication for biologic therapy is military in nature and is not appropriate for therapy and healing.It arouses associations of victory or failure, collateral damage, and a "fight to the end."It is not an accurate reflection of conventional anticancer therapies, which have always included the need to make weighted decisions on the likely benefits and harms of therapy.In particular, it does not reflect developments in anticancer therapy, which is increasingly directed toward the understanding and regulation of biologic behavior.Are there alternative metaphors?The metaphor of art itself might be considered and the section titled The Art of Oncology only.Art is created through intelligent and skilful responses to the complexities of life and the world around us.It is vital and transforming.It is in a continuous process of development and study.It is individual but also resonates in the broader world.At its best, The Art Of Oncology will reflect the principles that emerge after working through the complexities of integrated patient care.Would such a metaphor add the much needed weight to nonbiologic aspects of patient care?It should, and one knows that the published articles will do so.Are there any other offers?
Troglitazone induces p27Kip1-associated cell-cycle arrest through down-regulating Skp2 in human hepatoma cells
Authors: Hironori Koga, Masaru Harada, Motoaki Ohtsubo, Shoichiro Shishido, Hiroto Kumemura, Shinichiro Hanada, Eitaro Taniguchi, Katsumi Yamashita, Ryukichi Kumashiro, Takato Ueno, Michio Sata
Journal: Hepatology (2003)

Increasing evidence has confirmed that ligands for peroxisome proliferator–activated receptor γ (PPARγ) exhibit antitumoral effects through inhibition of cell proliferation and induction of cell differentiation in several malignant neoplasms. Recently, we have documented the accumulation of a cyclin–dependent kinase inhibitor, p27 Kip1 , as well as an unexpected accumulation in cyclin E in G1–arrested human hepatoma cells treated with the PPARγ ligand troglitazone. Simultaneous accumulations in both p27 Kip1 and cyclin E are known to be characteristic phenotypes in cells derived from mice lacking Skp2, an F–box protein component of the SCF ubiquitin–ligase complex. Thus, the aim of the present study was to assess whether Skp2 might be involved in the down–regulation of p27 Kip1 in troglitazone–treated human hepatoma cells. A striking decrease in Skp2 expression and a reciprocal increase in p27 Kip1 expression were found in troglitazone–treated hepatoma cells but not in those cells treated with other PPARγ ligands such as pioglitazone and ciglitazone. Quantitative real–time RT–PCR analysis showed that troglitazone down–regulated Skp2 at the mRNA levels. Consistently, ectopic overexpression in Skp2 brought resistance to troglitazone, resulting in a decreased population of arrested cells at the G1 phase compared with that in the mock–transfected cells. In surgically resected hepatocellular carcinoma (HCC) tissue, an increased expression in Skp2 was found in both the moderately differentiated HCCs and the poorly differentiated HCCs. In conclusion, troglitazone attenuated Skp2 expression, thereby promoting p27 Kip1 accumulation in human hepatoma cells. This therapeutic potential of the ligand may lead to new cell–cycle–based antitumor strategies for advanced HCCs.
Protein Flexibility and Computer-Aided Drug Design
Authors: Chung F. Wong, J. Andrew McCammon
Journal: The Annual Review of Pharmacology and Toxicology (2003)

Although computational techniques are increasingly being used in computer-aided drug design, the effects due to protein flexibility are still ignored in many applications. This review revisits rigorous statistical mechanical methods for predicting binding affinity, discusses some recent developments for improving their speed and reliability, and examines faster approximate models for facilitating virtual screening and lead optimization.
Inhibition of the Cardiomyocyte-Specific Troponin I–Interacting Kinase Limits Oxidative Stress, Injury, and Adverse Remodeling due to Ischemic Heart Disease
Authors: Dennis M. Abraham, Douglas A. Marchuk
Journal: Circulation Research (2014)

