tbuckley/cabot-search huggingface dataset:
Feasibility of a Clinical Trial of Augmentation Therapy for α<sub>1</sub>-Antitrypsin Deficiency
Authors: MARK D. SCHLUCHTER, JAMES K. STOLLER, ALAN F. BARKER, A. SONIA BUIST, RONALD G. CRYSTAL, JAMES F. DONOHUE, ROBERT J. FALLAT, GERARD M. TURINO, CAROL E. VREIM, MARGARET C. WU
Journal: American Journal of Respiratory and Critical Care Medicine (2000)

We examined the feasibility of a randomized clinical trial of intravenous augmentation therapy for individuals with alpha 1-antitrypsin ( α 1AT) deficiency, basing calculations on newly available data obtained from the NHLBI Registry of Patients with Severe Deficiency of Alpha 1-Antitrypsin. Using rate of FEV1 decline as the primary outcome and adjusting for noncompliance, a study of subjects with Stage II chronic obstructive pulmonary disease (COPD) (initial FEV1 35 to 49% predicted) with biannual spirometry measures obtained over 4 yr of follow-up would require 147 subjects per treatment arm to detect a difference in FEV1 decline of 23 ml/yr (i.e., a 28% reduction), the difference observed in the NHLBI Registry (1-sided test, α = 0.05, 90% power). To detect a 40% reduction in mortality in a 5-year study of subjects with baseline FEV1 35 to 49% predicted, recruited over the first 2 yr and then followed an additional 3 yr, 342 subjects per treatment arm would be needed. Though significant impediments to carrying out a clinical trial exist, including the cost of such a trial and the potential difficulties in recruiting patients for a placebo-controlled trial, we recommend a randomized controlled trial as the best method to evaluate the efficacy of intravenous augmentation therapy and of possible future treatments. Schluchter MD, Stoller JK, Barker AF, Buist AS, Crystal RG, Donohue JF, Fallat RJ, Turino GM, Vreim CE, Wu MC, for the Alpha 1-Antitrypsin Deficiency Registry Study Group. Feasibility of a clinical trial of augmentation therapy for α1-antitrypsin deficiency.
All-trans retinoic acid pharmacokinetics and bioavailability in acute promyelocytic leukemia: intracellular concentrations and biologic response relationship.
Authors: A Agadir, M Cornic, P Lefebvre, B Gourmel, M Jérôme, L Degos, P Fenaux, C Chomienne
Journal: Journal of Clinical Oncology (1995)

PURPOSE This study investigated the in vitro pharmacologic behavior and disposition kinetics of all-trans retinoic acid (ATRA) in acute myeloid leukemic (AML) cells, their sensitivity to its differentiating effect, and the in vivo response of acute promyelocytic leukemia (APL) patients after therapy. PATIENTS AND METHODS Fresh leukemic cells from 14 AML patients (nine APL and five non-APL), were incubated in suspension culture in the absence or presence of 10(-6) mol/L ATRA. Intracellular ATRA concentration and ATRA metabolism was determined by high-performance liquid chromatography (HPLC). RESULTS Immediate uptake is observed with maximal intracellular levels (Cmax) achieved after 24 hours of incubation. At this time, ATRA levels were variable, ranging from 20 to 230 pmol/10(6) cells (median, 100 pmol/10(6) cells). Comparison of ATRA intracellular levels with the in vitro response of patients' cell samples as measured by the percentage of nitro blue tetrazolium (NBT)-positive cells after a 3-day incubation period allowed us to discriminate a group of APL patients (n = 6) with high Cmax (group A; median, 200 pmol/10(6) cells) and maximal differentiation at day 3 (median, 80%), and a group of patients (n = 8, three APL and five non-APL) with low Cmax (group B; median, 35 pmol/10(6) cells) and poor in vitro response (median, 40%; APL cases only). Interestingly, all APL patients, except one included in group A (rapid in vitro ATRA uptakers), achieved a complete remission. CONCLUSION These findings suggest that intracellular ATRA concentrations are determinant for ATRA response and should be taken into account when monitoring the efficacy of ATRA differentiation therapeutic trials in malignant disorders.
Characterisation of the range of neutrophil stimulating mediators in cystic fibrosis sputum
Authors: K J Mackerness, G R Jenkins, A Bush, P J Jose
Journal: Thorax (2008)

