tbuckley/cabot-search huggingface dataset:
Preliminary Randomized, Double-Blind, Placebo-Controlled Trial of Pramipexole Added to Mood Stabilizers for Treatment-Resistant Bipolar Depression
Authors: Joseph F. Goldberg, Katherine E. Burdick, Carrie J. Endick
Journal: American Journal of Psychiatry (2004)

OBJECTIVE: Previous studies suggest that the dopamine agonist pramipexole may possess antidepressant properties. The authors conducted a preliminary randomized, placebo-controlled trial to determine the safety and antidepressant efficacy of pramipexole in treatment-resistant bipolar depression. METHOD: Twenty-two depressed outpatients with DSM-IV nonpsychotic bipolar disorder were randomly assigned to receive placebo or flexibly dosed pramipexole (mean maximum dose=1.7 mg/day, SD=1.3) added to existing mood stabilizers for 6 weeks. The primary outcome measure was response, defined as improvement in Hamilton Depression Rating Scale score of 50% or more over the baseline score; secondary analyses involved changes in Clinical Global Impression (CGI) severity scores. RESULTS: More patients given pramipexole (10 [83%] of 12) than patients given placebo (six [60%] of 10) completed the study. Eight (67%) of 12 patients taking pramipexole and two (20%) of 10 taking placebo had an improvement of at least 50% in their Hamilton depression scale scores. The mean percentage of improvement from baseline Hamilton depression scale scores was greater for patients taking pramipexole (48%) than for those taking placebo (21%). Mean improvements in CGI severity were also greater with pramipexole than placebo. No patients discontinued the study because of adverse events except for one patient who became hypomanic while taking pramipexole. CONCLUSIONS: Pramipexole was a safe and effective antidepressant among patients with bipolar depression. Larger randomized, controlled trials are needed to affirm these initial observations.
A5.11 alarmins S100A8/S100A9 stimulate osteophyte formation in experimental osteoarthritis and predict osteophyte progression in early human osteoarthritis
Authors: R F P Schelbergen, W de Munter, M H J van den Bosch, F P J G Lafeber, A Sloetjes, T Vogl, J Roth, W B van den Berg, P M van der Kraan, A B Blom, P L E M van Lent
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background and Objectives</h3> The main pathological feature of osteoarthritis (OA) is degradation of the articular cartilage. However, other important hallmarks include subclinical inflammation of the synovium and ectopic formation of new bone and cartilage at the ligaments or joint margins, termed osteophytes. Selective depletion of synovial macrophages prevents development of osteophytes in collagenase induced OA. Alarmins S100A8 and S100A9 are major products of activated macrophages regulating cartilage damage and synovial activation during murine and human osteoarthritis (OA). In the current study we investigated whether S100A8 and S100A9 are involved in osteophyte formation during experimental OA and if S100A8/A9 predicts osteophyte progression in early human OA. <h3>Materials and Methods</h3> OA was elicited in S100A9 -/- and wild-type C57Bl/6 mice in two experimental models that differ in degree of synovial activation. Osteophyte size, S100A8, S100A9 and VDIPEN expression was measured histologically. Chondrogenesis was induced in murine mesenchymal stem cells in the presence of S100A8. Levels of S100A8/A9 were determined in plasma of early symptomatic OA patients of the CHECK cohort study at baseline and development of osteophytes measured after 2 and 5 years. <h3>Results</h3> S100A8 and S100A9 protein levels in the synovial lining and serum coincide with osteophyte development in collagenase-induced OA (CIOA), in which synovial activation is high. Osteophyte size was drastically reduced in S100A9 -/- mice on day 21 and 42 of CIOA, in the medial collateral ligaments (58% and 93% reduction) and at medial femur and tibia (62% and 67% reduction). In contrast, osteophyte size was not reduced in S100A9 -/- mice during destabilised medial meniscus OA, in which synovial activation is scant. S100A8 increased expression and activation of MMPs during micromass chondrogenesis, thereby possibly increasing cartilage matrix remodelling allowing for larger osteophytes. Interestingly, early symptomatic OA patients of the CHECK study with osteophyte progression after two and five years had significantly elevated S100A8/A9 plasma levels at baseline, while CRP, COMP and ESR were not higher. <h3>Conclusions</h3> S100A8/A9 stimulate osteophyte formation in experimental OA with high synovial activation and may be used as a marker to predict osteophyte formation in early human OA.
Potential treatment for XDR-TB?
Authors: G Tack
Journal: Thorax (2009)

