tbuckley/cabot-search huggingface dataset:
Final Results of a Randomized Phase III Trial Comparing Cyclophosphamide, Epirubicin, and Fluorouracil With a Dose-Intensified Epirubicin and Cyclophosphamide + Filgrastim as Neoadjuvant Treatment in Locally Advanced Breast Cancer: An EORTC-NCIC-SAKK Multicenter Study
Authors: P. Therasse, L. Mauriac, M. Welnicka-Jaskiewicz, P. Bruning, T. Cufer, H. Bonnefoi, E. Tomiak, K. I. Pritchard, A. Hamilton, M.J. Piccart
Journal: Journal of Clinical Oncology (2003)

To compare the efficacy of a standard anthracycline-based regimen to a dose-intensified anthracycline regimen in locally advanced breast cancer.Locally advanced breast cancer patients were randomly assigned onto a study comparing cyclophosphamide (C; 75 mg/m(2) orally days 1 to 14), epirubicin (E; 60 mg/m(2) intravenously [IV] days 1, 8), and fluorouracil (F; 500 mg/m(2) IV days 1, 8) six cycles every 28 days versus E (120 mg/m(2) IV day 1), C (830 mg/m(2) IV day 1), and granulocyte colony-stimulating factor (filgrastim; 5 micro g/kg/d subcutaneously days 2 to 13) six cycles every 14 days. The study was designed to detect a 15% improvement; that is, from 50% to 65% in median progression-free survival (PFS) in favor of the dose-intensified regimen.A total of 448 patients were enrolled over a period of 3 years. The median dose intensity delivered for C and E reached, respectively, 85% and 87% of that planned in the CEF arm and 96% and 95% of that planned in the EC arm. The dose-intensified arm was slightly more emetogenic and generated more grade 3 to 4 anemia but less febrile neutropenia episodes. After a median follow-up of 5.5 years, 277 events have been reported. The median PFS was 34 and 33.7 months for CEF and EC, respectively (P =.68), and the 5-year survival rate was 53% and 51% for CEF and EC, respectively (P =.94).Dose-intensified EC does not provide a measurable therapeutic benefit over CEF as neoadjuvant chemotherapy for unselected locally advanced breast cancer patients.
Transfusion Requirements in Critical Care
Authors: P C Hébert, G Wells, J Marshall, C Martin, M Tweeddale, G Pagliarello, M Blajchman
Journal: JAMA (1995)

To evaluate the effects of a restrictive and a liberal red blood cell (RBC) transfusion strategy on mortality and morbidity in critically ill patients.Multicenter, prospective, randomized clinical trial.Sixty-nine normovolemic critically ill patients admitted to one of five tertiary level intensive care units with hemoglobin values less than 90 g/L within 72 hours of admission.Patients were randomly allocated to one of two RBC transfusion strategies. Hemoglobin values were maintained between 100 and 120 g/L in the liberal transfusion group and between 70 and 90 g/L in the restrictive group.Primary diagnosis and mean +/- SD age (58.6 +/- 15 vs 59.0 +/- 21 years and Acute Physiology and Chronic Health Evaluation II score (20 +/- 6.2 vs 21 +/- 7.2) were similar in the restrictive and liberal groups, respectively. Daily hemoglobin values averaged 90 g/L in the restrictive group vs 109 g/L in the liberal group (P < .001). The restrictive group received 2.5 U per patient compared with 4.8 U per patient in the liberal group. This represents a 48% relative decrease (P < .001) in RBC units transfused per patient. The 30-day mortality rate was 24% in the restrictive group compared with 25% in the liberal group; the 95% confidence interval around the absolute difference was -19% to 21%. Similar observations were noted for intensive care unit mortality (P = .76) and 120-day mortality (P > .99). In addition, survival analysis comparing time until death in both groups did not reveal any significant difference (P = .93) between groups. Organ dysfunction scores were also similar (P = .44).In this small randomized trial, neither mortality nor the development of organ dysfunction was affected by the transfusion strategy, which suggests that a more restrictive approach to the transfusion of RBCs may be safe in critically ill patients. However, the study lacked power to detect small but clinically significant differences. Therefore, further investigations of RBC transfusion strategies are warranted.
A potential cardioprotective role of hepatocyte growth factor in myocardial infarction in rats
Authors: H Ueda
Journal: Cardiovascular Research (2001)

