tbuckley/cabot-search huggingface dataset:
β-Adrenergic Receptor Polymorphisms and Response to Salmeterol
Authors: Michael E. Wechsler, Erik Lehman, Stephen C. Lazarus, Robert F. Lemanske, Homer A. Boushey, Aaron Deykin, John V. Fahy, Christine A. Sorkness, Vernon M. Chinchilli, Timothy J. Craig, Emily DiMango, Monica Kraft, Frank Leone, Richard J. Martin, Stephen P. Peters, Stanley J. Szefler, Wenlei Liu, Elliot Israel
Journal: American Journal of Respiratory and Critical Care Medicine (2005)

Several studies suggest that patients with asthma who are homozygous for arginine at the 16th position of the beta2-adrenergic receptor may not benefit from short-acting beta-agonists.We investigated whether such genotype-specific effects occur when patients are treated with long-acting beta-agonists and whether such effects are modified by concurrent inhaled corticosteroid (ICS) use.We compared salmeterol response in patients with asthma homozygous for arginine at B16 (B16Arg/Arg) with those homozygous for glycine at B16 (B16Gly/Gly) in two separate cohorts. In the first, subjects were randomized to regular therapy with salmeterol while simultaneously discontinuing ICS therapy. In the second, subjects were randomized to regular therapy with salmeterol while continuing concomitant ICS.In both trials, B16Arg/Arg subjects did not benefit compared with B16Gly/Gly subjects after salmeterol was initiated. In the first cohort, compared with placebo, the addition of salmeterol was associated with a 51.4 L/min lower A.M. peak expiratory flow (PEF; p = 0.005) in B16Arg/Arg subjects(salmeterol, n = 12; placebo, n = 5) as compared with B16Gly/Gly subjects (salmeterol, n = 13; placebo, n = 13). In the second cohort, B16Arg/Arg subjects treated with salmeterol and ICS concurrently (n = 8) had a lower A.M. PEF (36.8 L/min difference, p = 0.048) than B16Gly/Gly subjects (n = 22) treated with the same regimen. In addition, B16 Arg/Arg subjects in the second cohort had lower FEV1 (0.42 L, p = 0.003), increased symptom scores (0.2 units, p = 0.034), and increased albuterol rescue use (0.95 puffs/d, p = 0.004) compared with B16Gly/Gly subjects.Relative to B16Gly/Gly patients with asthma, B16Arg/Arg patients with asthma may have an impaired therapeutic response to salmeterol in either the absence or presence of concurrent ICS use. Investigation of alternate treatment strategies may benefit this group.
Mechanisms of Organophosphorus Ester-Induced Delayed Neurotoxicity: Type I and Type II
Authors: M B Abou-Donia, D M Lapadula
Journal: The Annual Review of Pharmacology and Toxicology (1990)

Heme oxygenases (HO) catabolize free heme, that is, iron (Fe) protoporphyrin (IX), into equimolar amounts of Fe2+, carbon monoxide (CO), and biliverdin. The stress-responsive HO-1 isoenzyme affords protection against programmed cell death. The mechanism ...Read More
T cell antiidiotypic antibodies reveal differences between two human leukemias.
Authors: D N Posnett, R D Bigler, Y Bushkin, D E Fisher, C Y Wang, L F Mayer, N Chiorazzi, H G Kunkel
Journal: The Journal of Experimental Medicine (1984)

Two different human T cell leukemias were compared, using antiidiotype-like murine monoclonal antibodies. In each case these antibodies immunoprecipitated disulfide-linked heterodimer molecules from their respective leukemic cells. On sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) analysis of the two idiotype-bearing molecules a major difference in molecular weight was observed, which could be attributed to a similar difference in size of the heavily iodinated chain of either heterodimer. The lightly iodinated chains of both molecules co-migrated at 43 Kd, but appeared to have different isoelectric points on two-dimensional gel analysis. The possibility that these two different heterodimers correspond to different classes of the putative T cell receptor for antigen is discussed. Assays of proliferation of the leukemic cells using Sepharose-bound antiidiotype-like monoclonal antibody showed that one of the leukemic cell types proliferated readily in response to its antiidiotypic antibody. This proliferation was not associated with measurable production of IL-2 and appeared to be a direct effect of the antiidiotypic antibody, which may mimic antigen in its interaction with the T cell receptor for antigen. The other leukemic cell type did not respond to Sepharose-bound antiidiotypic antibody and was generally unresponsive to lymphokines and mitogens. It is possible that the two leukemic cell types represent different stages of T cell differentiation.
Notch activation inhibits AML growth and survival: a potential therapeutic approach
Authors: Sankaranarayanan Kannan, Robert M. Sutphin, Mandy G. Hall, Leonard S. Golfman, Wendy Fang, Riitta M. Nolo, Lauren J. Akers, Richard A. Hammitt, John S. McMurray, Steven M. Kornblau, Ari M. Melnick, Maria E. Figueroa, Patrick A. Zweidler-McKay
Journal: The Journal of Experimental Medicine (2013)