Ischemia–reperfusion injury is strongly associated with increased oxidative stress, mitochondrial dysfunction, and cell death. These processes are diminished in an animal model of ischemia–reperfusion by the genetic loss or pharmacological inhibition of troponin I–interacting kinase.
Defining the Lower Limit of Normal for FEV<sub>1</sub>/ FVC
Authors: Martin R. Miller, Irene Steenbruggen, Philip H. Quanjer, Gregg Ruppel, Robert O. Crapo, Ole F. Pedersen
Journal: American Journal of Respiratory and Critical Care Medicine (2007)

1. Terragni PP, Rosboch G, Tealdi A, Corno E, Menaldo E, Davini O, Gandini G, Herrmann P, Mascia L, Quintel M, Slutsky AS, Gattinoni L, Ranieri VM. Tidal hyperinflation during low tidal volume ventilation in acute respiratory distress syndrome. Am J Respir Crit Care Med 2007;175:160–166. 2. HagerDN,Krishnan JA,HaydenDL, BrowerRG. Tidal volume reduction in patients with acute lung injury when plateau pressures are not high. Am J Respir Crit Care Med 2005;172:1241–1245. 3. Rouby JJ, Brochard L. Tidal recruitment and overinflation in acute respiratory distress syndrome: yin and yang. Am J Respir Crit Care Med 2007; 175:104–106.
Asymptomatic or “Silent” Atrial Fibrillation
Authors: Richard L. Page, Thomas W. Tilsch, Stuart J. Connolly, Daniel J. Schnell, Stephen R. Marcello, William E. Wilkinson, Edward L.C. Pritchett
Journal: Circulation (2003)

Asymptomatic, or "silent" atrial fibrillation could increase the risk of stroke. Little is known about the frequency of asymptomatic atrial fibrillation in patients who also have symptomatic atrial fibrillation; similarly, little is known about the effect of antiarrhythmic drug therapy on asymptomatic atrial fibrillation.Patients in sinus rhythm with a history of symptomatic atrial fibrillation or atrial flutter received placebo or azimilide (35 to 125 mg) once daily for 6 or 9 months in 4 similar double-blind trials. The end point was the first recurrence of a symptomatic ECG-documented supraventricular arrhythmia. Routine transtelephonic electrocardiograms, in the absence of symptoms, were recorded for 30 seconds every 2 weeks until patients completed follow-up or documented a symptomatic supraventricular arrhythmia. Of the 1380 patients, 489 received placebo. Among these patients receiving placebo, 303 transmitted at least one routine ECG while asymptomatic. Asymptomatic atrial fibrillation was recorded in 50 (17%) within 6 months and before recurrence of symptomatic supraventricular arrhythmia. In the 3 trials evaluating azimilide in therapeutic doses (100 and 125 mg), asymptomatic atrial fibrillation occurred in 49 of 382 (13%) receiving azimilide and 43 of 233 (18%) receiving placebo. Although drug effect on time to first asymptomatic event was not statistically significant (hazard ratio, 0.70; P=0.09), there was a 40% reduction in asymptomatic atrial fibrillation on azimilide compared with placebo (P=0.03) when repeated observations were considered.Asymptomatic atrial fibrillation is common in untreated patients with a history of symptomatic atrial fibrillation (and is likely underestimated by this analysis). Azimilide may reduce the occurrence of this silent arrhythmia.
THE MAGIC BULLETS AND TUBERCULOSIS DRUG TARGETS
Authors: Ying Zhang
Journal: The Annual Review of Pharmacology and Toxicology (2004)