Objective: Cardiotrophic growth factors with anti-cell death actions on cardiac myocytes have gained attention for treatment of patients with myocardial infarction. Hepatocyte growth factor (HGF) plays a role in tissue repair and protection from injuries, however, the physiological role of HGF in the myocardium has not been well defined. We asked if HGF would afford to the infarcted myocardium. Methods and results: Mature cardiac myocytes prepared from adult rats expressed barely detectable levels of the c-Met/HGF receptor, however, c-Met receptor expression increased during cultivation, which meant that cardiac myocytes are potential targets of HGF. Addition of hydrogen peroxide remarkably decreased the number of viable mature cardiac myocytes in primary culture, whereas treatment with HGF enhanced survival of the cells subjected to the oxidant stress. Although very low levels of c-Met/HGF receptor and HGF mRNA expression were seen in normal rat hearts, both c-Met/HGF receptor and HGF mRNA levels rapidly increased to much higher levels than normal, when the rats were subjected to myocardial infarction. Immunohistochemical analysis of the c-Met receptor indicated that this receptor was expressed in cardiomyocytes localized in the border regions of the viable myocardium and in non-infarcted regions following myocardial infarction. Conclusion: The c-Met/HGF receptor is induced in cardiomyocytes following myocardial infarction and HGF exhibits protective effect on cardiomyocytes against oxidative stress. Our working hypothesis is that HGF may afford myocardial protection from myocardial infarction.
Bacteria, bile salts, and intestinal monosaccharide malabsorption
Authors: M. Gracey, V. Burke, A. Oshin, J. Barker, E. F. Glasgow
Journal: Gut (1971)

Intestinal monosaccharide transport was studied in a series of rats with a self-filling jejunal blind loop using 3mM arbutin (p-hydroxyphenyl-B-glucoside) or 1mM D-fructose as substrate in vitro and 10 mM arbutin or 5mM D-fructose in vivo. These results were compared with changes in the bacterial flora and state of conjugation of intraluminal bile salts in those animals. Observations were also made of the microscopic and ultrastructural appearances of the small-intestinal epithelium. In the small intestine of blind-loop rats intestinal monosaccharide transport is impaired, and in vitro is most marked in the blind loop, less so in the efferent jejunum, and not significantly altered in the afferent jejunum. A similar pattern of disturbed monosaccharide absorption was demonstrated by perfusions in vivo. The degree of the transport defect correlates closely with the luxuriance of the anaerobic flora, which averaged 10(8) per millilitre in the blind loop, 10(7) in the efferent jejunum, and 10(6) in the afferent jejunum. A similar pattern of abnormality of bile salt conjugation occurred. In the blind loop the ratio of free to conjugated bile salts was grossly abnormal; this disturbance was somewhat less marked in the efferent jejunum and considerably less in the intraluminal contents of the afferent jejunum. An irregularly distributed lesion, consisting of swelling and vacuolation of microvilli and intracellular organelles, was demonstrated in the small-intestinal epithelium of blind-loop animals. Impaired absorption of monosaccharides is a further consequence of bacterial contamination of the upper gut. It is suggested that this defect is caused by the presence of high levels of deconjugated bile salts produced by an abnormal anaerobic bacterial flora in the small intestine.
Activation of Human Brown Adipose Tissue by a β3-Adrenergic Receptor Agonist
Authors: Aaron M. Cypess, Lauren S. Weiner, Carla Roberts-Toler, Elisa Franquet Elía, Skyler H. Kessler, Peter A. Kahn, Jeffrey English, Kelly Chatman, Sunia A. Trauger, Alessandro Doria, Gerald M. Kolodny
Journal: Cell Metabolism (2015)
Oral bile acids reduce bacterial overgrowth, bacterial translocation, and endotoxemia in cirrhotic rats
Authors: Vicente Lorenzo-Zúñiga, Ramón Bartolí, Ramón Planas, Alan F. Hofmann, Belén Viñado, Lee R. Hagey, José M. Hernández, Josep Mañé, Marco A. Alvarez, Vicente Ausina, Miquel Angel Gassull
Journal: Hepatology (2003)