Extensively drug-resistant tuberculosis (XDR-TB) is associated with alarmingly high rates of mortality and is thought to account for an increasing proportion of cases of the infection worldwide. Multidrug-resistant tuberculosis (MDR-TB) describes strains of tuberculosis that are resistant to at least two main first-line drugs. …
Signaling Danger
Authors: Hans-Joachim Anders, Bernhard Banas, Detlef Schlöndorff
Journal: Journal of the American Society of Nephrology (2004)

ABSTRACT. Toll-like receptors (TLR) are an emerging family of receptors that recognize pathogen-associated molecular patterns and promote the activation of leukocytes and intrinsic renal cells. Ligands of the TLR include exogenous microbial components such as LPS (TLR4), lipoproteins and peptidoglycans (TLR1, -2, -6), viral RNA (TLR3), bacterial and viral unmethylated cytosin-guanosin dinucleotide (CpG)-DNA (TLR9), and endogenous molecules including heat-shock proteins and extracellular matrix molecules. Upon stimulation, TLR induce expression of inflammatory cytokines or costimulatory molecules via the MyD88-dependent and MyD88-independent signaling pathways shared with the interleukin-1 receptors. TLR are differentially expressed on leukocyte subsets and non-immune cells and appear to regulate important aspects of innate and adaptive immune responses. Tubular epithelial cells are among the non-immune cells that express TLR1, -2, -3, -4, and -6, suggesting that these TLR might contribute to the activation of immune responses in tubulointerstitial injury (e.g., bacterial pyelonephritis, sepsis, and transplant nephropathy). In addition, TLR9 has been shown to be involved in antigen-induced immune complex glomerulonephritis and lupus nephritis by regulating humoral and cellular immune responses. TLR are evolutionary conserved regulators of innnate and adaptive immune reponses. It is likely that TLR are involved in many if not all types of renal inflammation. Here the authors provide an overview on the biology of TLR, summarize the present data on their expression in the kidney, and provide an outlook for the potential roles of TLR in kidney disease.
Drug Development: Portals of Discovery
Authors: Susan E. Bates, Laleh Amiri-Kordestani, Giuseppe Giaccone
Journal: Clinical Cancer Research (2012)

Abstract A British humorist said, “There is much to be said for failure. It is much more interesting than success.” This CCR Focus section is aimed at identifying lessons to be learned from difficulties encountered in recent years during development of anticancer agents. Clearly, we have not found a silver bullet tyrosine kinase inhibitor against solid tumors comparable with imatinib in chronic myelogenous leukemia. Although vemurafenib for B-Raf–mutated melanoma and crizotinib for non–small cell lung cancers with echinoderm microtubule-associated protein-like 4 (EML4)–anaplastic lymphoma kinase (ALK) rearrangements were developed rapidly and offer hope for individualized targeted therapies, the development of agents targeting a number of other pathways has been slower and less successful. These agents include drugs for blocking the insulin-like growth factor I/insulin receptor pathways, mitotic kinase inhibitors, and Hsp90 antagonists. Several potentially useful, if not groundbreaking, agents have had setbacks in clinical development, including trastuzumab emtansine, gemtuzumab ozogamicin, and satraplatin. From experience, we have learned the following: (i) not every altered protein or pathway is a valid anticancer target; (ii) drugs must effectively engage the target; (iii) the biology of the systems we use must be very well understood; and (iv) clinical trials must be designed to assess whether the drug reached and impaired the target. It is also important that we improve the drug development enterprise to enhance enrollment, streamline clinical trials, reduce financial risk, and encourage the development of agents for niche indications. Such enormous challenges are offset by potentially tremendous gains in our understanding and treatment of cancer. Clin Cancer Res; 18(1); 23–32. ©2012 AACR.
Breast Cancer Incidence Among Atomic Bomb Survivors: Implications for Radiobiologic Risk at Low Doses
Authors: C E Land, D H McGregor
Journal: JNCI Journal of the National Cancer Institute (1979)