Modern chemotherapy has played a major role in our control of tuberculosis. Yet tuberculosis still remains a leading infectious disease worldwide, largely owing to persistence of tubercle bacillus and inadequacy of the current chemotherapy. The increasing emergence of drug-resistant tuberculosis along with the HIV pandemic threatens disease control and highlights both the need to understand how our current drugs work and the need to develop new and more effective drugs. This review provides a brief historical account of tuberculosis drugs, examines the problem of current chemotherapy, discusses the targets of current tuberculosis drugs, focuses on some promising new drug candidates, and proposes a range of novel drug targets for intervention. Finally, this review addresses the problem of conventional drug screens based on inhibition of replicating bacilli and the challenge to develop drugs that target nonreplicating persistent bacilli. A new generation of drugs that target persistent bacilli is needed for more effective treatment of tuberculosis.
Comparison between Peak Inspiratory Flow Rate via Incheck-dial® with Turbutester and Accutester in Children with Asthma
Authors: W MANUYAKORN, C DIREKWATTANACHAI, S BENJAPONPITAK, W KAMCHAISATIAN, C SASISAKULPORN, W TEAESOMBOONKIT
Journal: Journal of Allergy and Clinical Immunology (2008)
Assembling an Arsenal: Origin and Evolution of the Snake Venom Proteome Inferred from Phylogenetic Analysis of Toxin Sequences
Authors: B. G. Fry
Journal: Molecular Biology and Evolution (2004)

We analyzed the origin and evolution of snake venom toxin families represented in both viperid and elapid snakes by means of phylogenetic analysis of the amino acid sequences of the toxins and related nonvenom proteins. Out of eight toxin families analyzed, five provided clear evidence of recruitment into the snake venom proteome before the diversification of the advanced snakes (Kunitz-type protease inhibitors, CRISP toxins, galactose-binding lectins, M12B peptidases, nerve growth factor toxins), and one was equivocal (cystatin toxins). In two others (phospholipase A2 and natriuretic toxins), the nonmonophyly of venom toxins demonstrates that presence of these proteins in elapids and viperids results from independent recruitment events. The ANP/BNP natriuretic toxins are likely to be basal, whereas the CNP/BPP toxins are Viperidae only. Similarly, the lectins were recruited twice. In contrast to the basal recruitment of the galactose-binding lectins, the C-type lectins were shown to be Viperidae only, with the α-chains and β-chains resulting from an early duplication event. These results provide strong additional evidence that venom evolved once, at the base of the advanced snake radiation, rather than multiple times in different lineages, with these toxins also present in the venoms of the "colubrid" snake families. Moreover, they provide a first insight into the composition of the earliest ophidian venoms and point the way toward a research program that could elucidate the functional context of the evolution of the snake venom proteome.
Targeted Drug-Aerosol Delivery in the Human Respiratory System
Authors: C. Kleinstreuer, Z. Zhang, J.F. Donohue
Journal: Annual Review of Biomedical Engineering (2008)

Inhalation of drug aerosols is a modern pathway to combat lung diseases. It is also becoming the preferred route for insulin delivery, pain management, cancer therapy, and nanotherapeutics. Popular delivery devices include nebulizers, metered-dose inhalers, and dry-powder inhalers. They are all nondirectional and hence have typically low particle deposition efficiencies in desired nasal or lung areas. Thus, for specific disease treatment with costly and/or aggressive medicine, it is necessary to provide targeted drug–aerosol delivery to predetermined sites in the human respiratory system. Experimental measurements and computer models of particle transport and deposition in nasal and lung airway models are presented. Furthermore, the underlying methodology and performance of pressurized metered dose inhalers as well as new smart inhaler systems are discussed. To maximize respiratory drug delivery to specific sites, an optimal combination of particle characteristics, inhalation waveform, particle release position, and drug-aerosol dosage has to be achieved.
STIMULATED LYMPHOCYTE CULTURES
Authors: Hans-Peter Lohrmann, Carole M. Graw, Robert G. Graw
Journal: The Journal of Experimental Medicine (1974)