<h3>Background:</h3> Most patients with cystic fibrosis (CF) die of respiratory failure due to chronic infection and destructive neutrophilic inflammation. <h3>Objective:</h3> To identify potential therapeutic targets by characterising the neutrophil stimulating mediators in the CF airway. <h3>Methods:</h3> Spontaneously expectorated CF sputum was extracted in phosphate buffered saline for assays of neutrophil chemotaxis, intracellular calcium mobilisation and cell shape change. Mediators were purified by ion exchange, C<sub>18</sub> reversed phase and size exclusion chromatography. <h3>Results:</h3> A pool of CF sputum contained considerable neutrophil stimulating activity but neutralisation of interleukin (IL)8/CXCL8 had little inhibitory effect on neutrophil chemotactic (10149 (2023) migrating cells vs 8661 (2597) at 62 mg sputum/ml; NS) or shape change (% forward scatter increase 46 (8) vs 38 (5) at 19 mg sputum/ml; p&lt;0.05) responses. Furthermore, the CF sputum pool induced an elevation in intracellular calcium ions even after desensitisation of the neutrophils to IL8. Chromatography identified contributions to the neutrophil shape change inducing activity from IL8, other CXC chemokines, leukotriene (LT) B<sub>4</sub> and two formyl peptides. There was also suggestive evidence for contributions from platelet activating factor (PAF) and C5a. Using non-chromatographed individual sputum samples, anti-IL8 alone did have an inhibitory effect on neutrophil chemotaxis (median inhibition 41%; p = 0.0002). However, even in this experiment, there were clearly significantly important, non-IL8 mediated, effects of CF sputum on neutrophils, and an inhibitor cocktail of anti-IL8 plus CXCR2, LTB<sub>4</sub>, formyl peptide, PAF and C5a receptor antagonists inhibited chemotaxis by a median of 97% (p = 0.0002). <h3>Conclusion:</h3> Many chemoattractants contribute to the neutrophil stimulating activity in CF sputum although the relative contribution of these mediators differs in different patients. Selective blockade of single mediators may not be sufficient to control neutrophil recruitment and activation in the CF airway.
Ligand-Dependent Platelet-Derived Growth Factor Receptor (PDGFR)-α Activation Sensitizes Rare Lung Cancer and Sarcoma Cells to PDGFR Kinase Inhibitors
Authors: Ultan McDermott, Rachel Y. Ames, A. John Iafrate, Shyamala Maheswaran, Hannah Stubbs, Patricia Greninger, Kaitlin McCutcheon, Randy Milano, Angela Tam, Diana Y. Lee, Laury Lucien, Brian W. Brannigan, Lindsey E. Ulkus, Xiao-Jun Ma, Mark G. Erlander, Daniel A. Haber, Sreenath V. Sharma, Jeffrey Settleman
Journal: Cancer Research (2009)