Supplemental dose-response analyses of breast cancer incidence data for Japanese A-bomb survivors during the period 1950–69 were presented. The first analysis led to an unpublished result cited in a report on risks associated with mammography in mass screening for breast cancer, namely, that the inference for a radiation among the A-bomb survivors did not depend solely on interpolation between values at 0 and high doses. In the second analysis, a theoretical form suggested by radiobiologic principles was used to investigate the extent to which linear interpolation may overestimate or underestimate breast cancer risk at low doses. The functional form, I(D) = (α0+α1D+α2D)e−β1D−β2D, where I(D) denoted breast cancer incidence at dose D and where all parameters were constrained to be positive, was treated as a basically linear form for description of the risk at low doses, with additional parameters to allow for upward curvature over the low-to-intermediate range and downward curvature at high doses. The analysis provided direct evidence of a radiation breast carcinogenesis effect at doses under 49 rads kerma (<40 rads to breast tissue). Evidence for an effect was contributed by the data from both Hiroshima and Nagasaki. The incidence data were too sparse to express all the subtleties of the above functional form for the dose response, and the form was simplified by the elimination of some parameters. The risk estimate obtained with the use of a simple linear model was not greater than estimates obtained with more general models that fit the data more closely.
Effect of verapamil on contractility, oxygen utilization, and calcium exchangeability in mammalian heart muscle
Authors: W. G. NAYLER, J. SZETO, D. BERRY
Journal: Cardiovascular Research (1972)

Journal Article Effect of verapamil on contractility, oxygen utilization, and calcium exchangeability in mammalian heart muscle Get access WINIFRED G. NAYLER, WINIFRED G. NAYLER 2 From the Baker Medical Research Institute,2 Melbourne, Australia 2 Address for reprints: Dr. W. G. Nayler. Baker Medical Research Institute, Commercial Road, Prahran, 3181, Victoria, Australia. Search for other works by this author on: Oxford Academic PubMed Google Scholar JULIE SZETO, JULIE SZETO From the Baker Medical Research Institute,2 Melbourne, Australia Search for other works by this author on: Oxford Academic PubMed Google Scholar D. BERRY D. BERRY From the Baker Medical Research Institute,2 Melbourne, Australia Search for other works by this author on: Oxford Academic PubMed Google Scholar Cardiovascular Research, Volume 6, Issue 2, March 1972, Pages 120–128, https://doi.org/10.1093/cvr/6.2.120 Published: 01 March 1972
TRANSGENIC ANIMALS AS NEW APPROACHES IN PHARMACOLOGICAL STUDIES
Authors: Li-Na Wei
Journal: The Annual Review of Pharmacology and Toxicology (1997)

▪ Abstract Transgenic animals are becoming useful tools for pharmacological studies. The use of transgenic technology raises two types of questions, “How are transgenic animals made?” and “What types of pharmacological questions can be answered using transgenic technologies?” Answers to these questions are discussed in this review. The production of animals with specific genetic alteration can be achieved by two strategies. The first involves the simple addition of DNA sequences to the chromosomes. The second strategy is to select particular genetic loci for site-specific changes. There are two well-established procedures for simple introduction of DNA into an animal genome, pronuclear DNA injection and transduction using a retrovirus. In contrast, methods for targeting specific DNA sequences to definite sites in the chromosomes are evolving rapidly. Some of these procedures can be used in combination to make a different variety of gene alterations in animals. Pharmacological studies where transgenic technology has been extensively used are discussed, including studies in the cardiovascular system, the nervous system, the endocrine system, cancer, and toxicology.
Ceftriaxone as effective as long-acting chloramphenicol in short-course treatment of meningococcal meningitis during epidemics: a randomised non-inferiority study
Authors: N Nathan, T Borel, A Djibo, D Evans, S Djibo, JF Corty, M Guillerm, KP Alberti, L Pinoges, PJ Guerin, D Legros
Journal: The Lancet (2005)
Harnessing Competing Endocytic Pathways for Overcoming the Tumor-Blood Barrier: Magnetic Resonance Imaging and Near-Infrared Imaging of Bifunctional Contrast Media
Authors: Helena Sheikhet Migalovich, Vyacheslav Kalchenko, Nava Nevo, Gila Meir, Fortune Kohen, Michal Neeman
Journal: Cancer Research (2009)