Although aberrant Notch activation contributes to leukemogenesis in T cells, its role in acute myelogenous leukemia (AML) remains unclear. Here, we report that human AML samples have robust expression of Notch receptors; however, Notch receptor activation and expression of downstream Notch targets are remarkably low, suggesting that Notch is present but not constitutively activated in human AML. The functional role of these Notch receptors in AML is not known. Induced activation through any of the Notch receptors (Notch1–4), or through the Notch target Hairy/Enhancer of Split 1 (HES1), consistently leads to AML growth arrest and caspase-dependent apoptosis, which are associated with B cell lymphoma 2 (BCL2) loss and enhanced p53/p21 expression. These effects were dependent on the HES1 repressor domain and were rescued through reexpression of BCL2. Importantly, activated Notch1, Notch2, and HES1 all led to inhibited AML growth in vivo, and Notch inhibition via dnMAML enhanced proliferation in vivo, thus revealing the physiological inhibition of AML growth in vivo in response to Notch signaling. As a novel therapeutic approach, we used a Notch agonist peptide that led to significant apoptosis in AML patient samples. In conclusion, we report consistent Notch-mediated growth arrest and apoptosis in human AML, and propose the development of Notch agonists as a potential therapeutic approach in AML.
Better Access to Information about Clinical Trials
Authors: Alexa T. McCray
Journal: Annals of Internal Medicine (2000)

Access to information about clinical trials is important to researchers, health care professionals, and patients. Many have argued for the establishment of clinical trials registries, citing their substantial benefits. Although some registries do exist, it has been difficult to create comprehensive, easily accessible systems. This paper briefly reviews existing registries, discusses the challenges in building registries, and reviews some of their benefits. The paper concludes with a description of a new, extensive Web-based registry called ClinicalTrials.gov (http://clinicaltrials. gov/), which was developed at the National Institutes of Health (NIH) by the National Library of Medicine as a result of recent legislation calling for a comprehensive, publicly accessible registry of clinical trials. The first version of the system became available in late February 2000 and contains information about approximately 5000 trials. The first release contains primarily NIH-sponsored trials, and new trials are regularly added to the system. Subsequent versions will contain information about trials sponsored by other federal agencies and by the private sector. The system was developed in accordance with basic informatics principles, including adherence to standards, usability considerations, and iterative testing and evaluation.
The Histology of Lung Cancer
Authors: J. B. Walter, D. M. Pryce
Journal: Thorax (1955)

With the great advances in thoracic surgery, radical excision for pulmonary carcinoma has become a relatively safe and frequent operation, offering to the patient new hope of cure.However, if the results of operative treatment are to be accurately assessed, the ordinary gross pathology must be carefully and fully recorded, for it is of little use comparing survival rates unless attention is paid not only to the different histological types of growth, but also to anatomical factors such as location, size, and site of origin, which can seriously affect the outcome.At present there is no uniformity in histological nomenclature and the site of origin is a matter of dispute.This paper gives our views on histology after a recent study of 207 surgical specimens and 159 necropsies.
Phase III trial of nonpegylated liposomal doxorubicin in combination with trastuzumab and paclitaxel in HER2-positive metastatic breast cancer
Authors: J. Baselga, A. Manikhas, J. Cortés, A. Llombart, L. Roman, V.F. Semiglazov, M. Byakhov, D. Lokanatha, S. Forenza, R.H. Goldfarb, J. Matera, N. Azarnia, C.A. Hudis, M. Rozencweig
Journal: Annals of Oncology (2014)
Tubal ligation and risk of ovarian cancer in carriers of BRCA1 or BRCA2 mutations: a case-control study
Authors: Steven A Narod, Ping Sun, Parviz Ghadirian, Henry Lynch, Claudine Isaacs, Judy Garber, Barbara Weber, Beth Karlan, David Fishman, Barry Rosen, Nadine Tung, Susan L Neuhausen
Journal: The Lancet (2001)
Electrocardiographic Characterization of the QTc Interval in Patients with Advanced Solid Tumors: Pharmacokinetic- Pharmacodynamic Evaluation of Sunitinib
Authors: Carlo L. Bello, Marilyn Mulay, Xin Huang, Shem Patyna, Melissa Dinolfo, Steven Levine, Andrew Van Vugt, Melvin Toh, Charles Baum, Lee Rosen
Journal: Clinical Cancer Research (2009)