Platelet-derived growth factor (PDGF) receptors (PDGFR) and their ligands play critical roles in several human malignancies. Sunitinib is a clinically approved multitargeted tyrosine kinase inhibitor that inhibits vascular endothelial growth factor receptor, c-KIT, and PDGFR, and has shown clinical activity in various solid tumors. Activation of PDGFR signaling has been described in gastrointestinal stromal tumors (PDGFRA mutations) as well as in chronic myeloid leukemia (BCR-PDGFRA translocation), and sunitinib can yield clinical benefit in both settings. However, the discovery of PDGFR activating mutations or gene rearrangements in other tumor types could reveal additional patient populations who might benefit from treatment with anti-PDGFR therapies, such as sunitinib. Using a high-throughput cancer cell line screening platform, we found that only 2 of 637 tested human tumor-derived cell lines show significant sensitivity to single-agent sunitinib exposure. These two cell lines [a non-small-cell lung cancer (NSCLC) and a rhabdomyosarcoma] showed expression of highly phosphorylated PDGFRA. In the sunitinib-sensitive adenosquamous NSCLC cell line, PDGFRA expression was associated with focal PFGRA gene amplification, which was similarly detected in a small fraction of squamous cell NSCLC primary tumor specimens. Moreover, in this NSCLC cell line, focal amplification of the gene encoding the PDGFR ligand PDGFC was also detected, and silencing PDGFRA or PDGFC expression by RNA interference inhibited proliferation. A similar codependency on PDGFRA and PDGFC was observed in the sunitinib-sensitive rhabdomyosarcoma cell line. These findings suggest that, in addition to gastrointestinal stromal tumors, rare tumors that show PDGFC-mediated PDGFRA activation may also be clinically responsive to pharmacologic PDGFRA or PDGFC inhibition.
Long-Term Follow-up of Patients with Prostate Cancer and Nodal Metastases Treated by Pelvic Lymphadenectomy and Radical Prostatectomy: The Positive Impact of Adjuvant Radiotherapy
Authors: Luigi F. Da Pozzo, Cesare Cozzarini, Alberto Briganti, Nazareno Suardi, Andrea Salonia, Roberto Bertini, Andrea Gallina, Marco Bianchi, Gemma V. Fantini, Angelo Bolognesi, Ferruccio Fazio, Francesco Montorsi, Patrizio Rigatti
Journal: European Urology (2009)
Acquired Resistance to EGFR Tyrosine Kinase Inhibitors in EGFR-Mutant Lung Cancer: Distinct Natural History of Patients with Tumors Harboring the T790M Mutation
Authors: Geoffrey R. Oxnard, Maria E. Arcila, Camelia S. Sima, Gregory J. Riely, Juliann Chmielecki, Mark G. Kris, William Pao, Marc Ladanyi, Vincent A. Miller
Journal: Clinical Cancer Research (2010)

Patients with epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma develop acquired resistance to EGFR tyrosine kinase inhibitors (TKI) after a median of 10 to 16 months. In half of these cases, a second EGFR mutation, T790M, underlies acquired resistance. We undertook this study to examine the clinical course of patients harboring the T790M mutation following progression on TKI.
Basal but not Luminal Mammary Epithelial Cells Require PI3K/mTOR Signaling for Ras-Driven Overgrowth
Authors: Kristin A. Plichta, Jessica L. Mathers, Shelley A. Gestl, Adam B. Glick, Edward J. Gunther
Journal: Cancer Research (2012)

The mammary ducts of humans and mice are comprised of two main mammary epithelial cell (MEC) subtypes: a surrounding layer of basal MECs and an inner layer of luminal MECs. Breast cancer subtypes show divergent clinical behavior that may reflect properties inherent in their MEC compartment of origin. How the response to a cancer-initiating genetic event is shaped by MEC subtype remains largely unexplored. Using the mouse mammary gland, we designed organotypic three-dimensional culture models that permit challenge of discrete MEC compartments with the same oncogenic insult. Mammary organoids were prepared from mice engineered for compartment-restricted coexpression of oncogenic H-RAS(G12V) together with a nuclear fluorescent reporter. Monitoring of H-RAS(G12V)-expressing MECs during extended live cell imaging permitted visualization of Ras-driven phenotypes via video microscopy. Challenging either basal or luminal MECs with H-RAS(G12V) drove MEC proliferation and survival, culminating in aberrant organoid overgrowth. In each compartment, Ras activation triggered modes of collective MEC migration and invasion that contrasted with physiologic modes used during growth factor-initiated branching morphogenesis. Although basal and luminal Ras activation produced similar overgrowth phenotypes, inhibitor studies revealed divergent use of Ras effector pathways. Blocking either the phosphoinositide 3-kinase or the mammalian target of rapamycin pathway completely suppressed Ras-driven invasion and overgrowth of basal MECs, but only modestly attenuated Ras-driven phenotypes in luminal MECs. We show that MEC subtype defines signaling pathway dependencies downstream of Ras. Thus, cells-of-origin may critically determine the drug sensitivity profiles of mammary neoplasia.
Coronary artery bypass surgery. Physical, psychological, social, and economic outcomes six months later
Authors: C. D. Jenkins
Journal: JAMA (1983)

