tbuckley/cabot-search huggingface dataset:
NHS 10 years away from harnessing the benefits of genome medicine
Authors: A. O'Dowd
Journal: BMJ (2009)

<b>Background</b>: The WIND classification groups mechanically ventilated (MV) patients into ‘short’, ‘difficult’, ‘prolonged’ and ‘no weaning’, stratifying distinct short-term outcomes in mostly medical populations. <b>Aims</b>: 1) To describe weaning group distribution, 2) To evaluate if ‘short wean’ patients can be divided into groups with distinct characteristics and outcomes, 3) To study 1-year outcomes related to weaning groups, in a mixed, mainly surgical ICU population. <b>Method</b>: Retrospective study in a tertiary centre including all MV patients from April 11 2018, for 1 year onwards. A refined WIND classification was used, dividing ‘short wean’ patients into patients MV≤24h versus MV&amp;gt;24. <b>Results</b>: Of 1801 MV patients, 65% were categorized as ‘short MV≤24h’, 13% ‘short MV&amp;gt;24h’, 8% ‘difficult’, 6% ‘prolonged’ and 8% ‘no weaning’ group. ‘Short MV≤24h’ patients were significant older, more frequently male, had lower disease severity and different admission categories compared to ‘short MV&amp;gt;24h’. Weaning duration and success rate, ICU and hospital length of stay and mortality worsened increasingly from ‘short MV≤24h’ to ‘prolonged’ weaning patients. 1-year mortality also increased from ‘short MV≤24h’ (9%), to ‘short MV&amp;gt;24h’ (27%), ‘difficult’ (39%) and ‘prolonged’ weaning (49%). In adjusted analyses, weaning groups were also independently associated with 1-year mortality. <b>Conclusions</b>: The high proportion of ‘short wean’ patients in this mainly surgical ICU population could be divided into 2 groups with distinct characteristics. This refined WIND classification allowed to enhance prognostication, also beyond hospitalization, highlighting the need to further optimize the weaning process.
STUDIES ON SUSCEPTIBILITY TO INFECTION FOLLOWING IONIZING RADIATION
Authors: Carolyn W. Hammond, David Ruml, Dorothy B. Cooper, C. Phillip Miller
Journal: The Journal of Experimental Medicine (1955)

Pseudomonas aeruginosa introduced directly into the stomach established itself more regularly in the intestinal tract of irradiated mice than of unirradiated mice. The irradiated mice had been exposed to 550 r total body x-irradiation 5 days before inoculation. This difference between irradiated and unirradiated mice could not be explained by differences in pH of gastric or duodenal contents, propulsive motility of the intestinal tract, or the ability of the intestinal contents to support growth of Pseudomonas in vitro.
Activated and resting regulatory T cell exhaustion concurs with high levels of interleukin-22 expression in systemic sclerosis lesions
Authors: Alexis Mathian, Christophe Parizot, Karim Dorgham, Salim Trad, Laurent Arnaud, Martin Larsen, Makoto Miyara, Miguel Hié, Jean-Charles Piette, Camille Frances, Hans Yssel, Zahir Amoura, Guy Gorochov
Journal: Annals of the Rheumatic Diseases (2012)

Transforming growth factor-β is considered to play a key role in the process of fibrosis in systemic sclerosis (SSc) and in the development of regulatory T cells (Treg) and pro-inflammatory Th17 T cells producing interleukin 17 (IL-17) and IL-22. The authors therefore postulated that SSc could be characterised by a marked Treg/Th17 imbalance. Previous works did not distinguish between the different subsets of Treg and the non-regulatory FoxP3(+) cells leading to inconsistent results.Combined phenotypic and functional analysis of Th17 cells and FoxP3(+)CD4 T cells, discriminating activated Tregs and resting Tregs from non-regulatory FoxP3(+) T cells, in blood and skin of SSc patients.In early disease stages, there is a decreased proportion of activated Tregs. A concomitant resting Treg deficit becomes more apparent with disease progression. Active and diffuse forms of the disease are characterised by a relatively higher proportion of all FoxP3(+) subsets, including non-regulatory T cells. No peripheral or local IL-17 amplification was observed. However, the authors found significantly increased IL-22 transcription levels in SSc lesional skin, as compared with healthy skin. Cytofluorometry confirmed the existence in SSc patients and controls of a distinct subset of T cells producing IL-22 in the absence of IL-17.SSc pathogenesis does not appear to be linked to IL-17-, but rather to IL-22-producing cells with skin-homing potential and a concomitant quantitative Treg defect. Active and diffuse forms of the disease are associated with a FoxP3 signature. Altogether, our data depict a status of regulatory/pro-inflammatory T cell imbalance in SSc.
Are Gender Differences Important for the Clinical Effects of Antidepressants?
Authors: Malene Grubbe Hildebrandt, Ewout Willem Steyerberg, Kurt Bjerregaard Stage, Jan Passchier, Per Kragh-Soerensen
Journal: American Journal of Psychiatry (2003)