Experiments were performed to test whether conjugated bile acid administration would decrease bacterial overgrowth, bacterial translocation, and endotoxemia in ascitic cirrhotic rats. Cholylsarcosine, a deconjugation–dehydroxylation resistant and cholylglycine, a deconjugation–dehydroxylation susceptible bile acid were used. Rats with CCl 4 –induced cirrhosis and ascites were fed cholylsarcosine, cholylglycine (both at 70 mg/kg/d), or placebo for 2 weeks. Healthy rats, as controls, were treated similarly. In cirrhotic rats receiving placebo, bile secretion from an acute biliary fistula was lower than in healthy rats (27.2 ± 6.5 vs. 53.0 ± 3.1 μL/kg/min; mean ± SE, P &lt; .05). The administration of conjugated bile acids to cirrhotic rats normalized bile secretion (cholylsarcosine, 51.8 ± 6.29; cholylglycine, 52.72 ± 8.9 μL/kg/min). Total ileal bacterial content was 6–fold higher in ascitic cirrhotic rats than in healthy rats. Conjugated bile acid administration reduced bacterial content to normal levels. Bacterial translocation was less in cirrhotic animals receiving conjugated bile acids (cholylsarcosine, 33%; cholylglycine, 26%) than in animals receiving placebo (66%). Endotoxemia was decreased in cirrhotic rats by conjugated bile acid feeding (cholylsarcosine, 0.098 ± 0.002; cholylglycine 0.101 ± 0.007 EU/mL) compared with placebo (0.282 ± 0.124, P &lt; .001). Survival was greater in animals receiving conjugated bile acids (cholylsarcosine, 10/15; cholylglycine, 11/15; placebo, 5/15). In conclusion, the administration of conjugated bile acids to ascitic cirrhotic rats increased bile acid secretion, eliminated intestinal bacterial overgrowth, decreased bacterial translocation, decreased endotoxemia, and increased survival. Oral conjugated bile acids may be useful in preventing bacterial translocation, endotoxemia, and spontaneous bacterial perotonitis in cirrhotic patients.
Fluorouracil versus combination of irinotecan plus cisplatin versus S-1 in metastatic gastric cancer: a randomised phase 3 study
Authors: Narikazu Boku, Seiichiro Yamamoto, Haruhiko Fukuda, Kuniaki Shirao, Toshihiko Doi, Akira Sawaki, Wasaburo Koizumi, Hiroshi Saito, Kensei Yamaguchi, Hiroya Takiuchi, Junichiro Nasu, Atsushi Ohtsu
Journal: The Lancet Oncology (2009)
CFC transition: the Emperor's new clothes. Each class of drug deserves a delivery system that meets its own requirements
Authors: M. L EVERARD
Journal: Thorax (2000)

It is likely that two related but very different events during this coming year will form milestones in the history of aerosol therapy. One is likely to represent a genuine advance, ushering a new era in which aerosol delivery systems will be used to deliver potent systemically acting drugs via the lungs. The other will be the culmination of an enormously expensive exercise aimed at perpetuating inappropriate technology.

It seems probable that, during the later part of 2000, the FDA will grant a licence to deliver insulin as an aerosol. The most exciting aspect of this is that, for the first time in half a century, an aerosol delivery system has been developed specifically to fulfil a specific task.1 The biggest market in North America for inhaled insulin is likely to be in the treatment of type II diabetes and, although the potential for significant adverse events related to swings in blood sugar is probably less than in those with traditional insulin dependent diabetes, it is still necessary to deliver the insulin in reproducible quantities to the lungs. If successful, this product is likely to be the first of a new generation of products designed to deliver systemically acting drugs via the respiratory tract. This concept is not new; early pioneers working with jet nebulisers in the 1930s and pressurised metered dose inhalers (pMDIs) in the 1950s considered delivering insulin as an aerosol but soon abandoned the idea because they realised that delivery of drug to the lung was so unpredictable that it was not possible to utilise aerosolised insulin safely with those devices.

In contrast, this year is also likely to see the widespread introduction of chlorofluorocarbon (CFC) free pMDIs delivering inhaled steroids.2 This “seamless” transition in which hydrofluorocarbon (HFC) replacement devices have been detuned to perform …
Sensitization of lymphocytes against pooled allogeneic cells. I. Generation of cytotoxicity against autologous human lymphoblastoid cell lines.
Authors: J M Zarling, F H Bach
Journal: The Journal of Experimental Medicine (1978)

Lymphocytes sensitized in vitro to a pool of X-irradiated allogeneic normal lymphocytes from 20 individuals develop cytotoxic activity for autologous human lymphoblastoid cells (LCL). Whereas pool sensitized T lymphocytes lyse autologous LCL cells, they fail to lyse autologous B-enriched or T-enriched normal target cells nor autologous phytohemagglutinin (PHA) blasts. In contrast to pool sensitization, stimulation with normal cells of single allogeneic individuals rarely led to development of cytotoxicity against autologous LCL cells. We conclude that human Epstein-Barr virus transformed LCL cells express target antigens cross-reactive with allogeneic target antigens expressed on normal cells and that sensitization with a pool of allogeneic cells is an effective means of generating effector cells directed against autologous abnormal cells.
Regulation of B-cell proliferative responses to lipopolysaccharide by a subclass of thymus T cells.
Authors: M A Norcross, R T Smith
Journal: The Journal of Experimental Medicine (1977)