Lymphocytes, stimulated with different doses of plant mitogens or allogeneic cells, incorporate varying amounts of [3H]thymidine. Theoretically, this may be due to different numbers of responding cells, to earlier proliferative response of these cells, and/or to their more or less rapid transit through the cell cycle. Dog peripheral blood lymphocytes were stimulated in vitro with different doses of phytohemagglutinin (PHA), or with allogeneic lymphocytes. After their synchronization by incubation with hydroxyurea (4 mM), the mean durations of the cell cycle, and of the different cell cycle phases were constant and unrelated to strength or type of stimulation. PHA-stimulated lymphocyte cultures were maintained in the presence of colchicine, to prevent clonal proliferation of responding lymphocytes. DNA uptake in this setting, attributed to first generation responders, was related to the strength of proliferative lymphocyte response in control cultures without colchicine. Furthermore, cell proliferation occurred earlier with greater stimulation. It is concluded that higher [3H]thymidine uptake in vitro by stimulated lymphocytes is due to greater numbers of responding cells, which are triggered into proliferative response earlier, and not to a more rapid transit of the responding cells through the cell cycle.
RELATIONSHIP BETWEEN RENAL FUNCTION AND OUTCOMES OF ENDOVASCULAR THERAPY FOR FEMOROPOPLITEAL LESION
Authors: Seiichi Hiramori, Yoshimitsu Soga, Osamu iida, Kenji Suzuki, Keisuke Hirano, Daizo Kawasaki, Yoshiaki Shintani, Nobuhiro Suematsu, Terutoshi Yamaoka
Journal: Journal of the American College of Cardiology (2014)
Obesity, gender, and colon cancer
Authors: E Giovannucci
Journal: Gut (2002)

Obesity is associated with an increased risk of colorectal cancer in premenopausal but not postmenopausal women

Many studies have shown that a high body mass index (BMI) is related to an increased risk of colon cancer in men but this relationship has not been as consistent in studies of women. However, an association between BMI and colon cancer risk is observed in cohorts of relatively young women, and among younger women in case control studies that stratified results by age.1 In addition, a recent cohort study found a positive association between BMI and colorectal cancer among women less than 55 years of age but not among older women.2 These studies did not examine the association between BMI and colon cancer risk by menopausal status but the clearer association with younger women suggested that an association between BMI and colon cancer risk may be stronger for, or perhaps even limited to, premenopausal women.2

A study by Terry and colleagues3 in the current issue of Gut tested the hypothesis that menopausal status modifies the relationship between BMI and colon cancer risk [see 191] . The investigators …
MPs raise fears over government's lack of plans for failures in NHS reforms
Authors: A. O'Dowd
Journal: BMJ (2011)

The government has inadequate safeguards in place to deal with any failures that may happen as part of the NHS reforms in England, MPs have warned.

No fully developed risk management protocol exists for the new commissioning bodies or providers under the new style NHS as envisaged by the Department of Health, said MPs on the House of Commons Public Accounts Committee in a new report.

The report, published on 27 April, raises several concerns about plans to reform the NHS, as outlined in the government’s Health and Social Care Bill, published in January ( BMJ 2011;342:d418, doi:10.1136/bmj.d418).

The government wants to transform the NHS into a devolved, market based model in which local commissioners (consortiums of GPs) and providers of health services are freed from central control.

MPs on the committee, however, said it was …
Potential Savings from Substituting Generic Drugs for Brand-Name Drugs: Medical Expenditure Panel Survey, 1997–2000
Authors: Jennifer S. Haas, Kathryn A. Phillips, Eric P. Gerstenberger, Andrew C. Seger
Journal: Annals of Internal Medicine (2005)