To evaluate the benefits of coronary artery bypass graft (CABG) surgery, we interviewed and tested 318 patients (268 men and 50 women) younger than age 70 before and six months after elective CABG at four university medical centers. Biomedical, psychoneurological, physical function, role function, occupational, social, family, sexual, emotional, and attitudinal variables were assessed. Quantitative comparisons showed improvement on many factors. Angina was completely relieved for 69% to 85% of persons, depending on whether it had been induced by exertion or other events. Disability days were reduced more than 80%. Seventy-five percent of employed persons had returned to work. Anxiety, depression, fatigue, and sleep problems declined. Vigor and well-being scores rose significantly. When losses were expected (eg, psychoneurological function, marital adjustment), they generally were not found. For none of the more than 60 outcome variables was widespread serious worsening found. The findings suggest that the great majority of patients are able to resume normal economic and social functioning within six months after CABG. (<i>JAMA</i>1983;250:782-788)
Urinary TMPRSS2:ERG and PCA3 in an Active Surveillance Cohort: Results from a Baseline Analysis in the Canary Prostate Active Surveillance Study
Authors: Daniel W. Lin, Lisa F. Newcomb, Elissa C. Brown, James D. Brooks, Peter R. Carroll, Ziding Feng, Martin E. Gleave, Raymond S. Lance, Martin G. Sanda, Ian M. Thompson, John T. Wei, Peter S. Nelson
Journal: Clinical Cancer Research (2013)

Active surveillance is used to manage low-risk prostate cancer. Both PCA3 and TMPRSS2:ERG are promising biomarkers that may be associated with aggressive disease. This study examines the correlation of these biomarkers with higher cancer volume and grade determined at the time of biopsy in an active surveillance cohort.Urine was collected after digital rectal examination prospectively as part of the multi-institutional Canary Prostate Active Surveillance Study (PASS). PCA3 and TMPRSS2:ERG levels were analyzed in urine collected at study entry. Biomarker scores were correlated to clinical and pathologic variables.In 387 men, both PCA3 and TMPRSS2:ERG scores were significantly associated with higher volume disease. For a negative repeat biopsy, and 1% to 10%, 11% to 33%, 34% or more positive cores, median PCA3, and TMPRSS2:ERG scores increased incrementally (P < 0.005). Both PCA3 and TMPRSS2:ERG scores were also significantly associated with the presence of high-grade disease. For a negative repeat biopsy, Gleason 6 and Gleason ≥7 cancers, the median PCA3, and TMPRSS2:ERG scores also increased incrementally (P = 0.02 and P = 0.001, respectively). Using the marker scores as continuous variables, the ORs for a biopsy in which cancer was detected versus a negative repeat biopsy (ref) on modeling was 1.41 (95% CI: 1.07-1.85), P = 0.01 for PCA3 and 1.28 (95% CI: 1.10-1.49), P = 0.001 for TMPRSS2:ERG.For men on active surveillance, both PCA3 and TMPRSS2:ERG seem to stratify the risk of having aggressive cancer as defined by tumor volume or Gleason score.
High intrahepatic HHV-6 virus loads but neither CMV nor EBV are associated with decreased graft survival after diagnosis of graft hepatitis
Authors: Sven Pischke, Juliane Gösling, Ilka Engelmann, Jerome Schlue, Benno Wölk, Elmar Jäckel, Christoph Meyer-Heithuis, Ulrich Lehmann, Christian P. Strassburg, Hannelore Barg-Hock, Thomas Becker, Michael P. Manns, Thomas Schulz, Heiner Wedemeyer, Albert Heim
Journal: Journal of Hepatology (2012)
Epidemiological, clinical, and laboratory characteristics of 48 cases of “Babesia venatorum” infection in China: a descriptive study
Authors: Jia-Fu Jiang, Yuan-Chun Zheng, Rui-Ruo Jiang, Hao Li, Qiu-Bo Huo, Bao-Gui Jiang, Yi Sun, Na Jia, Ya-Wei Wang, Lan Ma, Hong-Bo Liu, Yan-Li Chu, Xue-Bing Ni, Kun Liu, Yu-Dong Song, Nan-Nan Yao, Hong Wang, Tie Sun, Wu-Chun Cao
Journal: The Lancet Infectious Diseases (2014)
Expression of Pigment Epithelium-Derived Factor Decreases Liver Metastasis and Correlates with Favorable Prognosis for Patients with Ductal Pancreatic Adenocarcinoma
Authors: Hirofumi Uehara, Masaki Miyamoto, Kentaro Kato, Yuma Ebihara, Hiroyuki Kaneko, Hiroyuki Hashimoto, Yoshihiro Murakami, Ryunosuke Hase, Ryo Takahashi, Seiji Mega, Toshiaki Shichinohe, You Kawarada, Tomoo Itoh, Shunichi Okushiba, Satoshi Kondo, Hiroyuki Katoh
Journal: Cancer Research (2004)