When thymus cells which are unresponsive to LPS are combined with numbers of peripheral lymphoid cells giving minimal responses to LPS, synergistic incorporation of [3H]thymidine occurs. Synergy requires that both components proliferate, but most of the augmented response is the result of peripheral cell proliferation. The thymus cell is a T cell of variable density, low in thy-1.2 antigen, not concanavalin A responsive, present in the major thymus subpopulation, and may be from lipopolysaccharide (LPS)-unresponsive strains. The peripheral cell is sensitive to anti-IgG or IgM plus complement (C'), resistant to anti-Thy-1.2 and C', exhibits adherence properties of B lymphocytes, and must be from LPS-responsive strains. Synergistic responses depend on critical thymus/peripheral cell ratios, inhibition occurring at high peripheral cell numbers. The data provide evidence that B-cell proliferative responses to LPS may be regulated by a subclass of thymus T cells.
Does it all ADA up? Adalimumab for ulcerative colitis
Authors: S. Travis
Journal: Gut (2011)

The results of the randomised controlled trial of adalimumab (ADA) for inducing remission in outpatients with moderate to severely active ulcerative colitis (UC) are published in this issue of Gut ( see page 780 ).1 On the face of it, the response appears modest: at week 8, 18.5% of those induced with ADA160/80, then 40 mg every other week entered remission, compared with 9.2% (p=0.031) in the placebo group and just 10.0% in the ADA80/40 group (p=0.833 vs placebo). The results will inevitably be compared with those of infliximab (IFX),2 for which the pooled 8 week remission rates were 38.8% of those randomised to 5 mg/kg in ACT 1 and 14.9% on placebo (p<0.001), but caveats are necessary.

As with any clinical trial in UC, the first thing is to check the activity index, inclusion criteria, definitions of response, remission and statistical approach. The ADA study can only reasonably be compared with the induction phase of ACT 1, because it recruited patients with active disease refractory to (or intolerant of) steroids and immunomodulators. However, the two trials turn out to be more comparable than most. Both used the Mayo Clinic activity index,3 the same definition of remission (Mayo Clinic score ≤2, with no subscore >1) and response (decrease in Mayo score and 30% of starting value, with a 1 point decrease or rectal bleeding subscore ≤1). Both had similar patient numbers (130/group in ADA, 121 in ACT 1), mean Mayo score on trial entry (8.8±1.61 for ADA vs 8.7±1.56 placebo and 8.5±1.7 vs 8.4±1.8 in ACT 1), age (median 36.5 years (range 18–75) for ADA, mean 42.4±14.3 years for ACT 1), disease duration (6.1 years ADA, 5.9 years ACT 1) …
The promise of translational and personalised approaches for paediatric obstructive sleep apnoea: an ‘Omics’ perspective
Authors: Hui-Leng Tan, Leila Kheirandish-Gozal, David Gozal
Journal: Thorax (2014)

Obstructive sleep apnoea (OSA) can result in significant morbidities including the cardiovascular, metabolic and neurocognitive systems. These effects are purportedly mediated via activation of inflammatory cascades and the induction of oxidative stress, ultimately resulting in cellular injury and dysfunction. While great advances have been made in sleep medicine research in the past decades, there are still wide gaps in our knowledge concerning the exact underlying pathophysiological mechanisms of OSA and consequences. Without resolving these issues, the reasons why patients with a similar severity of OSA can have markedly different clinical presentation and end-organ morbidity, that is, phenotype, will continue to remain elusive. This review aims to highlight the recent exciting discoveries in genotype-phenotype interactions, epigenetics, genomics and proteomics related to OSA. Just as PCR revolutionised the field of genetics, the potential power of 'Omics' promises to transform the field of sleep medicine, and provide critical insights into the downstream pathological cascades inherent to OSA, thereby enabling personalised diagnosis and management for this highly prevalent sleep disorder.
Recent developments and current status of gene therapy using viral vectors in the United Kingdom: Table 1
Authors: Kate Relph, Kevin Harrington, Hardev Pandha
Journal: BMJ (2004)

Viral vectors remain the vehicles of choice for gene transfer in clinical trials of gene therapy in the United Kingdom and worldwide. In the United Kingdom alone, 88 clinical trials are registered with the Gene Therapy Advisory Committee (GTAC, www.advisorybodies.doh.gov.uk/genetics/gtac).