To evaluate the effects of sunitinib, a multitargeted tyrosine kinase inhibitor, on the QT interval in patients with cancer.Patients received sunitinib loading doses (150-200 mg) on days 3 and 9 and maintenance doses (50 mg/d) on days 4 to 8. Moxifloxacin (day 1), placebo (day 2), and granisetron [with placebo (day 2) or sunitinib (days 3 and 9)] were also administered. Treatment effects were evaluated by time-matched, serial electrocardiograms, and manually overread.Twenty-four of 48 patients were QT/PK evaluable. Moxifloxacin produced a time-matched, maximum mean placebo-adjusted corrected QT interval (QT(c)F) of 5.6 ms [90% confidence interval (CI), 1.9-9.3]. Sunitinib QT(c)F changes correlated with exposure, but not T(max). Maximum mean time-matched, placebo-adjusted QT(c)F was 9.6 ms (90% CI, 4.1-15.1) at steady state/therapeutic concentrations (day 3) and 15.4 ms (90% CI, 8.4-22.4) at supratherapeutic concentrations (day 9). No patient had a QT(c)F >500 ms. Concomitant granisetron produced no significant QT(c)F prolongation. Sunitinib-related adverse events were as previously described.Sunitinib has a dose-dependent effect on QT interval. The increased risk of ventricular arrhythmias must be weighed against the therapeutic benefit sunitinib provides to patients with advanced cancer.
Extrahepatic biliary obstruction impairs microvascular perfusion and increases leukocyte adhesion in rat liver
Authors: T A Koeppel, M Trauner, J C Baas, J C Thies, S F Schlosser, S Post, M Gebhard, C Herfarth, J L Boyer, G Otto
Journal: Hepatology (1997)

To determine if disturbances of the liver microcirculation may be of pathophysiological relevance for liver damage during acute biliary obstruction, we studied the effects of bile duct ligation (BDL) on hepatic microhemodynamics and leukocyte adhesion in rat liver in vivo. Male Wistar rats were subjected to BDL for 3 days and 7 days, respectively. Sham-operated controls underwent laparotomy without BDL. After 3 days, intravital fluorescence microscopy (IVM) and hydrogen gas (H2) clearance were performed to study hepatic microvascular perfusion. Furthermore, leukocyte-endothelial cell interactions were assessed by IVM. Intercellular adhesion molecule 1 (ICAM-1) protein expression was studied by Western blot analysis and tissue immunofluorescence after 3 and 7 days, respectively. Analysis of microvascular perfusion by IVM revealed a marked impairment of sinusoidal perfusion after 3 days. Assessment of H2 clearance confirmed that overall hepatic microvascular perfusion was decreased. In addition, increased leukocyte adhesion in sinusoids and venules could be observed. A concomitant increase of ICAM-1 expression in liver tissue was also noted within the first week after BDL. Our results show that BDL is followed by a marked depression of the hepatic microcirculation and increased leukocyte adhesion in vivo within 3 to 7 days. Together, these findings suggest that deficits in microvascular perfusion and increased neutrophil infiltration may represent a potential source of liver injury during acute biliary obstruction.
Association Between Imposition of a Maintenance of Certification Requirement and Ambulatory Care–Sensitive Hospitalizations and Health Care Costs
Authors: Bradley M. Gray, Jonathan L. Vandergrift, Mary M. Johnston, James D. Reschovsky, Lorna A. Lynn, Eric S. Holmboe, Jeffrey S. McCullough, Rebecca S. Lipner
Journal: JAMA (2014)