Gender differences in antidepressant treatment response, side effects, dropout rates, and plasma concentrations were examined in patients with major and predominantly melancholic depression.The study included a subgroup of 292 inpatients (96 men, 196 women) from three Danish double-blind, randomized, controlled trials. All patients completed a 5-week treatment period and fulfilled the DSM-III or DSM-III-R criteria for major depression. Clomipramine (150 mg/day) was the reference treatment, and comparable treatments were citalopram (40 mg/day), paroxetine (30 mg/day), and moclobemide (400 mg/day). Assessments were performed by using the 17-item Hamilton Depression Rating Scale and the Udvalg for Kliniske Undersøgelser Side Effect Rating Scale. In a subgroup of 110 patients, weekly measurements of clomipramine plasma concentrations were obtained. Nonparametric statistical tests and multiple linear and logistic regression models were used for statistical evaluations.Both genders had similar remission rates (Hamilton depression scale score <8) when treated with clomipramine and had significantly higher remission rates with clomipramine than with the comparable treatments. The plasma concentrations of clomipramine were significantly higher for female than for male patients. No gender differences were found in posttreatment Hamilton depression scale scores, nor did the therapeutic effects of treatment depend on gender. Rates of dropout and side effects were similar for men and women. No relationship between plasma concentrations, gender, and therapeutic outcome was found.In a group of patients with major and predominantly melancholic depression, differentiation according to gender was not important in treatment with common antidepressants. Women appeared to have higher plasma concentrations of tricyclic antidepressants than men. The consequences of this difference for clinical effects are unclear. Gender-specific recommendations for dosing of tricyclic antidepressants may be considered.
Congestive Heart Failure: Fifty Years of Progress
Authors: E. Braunwald, M. R. Bristow
Journal: Circulation (2000)

Volume 1 of Circulation provides an excellent snapshot of the understanding of the mechanisms and treatment of heart failure a half century ago. During that era, circulatory pathophysiology was at the center of investigative attention. For example, Tinsley Harrison and his group divided heart failure into “primary disorders of filling and primary disorders of emptying,”1 a forerunner of our current terms diastolic and systolic heart failure. The great Swedish clinical physiologist Gustav Nylin used 32P-labeled red blood cells for measuring cardiac output and cardiothoracic blood volume by the indicator-dilution method in normal subjects and in patients with heart failure.2 Andre Cournand’s group defined the pathophysiology of heart failure secondary to cor pulmonale, distinguished it from left ventricular failure, and compared the acute hemodynamic effects of digoxin in these 2 conditions.3 In a seminal paper, Raab and Lepeschkin extracted sympathin from the heart and established norepinephrine as the cardiac adrenergic neurotransmitter.4 In one of the earliest efforts to manage patients with chronic congestive heart failure on an outpatient basis, Vander Veer and colleagues demonstrated the effectiveness and tolerability of an oral form of the widely used parenteral diuretic mercuhydrin.5 

In the 1950s, the role of hypertrophy in the heart’s adaptation to hemodynamic overload was examined. After Laplace’s law was applied to the heart and permitted the calculation of wall stress in the human heart,6 it became clear that myocardial hypertrophy prevents excessive elevation of wall stress consequent to hemodynamic overload.7 8 In the 1960s, there was a lively debate about the mechanism of heart failure secondary to pressure overload. The question was framed as follows: “Does failure of the ventricle as a pump occur in the presence of (an) inadequate contractile mass while the contractile function of each unit (of myocardium) is normal …
Malignant B-Lymphoid Cells with Bone Lesions Express Receptor Activator of Nuclear Factor-κB Ligand and Vascular Endothelial Growth Factor to Enhance Osteoclastogenesis
Authors: Hironobu Shibata, Masahiro Abe, Kenji Hiura, Javier Wilde, Keiji Moriyama, Toshiaki Sano, Ken-ichi Kitazoe, Toshihiro Hashimoto, Shuji Ozaki, Shingo Wakatsuki, Shinsuke Kido, Daisuke Inoue, Toshio Matsumoto
Journal: Clinical Cancer Research (2005)