Pigment epithelium-derived factor (PEDF) is expressed in several normal organs and identified as an inhibitor of neovascularization. In the present study, we screened the expression of PEDF immunohistochemically and investigated its correlation with clinicopathological features in patients who underwent surgery for ductal pancreatic adenocarcinoma. Of the 80 patients, 22 cases (27.5%) were positive for PEDF. A significant association was found between the PEDF expression and low microvessel density (P = 0.0003). No correlation was found between PEDF expression and age, gender, depth of invasion, tumor diameter, lymphatic invasion, venous, invasion or histopathological grading. The patients in pathological stage II had a significantly higher incidence of PEDF-positive expression than those in pathological stage III or IVA (P = 0.0418). PEDF immunoreactivity was inversely associated with liver metastasis (P = 0.0422). The survival of patients that were PEDF positive was significantly longer than that of those with negative expression (P = 0.0026). Multivariate analysis using the Cox regression model indicated that PEDF-positive expression was an independent favorable prognostic factor (risk ratio, 0.394; P = 0.0016). We conclude that PEDF expression suggests a more favorable prognosis than in patients whose carcinomas lack PEDF expression.
LATENT HERPES SIMPLEX VIRUS IN THE CENTRAL NERVOUS SYSTEM OF RABBITS AND MICE
Authors: F. B. Knotts, M. L. Cook, J. G. Stevens
Journal: The Journal of Experimental Medicine (1973)

Herpes simplex virus (HSV) type 1 induces a long-standing latent infection in the central nervous system of mice and rabbits. The infection was extablished in the brain stems of rabbits after corneal inoculation of the virus, and in the spinal cords of mice after rear footpad infection. In these animals, infectious virus could not be recovered by direct isolation from tissues; it was detected only after the tissues were maintained as organ cultures in vitro.
Long-term effects of darusentan on left-ventricular remodelling and clinical outcomes in the Endothelin A Receptor Antagonist Trial in Heart Failure (EARTH): randomised, double-blind, placebo-controlled trial
Authors: Inder Anand, John McMurray, Jay N Cohn, Marvin A Konstam, Thomas Notter, Kurt Quitzau, Frank Ruschitzka, Thomas F Lüscher
Journal: The Lancet (2004)
Lupoid sclerosis: a possible pathogenetic role for antiphospholipid antibodies.
Authors: E N Harris, A E Gharavi, C G Mackworth-Young, B M Patel, G Derue, G R Hughes
Journal: Annals of the Rheumatic Diseases (1985)