Ovarian cancer is the most lethal gynecologic malignancy, often diagnosed at advanced stage leading to poor prognosis. In the study reported here, magnetic resonance imaging and near-infrared reflectance imaging were applied for in vivo analysis of two competing endocytic pathways affecting retention of bifunctional daidzein-bovine serum albumin (BSA)-based contrast media by human epithelial ovarian carcinoma cells. Suppression of caveolae-mediated uptake using nystatin or by BSA competition significantly enhanced daidzein-BSA-GdDTPA/CyTE777 uptake by tumor cells in vitro. In vivo, perivascular myofibroblasts generated an effective perivascular barrier excluding delivery of BSA-GdDTPA/CyTE777 to tumor cells. The ability to manipulate caveolae-mediated sequestration of albumin by perivascular tumor myofibroblasts allowed us to effectively overcome this tumor-stroma barrier, increasing delivery of daidzein-BSA-GdDTPA/CyTE777 to the tumor cells in tumor xenografts. Thus, both in vitro and in vivo, endocytosis of daidzein-BSA-GdDTPA/CyTE777 by ovarian carcinoma cells was augmented by albumin or by nystatin. In view of the cardinal role of albumin in affecting the availability and pharmacokinetics of drugs, this approach could potentially also facilitate the delivery of therapeutics and contrast media to tumor cells.
Alterations in Large and Small Proteoglycans in Bleomycin-Induced Pulmonary Fibrosis in Rats
Authors: NARAYANAN VENKATESAN, TAKAE EBIHARA, PETER J. ROUGHLEY, MARA S. LUDWIG
Journal: American Journal of Respiratory and Critical Care Medicine (2000)

In bleomycin (BM)-induced lung fibrosis, alterations have been shown in the expression and deposition of small proteoglycans (PGs). Less, however, is known about changes in large PGs. We investigated changes in large aggregating (versican [VS]), basement membrane (heparan sulfate proteoglycan [HSPG]), and small (biglycan and fibromodulin) PGs during the development of BM-induced pulmonary fibrosis. BM (1.5 U) was instilled intratracheally into male Sprague–Dawley rats. Control rats received saline. At 7, 14, and 28 d after administration of BM, lungs were excised; one lung was fixed in formalin and 5- μ m sections were cut and stained with hematoxylin–eosin. The other lung was used for PG extraction. PGs were extracted with guanidine and were separated through composite gel polyacrylamide gel electrophoresis (PAGE) (large PGs) and sodium dodecylsulfate–PAGE (small PGs). Gels were either stained or electrophoretically transferred and probed with antibodies to VS, HSPG, biglycan, and fibromodulin. Histologic samples showed prominent inflammation, with abundant proteinaceous material, most evident in the samples obtained at 7 and 14 d after administration of BM. By 28 d after BM, much of the inflammatory response had resolved, and heterogeneous distribution of fibrosis was observed. Immunoblots showed a relative abundance of VS at 7 and 14 d. Control lungs stained minimally for VS. Levels of HSPG, biglycan, and fibromodulin were increased maximally at 14 d after administration of BM. Immunocytochemistry showed intense immunostaining of biglycan and fibromodulin in the areas of injured lung tissue from rats 14 and 28 d after BM administration. Control lungs revealed minimal staining for small PGs. Our findings indicate that changes in all subclasses of PGs occur during the development of BM-induced pulmonary fibrosis.
Development of Cancer Immunotherapies Based on Identification of the Genes Encoding Cancer Regression Antigens
Authors: S. A. Rosenberg
Journal: JNCI Journal of the National Cancer Institute (1996)

Tumor-infiltrating lymphocytes (TILs) have been grown from patients with metastatic melanoma and administered to the autologous patients to identify those TIL populations capable of mediating tumor regression. These TILs have been used to clone the genes that encode melanoma antigens. With the use of this strategy, we have identified six different genes encoding antigens restricted by multiple HLA alleles that appear to be related to tumor regression in patients. These antigens are now being used to develop immunization approaches for the treatment of patients with metastatic melanoma. The availability of genes encoding unique cancer antigens is opening new possibilities for the development of immunotherapies for the treatment of patients with cancer.
Inhaled corticosteroids for chronic obstructive pulmonary disease
Authors: H. Y. Park, S. F. P. Man, D. D. Sin
Journal: BMJ (2012)

A 65 year old female former smoker presents to your practice with gradually worsening shortness of breath while walking up a flight of stairs and a daily cough, productive of small amounts of white phlegm. She has a smoking history of 20 cigarettes a day for 20 years and chronic obstructive pulmonary disease (COPD). Her breathlessness had gradually worsened since an influenza-like illness six months ago, which was treated with a two week course of oral prednisolone and antibiotics. Since the illness she has used inhaled tiotropium 18 µg once daily and inhaled salbutamol as needed. Spirometry at the general practice shows a forced expiratory volume in one second (FEV1) of 63% predicted and a ratio of FEV1 to forced vital capacity of 0.65 after use of a bronchodilator. These values have not changed significantly over the previous year. As she is still symptomatic, her general practitioner recommends stopping tiotropium and starting a combination inhaler of a corticosteroid and a long acting β2 agonist.