Receptor activator of nuclear factor-kappaB ligand (RANKL) is a key mediator of osteoclastogenesis. Because certain types of tumor cells aberrantly express RANKL, and because bone destruction also develops in B-cell lymphomas of bone origin, we investigated RANKL expression and the mechanisms of osteoclastogenesis in B-lymphoid neoplasms.Immunohistochemistry of bone specimens resected from patients with primary B-cell lymphoma of bone with bone destruction revealed that lymphoma cells express RANKL as well as vascular endothelial cell growth factor (VEGF). The tumor cells isolated from the bone specimens enhanced osteoclastogenesis in vitro. In contrast, B-cell lymphoma infiltrating to the bone marrow without bone destruction did not express RANKL. Both RANKL and VEGF were expressed by a portion of B-lymphoid cell lines, including Daudi and IM-9. These RANKL-expressing tumor cells enhanced osteoclastogenesis from RAW264.7 cells and human monocyte-derived preosteoclasts in the absence of stromal cells/osteoblasts in a RANKL-dependent manner. Furthermore, conditioned media from Daudi cells enhanced transmigration of preosteoclasts that was inhibited by anti-VEGF antibody, suggesting that tumor cell-derived VEGF mediates recruitment of osteoclast precursors. Moreover, cocultures of B-lymphoid cell lines with osteoclasts enhanced the growth of B-lymphoid cells.Some malignant B cells aberrantly express functional RANKL as well as VEGF to enhance osteoclastogenesis. The coexpression of RANKL and VEGF may also contribute to the close cellular interactions with osteoclastic cells, thereby forming a vicious cycle between osteoclastic bone destruction and tumor expansion in bone.
Noninvasive Bioluminescence Imaging of Normal and Spontaneously Transformed Prostate Tissue in Mice
Authors: Scott K. Lyons, Ed Lim, Anne O. Clermont, Joan Dusich, Lingyun Zhu, Kenneth D. Campbell, Richard J. Coffee, David S. Grass, John Hunter, Tony Purchio, Darlene Jenkins
Journal: Cancer Research (2006)

Abstract Several transgenic mouse models of prostate cancer have been developed recently that are able to recapitulate many key biological features of the human condition. It would, therefore, be desirable to employ these models to test the efficacy of new therapeutics before clinical trial; however, the variable onset and nonvisible nature of prostate tumor development limit their use for such applications. We now report the generation of a transgenic reporter mouse that should obviate these limitations by enabling noninvasive in vivo bioluminescence imaging of normal and spontaneously transformed prostate tissue in the mouse. We used an 11-kb fragment of the human prostate-specific antigen (PSA) promoter to achieve specific and robust expression of firefly luciferase in the prostate glands of transgenic mice. Ex vivo bioluminescence imaging and in situ hybridization analysis confirmed that luciferase expression was restricted to the epithelium in all four lobes of the prostate. We also show that PSA-Luc mice exhibit decreased but readily detectable levels of in vivo bioluminescence over extended time periods following androgen ablation. These results suggest that this reporter should enable in vivo imaging of both androgen-dependent and androgen-independent prostate tumor models. As proof-of-principle, we show that we could noninvasively image SV40 T antigen–induced prostate tumorigenesis in mice with PSA-Luc. Furthermore, we show that our noninvasive imaging strategy can be successfully used to image tumor response to androgen ablation in transgenic mice and, as a result, that we can rapidly identify individual animals capable of sustaining tumor growth in the absence of androgen. (Cancer Res 2006; 66(9): 4701-7)
Developmental timing of CCM2 loss influences cerebral cavernous malformations in mice
Authors: Gwénola Boulday, Noemi Rudini, Luigi Maddaluno, Anne Blécon, Minh Arnould, Alain Gaudric, Françoise Chapon, Ralf H. Adams, Elisabetta Dejana, Elisabeth Tournier-Lasserve
Journal: The Journal of Experimental Medicine (2011)