In 1990, the American Board of Internal Medicine (ABIM) ended lifelong certification by initiating a 10-year Maintenance of Certification (MOC) program that first took effect in 2000. Despite the importance of this change, there has been limited research examining associations between the MOC requirement and patient outcomes.To measure associations between the original ABIM MOC requirement and outcomes of care.Quasi-experimental comparison between outcomes for Medicare beneficiaries treated in 2001 by 2 groups of ABIM-certified internal medicine physicians (general internists). One group (n = 956), initially certified in 1991, was required to fulfill the MOC program in 2001 (MOC-required) and treated 84 215 beneficiaries in the sample; the other group (n = 974), initially certified in 1989, was grandfathered out of the MOC requirement (MOC-grandfathered) and treated 69 830 similar beneficiaries in the sample. We compared differences in outcomes for the beneficiary cohort treated by the MOC-required general internists before (1999-2000) and after (2002-2005) they were required to complete MOC, using the beneficiary cohort treated by the MOC-grandfathered general internists as the control.Quality measures were ambulatory care-sensitive hospitalizations (ACSHs), measured using prevention quality indicators. Ambulatory care-sensitive hospitalizations are hospitalizations triggered by conditions thought to be potentially preventable through better access to and quality of outpatient care. Other outcomes included health care cost measures (adjusted to 2013 dollars).Annual incidence of ACSHs (per 1000 beneficiaries) increased from the pre-MOC period (37.9 for MOC-required beneficiaries vs 37.0 for MOC-grandfathered beneficiaries) to the post-MOC period (61.8 for MOC-required beneficiaries vs 61.4 for MOC-grandfathered beneficiaries) for both cohorts, as did annual per-beneficiary health care costs (pre-MOC period, $5157 for MOC-required beneficiaries vs $5133 for MOC-grandfathered beneficiaries; post-MOC period, $7633 for MOC-required beneficiaries vs $7793 for MOC-grandfathered beneficiaries). The MOC requirement was not statistically associated with cohort differences in the growth of the annual ACSH rate (per 1000 beneficiaries, 0.1 [95% CI, -1.7 to 1.9]; P = .92), but was associated with a cohort difference in the annual, per-beneficiary cost growth of -$167 (95% CI, -$270.5 to -$63.5; P = .002; 2.5% of overall mean cost).Imposition of the MOC requirement was not associated with a difference in the increase in ACSHs but was associated with a small reduction in the growth differences of costs for a cohort of Medicare beneficiaries.
Effects of tetrahydrouridine on pharmacokinetics and pharmacodynamics of oral decitabine
Authors: Donald Lavelle, Kestis Vaitkus, Yonghua Ling, Maria A. Ruiz, Reda Mahfouz, Kwok Peng Ng, Soledad Negrotto, Nicola Smith, Pramod Terse, Kory J. Engelke, Joseph Covey, Kenneth K. Chan, Joseph DeSimone, Yogen Saunthararajah
Journal: Blood (2011)
Urogenital Carcinogenesis in Female CD1 Mice Induced by <i>In utero</i> Arsenic Exposure Is Exacerbated by Postnatal Diethylstilbestrol Treatment
Authors: Michael P. Waalkes, Jie Liu, Jerrold M. Ward, Douglas A. Powell, Bhalchandra A. Diwan
Journal: Cancer Research (2006)

Abstract Transplacental inorganic arsenic carcinogenicity, together with postnatal exposure to diethylstilbestrol or tamoxifen, was studied. Pregnant CD1 mice received 85 ppm arsenic in the drinking water from gestation days 8 to 18 and were allowed to give birth. Groups (n = 35) of female offspring were injected s.c. on postpartum days 1 through 5 with diethylstilbestrol (2 μg/pup/d) or tamoxifen (10 μg/pup/d) and observed for 90 weeks. Arsenic alone induced some urogenital system tumors, including mostly benign tumors of the ovary and uterus, and adrenal adenoma. Diethylstilbestrol alone induced some tumors (primarily cervical) but when given after in utero arsenic, it greatly enhanced urogenital tumor incidence, multiplicity, and progression. For instance, compared with the incidence of urogenital malignancies in the control (0%), arsenic alone (9%), and diethylstilbestrol alone (21%) groups, arsenic plus diethylstilbestrol acted synergistically, inducing a 48% incidence of malignant urogenital tumors. Of the urogenital tumors induced by arsenic plus diethylstilbestrol, 80% were malignant, and 55% were multiple site. Arsenic plus diethylstilbestrol increased ovarian, uterine, and vaginal tumors, and urinary bladder proliferative lesions, including three transitional cell carcinomas. Tamoxifen alone did not increase urogenital tumors or affect arsenic-induced neoplasia but did increase arsenic-induced uroepithelial proliferative lesions. Uterine and bladder carcinoma induced by arsenic plus diethylstilbestrol greatly overexpressed estrogen receptor-α (ER-α) and pS2, an estrogen-regulated gene. In neonatal uteri, prenatal arsenic increased ER-α expression and enhanced estrogen-related gene expression induced by postnatal diethylstilbestrol. Thus, arsenic acts with estrogens to enhance production of female mouse urogenital cancers. (Cancer Res 2006; 66(3): 1337-45)
TV: The Trust
Authors: H. Scott
Journal: BMJ (2002)