Inhaled corticosteroids are glucocorticoids that bind to the glucocorticoid receptors in the airways and cause a reduction in lung inflammation.1 They are taken via metered dose inhalers or dry powder inhalers. The most commonly used inhaled corticosteroids in COPD are fluticasone propionate, budesonide, and beclometasone dipropionate (table 1⇓). 

View this table:

Table 1  
Combinations of inhaled corticosteroids plus long acting β2 agonists for chronic obstructive pulmonary disease (COPD). Monotherapy with inhaled corticosteroids is not approved for the treatment of COPD



The role of inhaled corticosteroids in COPD is controversial. However, on the basis of current evidence, using them as monotherapy cannot be recommended for most patients with this condition. The effect of such monotherapy in relieving dyspnoea and improving lung function is modest and weaker than that of long acting bronchodilators.2 Inhaled corticosteroids also …
Fluorouracil, Doxorubicin, and Cyclophosphamide (FAC) Versus FAC Followed by Weekly Paclitaxel As Adjuvant Therapy for High-Risk, Node-Negative Breast Cancer: Results From the GEICAM/2003-02 Study
Authors: Miguel Martín, Amparo Ruiz, Manuel Ruiz Borrego, Agustí Barnadas, Sonia González, Lourdes Calvo, Mireia Margelí Vila, Antonio Antón, Alvaro Rodríguez-Lescure, Miguel Angel Seguí-Palmer, Montserrat Muñoz-Mateu, Joan Dorca Ribugent, José Manuel López-Vega, Carlos Jara, Enrique Espinosa, César Mendiola Fernández, Raquel Andrés, Nuria Ribelles, Arrate Plazaola, Pedro Sánchez-Rovira, Javier Salvador Bofill, Carmen Crespo, Francisco J. Carabantes, Sonia Servitja, José Ignacio Chacón, César A. Rodríguez, Blanca Hernando, Isabel Álvarez, Eva Carrasco, Ana Lluch
Journal: Journal of Clinical Oncology (2013)

Adding taxanes to anthracycline-based adjuvant therapy improves survival outcomes of patients with node-positive breast cancer (BC). Currently, however, most patients with BC are node negative at diagnosis. The only pure node-negative study (Spanish Breast Cancer Research Group 9805) reported so far showed a docetaxel benefit but significant toxicity. Here we tested the efficacy and safety of weekly paclitaxel (wP) in node-negative patients, which is yet to be established.Patients with BC having T1-T3/N0 tumors and at least one high-risk factor for recurrence (according to St. Gallen 1998 criteria) were eligible. After primary surgery, 1,925 patients were randomly assigned to receive fluorouracil, doxorubicin, and cyclophosphamide (FAC) × 6 or FAC × 4 followed by wP × 8 (FAC-wP). The primary end point was disease-free survival (DFS) after a median follow-up of 5 years. Secondary end points included toxicity and overall survival.After a median follow-up of 63.3 months, 93% and 90.3% of patients receiving FAC-wP or FAC regimens, respectively, remained disease free (hazard ratio [HR], 0.73; 95% CI, 0.54 to 0.99; log-rank P = .04). Thirty-one patients receiving FAC-wP versus 40 patients receiving FAC died (one and seven from cardiovascular diseases, respectively; HR, 0.79; 95% CI, 0.49 to 1.26; log-rank P = .31). The most relevant grade 3 and 4 adverse events in the FAC-wP versus the FAC arm were febrile neutropenia (2.7% v 3.6%), fatigue (7.9% v 3.4%), and sensory neuropathy (5.5% v 0%).For patients with high-risk node-negative BC, the adjuvant FAC-wP regimen was associated with a small but significant improvement in DFS compared with FAC therapy, in addition to manageable toxicity, especially regarding long-term cardiac effects.