Cerebral cavernous malformations (CCM) are vascular malformations of the central nervous system (CNS) that lead to cerebral hemorrhages. Familial CCM occurs as an autosomal dominant condition caused by loss-of-function mutations in one of the three CCM genes. Constitutive or tissue-specific ablation of any of the Ccm genes in mice previously established the crucial role of Ccm gene expression in endothelial cells for proper angiogenesis. However, embryonic lethality precluded the development of relevant CCM mouse models. Here, we show that endothelial-specific Ccm2 deletion at postnatal day 1 (P1) in mice results in vascular lesions mimicking human CCM lesions. Consistent with CCM1/3 involvement in the same human disease, deletion of Ccm1/3 at P1 in mice results in similar CCM lesions. The lesions are located in the cerebellum and the retina, two organs undergoing intense postnatal angiogenesis. Despite a pan-endothelial Ccm2 deletion, CCM lesions are restricted to the venous bed. Notably, the consequences of Ccm2 loss depend on the developmental timing of Ccm2 ablation. This work provides a highly penetrant and relevant CCM mouse model.
Time to diagnosis and time to therapy in patients with malignant pleural mesothelioma (MPM) compared to patients with lung cancer in Denmark 2007 to 2011. A quality assurance analysis
Authors: Niels-Chr. G. Hansen, Christian B. Laursen, Karen Ege Olsen, Peter Licht
Journal: European Respiratory Journal (2012)

In Denmark patients with pleural diseases are usually first seen by departments taking care of patients with suspected lung cancer. When diagnostic packages was published in 2008 by the National Board of Health a 28 days maximal time to diagnosis and a 42 days maximal time to treatment were stated for lung cancer as well as for MPM. We wanted to study how well these time frames are fulfilled for MPM. For the 5-year period 2007 to 2011, we have found 146 MPM patients in the pathology registry of Odense University Hospital. This is about 30% of all incident cases in Denmark in the period. MPM was confirmed by histology in 92% of the cases. Five patients died before the final diagnosis was known. Forty-two (30%) of 141 patients were treated by best supportive care. Two patients were lost for follow-up. In three patients therapy was initiated at progression, but in 94 patients therapy began as soon as possible after the diagnosis. Eighty-three had chemotherapy, 10 had radiotherapy, and one had resection as the first step of the treatment. For the 141 patients the median time to diagnosis was 38 days (range: 6-127 days). Only 30% of the patients were diagnosed within 28 days. The median time to therapy for the 94 patients was 58 days (range: 19 - 142 days) - 21% were treated within 42 days. Among the 77 MPM patients from our primary uptake area 42% were diagnosed within 28 days and 17 out of 54 (32%) were treated within 42 days. In the same period, 84% of patients with lung cancer from our primary uptake area were diagnosed within 28 days and 74% had started treatment within 42 days.
Modeling the Pharmacodynamics of Highly Schedule-Dependent Agents: Exemplified by Cytarabine-Based Regimens in Acute Myeloid Leukemia
Authors: Jan Braess, Michael Fiegl, Isolde Lorenz, Karin Waxenberger, Wolfgang Hiddemann
Journal: Clinical Cancer Research (2005)

Abstract Background: Many agents in antineoplastic chemotherapy are highly schedule dependent. Therefore, variables such as total dose and also the area under the curve (AUC) that are schedule insensitive are generally insufficient to adequately represent treatment strength. Purpose: To establish a descriptor of treatment strength that takes into account the differential contribution of plasma concentrations (C) and exposure times (T) towards the cytotoxic effect and to investigate whether such a pharmacodynamically weighed descriptor is better correlated to the clinical effect than conventional variables. Patients and Methods: The paradigm “CN × T = constant” (for an isoeffect) incorporates a weighing factor N (concentration coefficient) into the conventional description of the AUC that quantitates the differential contribution of C and T towards the cytotoxic effect. N was to be numerically derived from a multitude of in vitro isoeffect analyses of the major agents in acute myeloid leukemia (AML) therapy from patient samples (n = 57). Results: For cytarabine, N was 0.45, numerically expressing the substantially higher relevance of T versus C for its cytotoxic effect. In a meta-analysis of 49 study arms involving &amp;gt;10,000 patients, neither total dose, dose intensity, nor AUC was correlated to the clinical effect. However, when AUC was pharmacodynamically weighed (N-weighed AUC, N-AUC = C0.45 × T), this new descriptor was highly significantly correlated to the clinical effect (P &amp;lt; 0.001). Conclusion: The N-AUC concept is able to characterize schedule-dependent agents and is the only descriptor of cytarabine treatment strength actually correlated to the clinical effect in AML.
Blood pressure variability and outcome after acute intracerebral haemorrhage: a post-hoc analysis of INTERACT2, a randomised controlled trial
Authors: Lisa Manning, Yoichiro Hirakawa, Hisatomi Arima, Xia Wang, John Chalmers, Jiguang Wang, Richard Lindley, Emma Heeley, Candice Delcourt, Bruce Neal, Pablo Lavados, Stephen M Davis, Christophe Tzourio, Yining Huang, Christian Stapf, Mark Woodward, Peter M Rothwell, Thompson G Robinson, Craig S Anderson
Journal: The Lancet Neurology (2014)
Associations and Interactions between Ets-1 and Ets-2 and Coregulatory Proteins, SRC-1, AIB1, and NCoR in Breast Cancer
Authors: Eddie Myers, Arnold D.K. Hill, Gabrielle Kelly, Enda W. McDermott, Niall J. O'Higgins, Yvonne Buggy, Leonie S. Young
Journal: Clinical Cancer Research (2005)