The case of a 45-year-old woman is described who developed transverse myelitis over a one-year period. Serological tests suggested a lupus-like illness. Antibodies to cardiolipin of the IgM class were detected in high titres in her serum. These may have played a part in the pathogenesis of her disease.
Lack of short-term effect of the thromboxane synthetase inhibitor UK-38,485 on airway reactivity to methacholine in asthmatic subjects
Authors: PV Gardiner, CL Young, K Holmes, DJ Hendrick, EH Walters
Journal: European Respiratory Journal (1993)

Previous open studies have suggested that thromboxane receptor antagonists or synthesis inhibitors lower airway hyperresponsiveness in human subjects. This would indicate a role of thromboxane A2 in the development or maintenance of hyperresponsiveness in asthma. Ten nonsmoking asthmatics (aged 23-64 yrs, 9 male) were included in a randomized, double-blind, placebo-controlled, cross-over study of the effect of one week of treatment with a potent selective thromboxane synthetase inhibitor (UK-38,485, 600 mg daily) on airway responsiveness. The study was preceded by a two week run-in period, and two weeks were used for wash-out between the two trial periods. Adequacy of dosage and patient compliance was confirmed by a reduction in the ex vivo formation of thromboxane B2 (median concentration 3.22 micrograms.ml-1 after placebo, 0.10 microgram.ml-1 after UK-38,485, p < 0.05). The mean forced expiratory volume in one second (FEV1) after UK-38,485 was 2.55 l, compared to 2.56 l after treatment with placebo (p = 0.74). The geometric mean provocative dose of methacholine producing a 20% fall in FEV1 (PD20) before and after UK-38,485 was 23.9 and 32.2 micrograms, respectively, compared to 25.1 and 26.3 micrograms respectively, before and after placebo (p = 0.31). The results of this study suggest that thromboxane A2 does not play an important role in the maintenance of increased airway responsiveness in moderately severe asthmatics treated with low doses of inhaled steroids.
THE ANTISTREPTOCOCCAL PROPERTY OF MILK
Authors: Armine T. Wilson, Herman Rosenblum
Journal: The Journal of Experimental Medicine (1952)

The measurement in vitro of lactenin, the antistreptococcal substance of milk, is affected by the size of the inoculum, the temperature of incubation, and the type of medium employed. Hemolytic streptococci belonging to the several serological groups vary in susceptibility to lactenin. All group A streptococci, regardless of type, are highly sensitive to it, and milk receiving a small inoculum sterilizes itself within 48 hours or less. By contrast, most strains of groups B, C, D, and E, although they may temporarily be inhibited, ultimately achieve full growth. Strains belonging to groups F, G, H, K, and L vary in sensitivity, some being fully inhibited and others achieving full growth. When streaked on the surface of milk-agar plates and examined at the end of 24 hours the streptococci fall into two classes: sensitive strains which do not produce visible colonies on the plate, and resistant strains which grow excellently. Very few strains show an intermediate degree of sensitivity. Human and goat milk contain an antistreptococcal principle which appears to be the same as the lactenin of cow milk, since streptococci which are inhibited by milk from one species are inhibited by milk from the others, and vice versa.
Reproduction in females: the role of the early life environment
Authors: D. M. Sloboda, M. Hickey, R. Hart
Journal: Human Reproduction Update (2010)

There is now compelling evidence that long-term health and physiological function are modified by events that occur early in life and involve interactions between the genome and the developmental environment. That reproductive function may similarly be influenced by early life events has been established in selected human populations, and investigations into underlying mechanisms are the subject of current animal studies.No systematic literature search was conducted. This review highlights early life influences on reproduction with a particular focus on nutritional impacts, and provides a brief overview with reference to some key studies in both the human and animal literature. We highlight the controversies, current unanswered questions and mechanisms underlying the association between the early life environment and long-term reproductive function.Currently, the impact of early life events on reproductive health and disease risk is poorly understood. It is clear, however, that nutrition spanning the entire developmental lifespan plays an integral role. Improved insight into the underlying mechanisms is likely to have significant implications for our current understanding of reproductive disorders, and therefore for the health and reproductive potential of future generations.