Channel 4, Wednesdays at 9 pm, 16 January to 14 February Rating: ![Graphic][1]</img>![Graphic][2]</img>![Graphic][3]</img>![Graphic][4]</img> This five part documentary observes the parallel lives of NHS staff and the people they care for during several weeks last year at Queen's Medical Centre, Nottingham. In the intensive care unit, on the admissions ward, in the children's unit, and at the end of life, complete strangers make the best relationships they can in difficult circumstances. People who investigate complaints about health services will probably find the third programme, “System Error” (30 January), like a moving-picture version of their jobs. It covers the way that Queen's responded to two serious matters: the death of Wayne Jowett, following intrathecal rather than intravenous administration of vincristine; and the recognition that Queen's had stored a large number of human organs and other tissue, after death. It tells the stories from both … [1]: /embed/inline-graphic-1.gif [2]: /embed/inline-graphic-2.gif [3]: /embed/inline-graphic-3.gif [4]: /embed/inline-graphic-4.gif
Combination Therapy With Thalidomide Plus Dexamethasone for Newly Diagnosed Myeloma
Authors: S. Vincent Rajkumar, Suzanne Hayman, Morie A. Gertz, Angela Dispenzieri, Martha Q. Lacy, Philip R. Greipp, Susan Geyer, Nancy Iturria, Rafael Fonseca, John A. Lust, Robert A. Kyle, Thomas E. Witzig
Journal: Journal of Clinical Oncology (2002)

Multiple myeloma is a malignancy of plasma cells and is characterized by increased marrow angiogenesis. Thalidomide, an agent with antiangiogenic properties, is effective in relapsed myeloma. We report the results of a study combining thalidomide and dexamethasone as initial therapy for myeloma.Fifty patients with newly diagnosed myeloma were studied. Thalidomide was given at a dose of 200 mg/d orally. Dexamethasone was given at a dose of 40 mg/d orally on days 1 to 4, 9 to 12, and 17 to 20 (odd cycles) and 40 mg/d on days 1 to 4 (even cycles), repeated monthly.Of all 50 patients, a confirmed response was seen in 32 patients yielding a response rate of 64% (95% confidence interval, 49% to 77%). Thirty-one patients (62%) proceeded to stem-cell collection after four cycles of therapy including 26 who underwent stem-cell transplantation and five who chose stem-cell cryopreservation. Major grade 3 or 4 toxicities were observed in 16 patients (32%), and the most frequent were deep vein thrombosis (six patients), constipation (four patients), rash (three patients), and dyspnea (two patients). Three deaths occurred during active therapy because of a pancreatitis, pulmonary embolism, and infection.We conclude that the combination of thalidomide plus dexamethasone is a feasible and active regimen in the treatment of multiple myeloma. It merits further study as an oral alternative to infusional chemotherapy with vincristine, doxorubicin, and dexamethasone and other intravenous regimens currently used as pretransplantation induction therapy for myeloma.
Long-Term Ambient Air Pollution and Respiratory Symptoms in Adults (SAPALDIA Study)
Authors: ELIZABETH ZEMP, SERGE ELSASSER, CHRISTIAN SCHINDLER, NINO KÜNZLI, ANDRÉ P. PERRUCHOUD, GUIDO DOMENIGHETTI, TULLIO MEDICI, URSULA ACKERMANN-LIEBRICH, PHILIPP LEUENBERGER, CHRISTIAN MONN, GIANFRANCO BOLOGNINI, JEAN-PIERRE BONGARD, OTTO BRÄNDLI, WERNER KARRER, ROLAND KELLER, MARTIN H. SCHÖNI, JEAN-MARIE TSCHOPP, BEA VILLIGER, JEAN-PIERRE ZELLWEGER
Journal: American Journal of Respiratory and Critical Care Medicine (1999)

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