Associations between p160 coactivator proteins and the development of resistance to endocrine treatment have been described. We hypothesized that nuclear receptor coregulatory proteins may interact with nonsteroid receptors. We investigated the mitogen-activated protein kinase-activated transcription factors, Ets, as possible interaction proteins for the coactivators SRC-1 and AIB1 and the corepressor NCoR in human breast cancer.Expression and coexpression of Ets and the coregulatory proteins was investigated using immunohistochemistry and immunofluorescence in a cohort of breast tumor patients (N = 134). Protein expression, protein-DNA interactions and protein-protein interactions were assessed using Western blot, electromobility shift, and coimmunoprecipitation analysis, respectively.Ets-1 and Ets-2 associated with reduced disease-free survival (P < 0.0292, P < 0.0001, respectively), whereas NCoR was a positive prognostic indicator (P < 0.0297). Up-regulation of Ets-1 protein expression in cell cultures derived from patient tumors in the presence of growth factors associated with tumor grade (P < 0.0013; n = 28). In primary breast tumor cell cultures and in the SKBR3 breast cell line, growth factors induced interaction between Ets and their DNA response element, induced recruitment of coactivators to the transcription factor-DNA complex, and up-regulated protein expression of HER2. Ets-1 and Ets-2 interacted with the coregulators under basal conditions, and growth factors up-regulated Ets-2 interaction with SRC-1 and AIB1. Coexpression of Ets-2 and SRC-1 significantly associated with the rate of recurrence and HER expression, compared with patients who expressed Ets-2 but not SRC-1 (P < 0.0001 and P < 0.0001, respectively).These data describe associations and interactions between nonsteroid transcription factors and coregulatory proteins in human breast cancer.
Impact of Age on Outcomes After Initial Therapy With Chemotherapy and Different Chemoimmunotherapy Regimens in Patients With Chronic Lymphocytic Leukemia: Results of Sequential Cancer and Leukemia Group B Studies
Authors: Jennifer A. Woyach, Amy S. Ruppert, Kanti Rai, Thomas S. Lin, Susan Geyer, Jonathan Kolitz, Frederick R. Appelbaum, Martin S. Tallman, Andrew R. Belch, Vicki A. Morrison, Richard A. Larson, John C. Byrd
Journal: Journal of Clinical Oncology (2012)

Purpose Chronic lymphocytic leukemia (CLL) is a disease of the elderly, yet few clinical trials include a significant number of older patients, and outcomes after specific therapies can be different depending on age. Patients and Methods We examined patients enrolled onto successive first-line CALGB CLL trials to determine whether efficacy of regimens varied by age, focusing on ideal chemotherapy choice and benefit of immunotherapy addition to chemotherapy in older patients. Regimens included chlorambucil, fludarabine, fludarabine plus rituximab (FR), fludarabine with consolidation alemtuzumab, and FR with consolidation alemtuzumab. Results A total of 663 patients were evaluated for response, progression-free survival (PFS), and overall survival (OS) by age group. Interaction effects of fludarabine versus chlorambucil by age group (PFS, P = .046; OS, P = .006) showed that among patients younger than 70 years, PFS and OS was improved with fludarabine over chlorambucil (PFS: hazard ratio [HR] = 0.6, 95% CI, 0.5 to 0.8; OS: HR = 0.7, 95% CI, 0.5 to 0.9), but not in older adults (PFS, HR = 1.0, 95% CI, 0.6 to 1.7; OS: HR = 1.5, 95% CI, 0.9 to 2.3). In contrast, FR improved outcomes relative to fludarabine, irrespective of age (PFS: HR = 0.6, 95% CI, 0.4 to 0.7; OS: HR = 0.7, 95% CI, 0.5 to 0.9). Alemtuzumab consolidation did not provide benefit over similar regimens without alemtuzumab (P &gt; .20), irrespective of age. Conclusion These data support the use of chlorambucil as an acceptable treatment for many older patients with CLL and suggest rituximab is beneficial regardless of age. These findings bear relevance to both routine care of CLL patients 70 years and older and also future clinical trials in this population.