Generic substitution is one mechanism of curtailing prescription drug expenditures. Limited information is available about the potential savings associated with generic substitution.To estimate the potential savings associated with broad substitution of generic drugs.Cross-sectional, nationally representative survey of noninstitutionalized adults.United States.Adults included in the Medical Expenditure Panel Survey Household Component, 1997-2000.Use of a multisource drug (that is, a drug available in a brand-name and > or =1 generic formulation) or a generic drug and the potential cost savings associated with broad generic substitution for all multisource products.Fifty-six percent of all outpatient drugs were multisource products, accounting for 41% of total outpatient drug expenditures. Of these multisource drugs, 61% were dispensed as a generic. If a generic had been substituted for all corresponding brand-name outpatient drugs in 2000, the median annual savings in drug expenditures per person would have been 45.89 dollars (interquartile range, 10.35 dollars to 158.06) for adults younger than 65 years of age and 78.05 dollars (interquartile range, 19.94 dollars to 241.72 dollars) for adults at least 65 years of age. In these age groups, the national savings would have been 5.9 billion dollars (95% CI, 5.5 billion dollars to 6.2 billion dollars) and 2.9 billion dollars (CI, 2.6 billion dollars to 3.1 billion dollars), respectively, representing approximately 11% of drug expenditures.Specific information about an individual's formulary was not available, so the authors could not estimate how much of the potential savings would benefit an individual or his or her health plan.Although broad substitution of generic drugs would affect only a modest percentage of drug expenditures, it could result in substantial absolute savings.
Self-reported long-term effects of diving and decompression illness in recreational scuba divers.
Authors: D McQueen, G Kent, A Murrison
Journal: British Journal of Sports Medicine (1994)

The aim of this study was to examine the long-term effects of neurological decompression illness (NDCI) on recreational divers. Thirty-seven divers who had been treated for neurological decompression illness at least 2 years previously, and a control group of 50 divers with no history of decompression illness, responded to a postal questionnaire. Divers in the accident group reported more symptoms of neurological damage, were more likely to believe that diving had a deleterious effect on their health and were more likely to indicate symptoms of psychiatric morbidity. The quantity of diving in the year preceding the survey was associated with reports of neurological damage in both groups and with symptoms of psychiatric morbidity in the accident group. Although requiring confirmation from a longitudinal study, these results suggest that recreational diving can have negative long-term consequences for health, particularly after decompression illness.
A point mutation in the murine Hem1 gene reveals an essential role for Hematopoietic Protein 1 in lymphopoiesis and innate immunity
Authors: Heon Park, Karen Staehling-Hampton, Mark W. Appleby, Mary E. Brunkow, Tania Habib, Yi Zhang, Fred Ramsdell, H. Denny Liggitt, Brian Freie, Mark Tsang, George Carlson, Sherree Friend, Charles Frevert, Brian M. Iritani
Journal: The Journal of Experimental Medicine (2008)

Hem1 (Hematopoietic protein 1) is a hematopoietic cell-specific member of the Hem family of cytoplasmic adaptor proteins. Orthologues of Hem1 in Dictyostelium discoideum, Drosophila melanogaster, and Caenorhabditis elegans are essential for cytoskeletal reorganization, embryonic cell migration, and morphogenesis. However, the in vivo functions of mammalian Hem1 are not known. Using a chemical mutagenesis strategy in mice to identify novel genes involved in immune cell functions, we positionally cloned a nonsense mutation in the Hem1 gene. Hem1 deficiency results in defective F-actin polymerization and actin capping in lymphocytes and neutrophils caused by loss of the Rac-controlled actin-regulatory WAVE protein complex. T cell development is disrupted in Hem1-deficient mice at the CD4−CD8− (double negative) to CD4+CD8+ (double positive) cell stages, whereas T cell activation and adhesion are impaired. Hem1-deficient neutrophils fail to migrate in response to chemotactic agents and are deficient in their ability to phagocytose bacteria. Remarkably, some Rac-dependent functions, such as Th1 differentiation and nuclear factor κB (NF-κB)–dependent transcription of proinflammatory cytokines proceed normally in Hem1-deficient mice, whereas the production of Th17 cells are enhanced. These results demonstrate that Hem1 is essential for hematopoietic cell development, function, and homeostasis by controlling a distinct pathway leading to cytoskeletal reorganization, whereas NF-κB–dependent transcription proceeds independently of Hem1 and F-actin polymerization.