Although notable successes have been achieved in some inherited diseases, viral vectors have not been without their problems. We review the adverse events encountered to date and describe lessons that can be learnt from them to improve vector biology and pharmacology in order to make gene therapy with viral vectors a viable treatment for the future.

We searched Medline and Google, using the terms “gene therapy” and “viral vectors.” We also studied the websites www.wiley.co.uk/genmed/clinical and www.advisorybodies.doh.gov.uk/genetics/gtac for information on ongoing trials using viral vectors in the United Kingdom.

In April 2002 the BBC online news service in the United Kingdom carried an emotive headline: “Bubble boy saved by gene therapy.”1 The 18 month old infant featured had a rare immune disorder, X linked severe combined immunodeficiency (X-SCID), caused by a defective gene on the X chromosome. This gene encodes the common γC chain, an essential component of five cytokine receptors, all of which are necessary for the development of T cells and natural killer cells. Without the γC chain, mature T cells and natural killer cells are completely absent, whereas B cells are usually present in normal or increased numbers. X-SCID is fatal during the first year of life because of severe recurrent infections. As a result, much of the child's short life is spent in a sterile plastic bubble, a barrier to potentially life threatening infectious organisms. A collaboration of scientists from London, Paris, and Milan used a retroviral vector to introduce a functional copy of the defective gene into bone marrow stem cells taken from …
Human health effects and Pfiesteria exposure: a synthesis of available clinical data.
Authors: J G Morris
Journal: Environmental Health Perspectives (2001)

An association between human illness and exposure to Pfiesteria was first observed among laboratory personnel working with the microorganism. In 1997, in the setting of Pfiesteria activity on the Pocomoke River in Maryland, difficulties with learning and memory were epidemiologically associated with high-level exposure to waterways in which the organism was known to be present. In the Maryland studies, neurocognitive function of affected persons returned to within normal ranges within a period of 3-6 months. Persons with the most severe neurocognitive deficits were significantly more likely to have skin lesions characterized on biopsy by evidence of a toxic/allergic inflammatory reaction. Acute high-level exposures to waterways where Pfiesteria has been identified have been linked with eye and respiratory irritation, headache, and gastrointestinal complaints. Recent data, collected using molecular techniques, suggest that the organism is present in multiple locations in the Chesapeake Bay environment; available data are insufficient to comment on the possible cumulative health impact of chronic low-level environmental exposure to Pfiesteria.
Bilateral Massive Adrenal Hemorrhage: Early Recognition and Treatment
Authors: R H Rao, A H Vagnucci, J A Amico
Journal: Annals of Internal Medicine (1989)

Purpose: To develop a clinical perspective on bilateral massive adrenal hemorrhage and an algorithm for its diagnosis and treatment. Data Identification: Case reports were identified through a computer search using MEDLINE (1976 to 1987), and from bibliographies in review articles (up to 1978). Study Selection: Twelve reports published since 1978 were found. Data Extraction: Data from 20 recently reported cases and 5 cases from personal records were compared with data from 142 previously reported, autopsy-proven cases summarized in a 1978 review article. Results of Data Analysis: Thromboembolic disease, coagulopathy, and the postoperative state were the three major risk factors. Except for abdominal pain and remittent fever, clinical features were not helpful in diagnosis. A fall in hemoglobin, and progressive biochemical hypoadrenalism were important clues. Diagnosis was confirmed by computed tomography and an absent cortisol response to intravenous corticotropin. Long-term follow-up showed complete atrophy and functional failure of the adrenal gland. Conclusions: Death from bilateral massive adrenal hemorrhage can be prevented by pre-emptive steroid therapy in high-risk patients who have certain clinical and laboratory features.
Estrogen plus Progestin and Colorectal Cancer in Postmenopausal Women
Authors: Rowan T. Chlebowski, Jean Wactawski-Wende, Cheryl Ritenbaugh, F. Allan Hubbell, Joao Ascensao, Rebecca J. Rodabough, Carol A. Rosenberg, Victoria M. Taylor, Randall Harris, Chu Chen, Lucile L. Adams-Campbell, Emily White
Journal: New England Journal of Medicine (2004)

Although the Women's Health Initiative (WHI) trial of estrogen plus progestin in postmenopausal women identified more overall health risks than benefits among women in the hormone group, the use of estrogen plus progestin was associated with a significant decrease in the risk of colorectal cancer. We analyzed features of the colorectal cancers that developed and their relation to the characteristics of the participants.