tbuckley/cabot-search huggingface dataset:
Suppression of haematopoiesis during therapy of chronic hepatitis C with different interferon mono and combination therapy regimens
Authors: M Schmid
Journal: Gut (2005)

Treatment of chronic hepatitis C with interferon (IFN)-alpha and ribavirin has haematotoxic effects. We evaluated the effects of four different IFN/IFN-ribavirin treatment regimens on haematopoiesis.Haematopoiesis was studied in 133 patients with chronic hepatitis C receiving IFN-alpha2b alone (group A) or in combination with ribavirin (group B), pegylated IFN-alpha2a (group C), or pegylated IFN-alpha2b (group D) in combination with ribavirin.At week 4, haemoglobin levels were diminished in all groups receiving combination therapy. In the monotherapy group, haemoglobin decreased slightly after eight weeks. In all groups, haemoglobin remained diminished throughout therapy. In all patients, leucocytes (while blood cells) decreased after four weeks and remained low during treatment. Platelets (peripheral platelet count (PPC)) were decreased in all groups after four weeks and remained below baseline levels during therapy in group A, C, and D whereas in group B PPC recovered early and reached baseline levels at week 16 of therapy. Concomitantly with the decreases in haemoglobin and PPC, erythropoietin increased in all groups receiving combination therapy and thrombopoietin in all groups. Patients treated with pegylated IFN-alpha2a and those who received pegylated IFN-alpha2b combination therapy differed only in leucopoiesis, whereas erythropoiesis and thrombopoiesis were comparable.IFN-alpha based therapies are associated with a decrease in all three haematopoietic lineages, irrespective of the type of therapy used. The stronger suppressive effect of pegylated IFN-alpha2a on leucopoiesis could be due to a dose effect. Overall, concentrations of endogenous haematopoietic growth factors are increased but can only partially alleviate haematotoxicity. Potential uses of exogenous haematopoietic growth factors and their impact on the virological response need to be explored.
Role of Bcl-xL in hepatocyte growth factor elicited epithelial protection in idiopathic lung fibrosis
Authors: Sylwia Skwarna, Ingrid Henneke, Werner Seeger, Andreas Guenther, Clemens Ruppert
Journal: European Respiratory Journal (2013)

Hepatocyte growth factor (HGF) is a cytokine with pleiotropic functions during wound healing and repair. Its anti-fibrotic effects were shown in animal models of lung fibrosis and linked to improved cellular survival and proliferation and reduced myofibroblast accumulation. HGF-elicited, pro-survival pathways have yet not been investigated in detail in lung epithelial cells. Based on literature, our study is focused on Bcl-xL, prosurvival protein involved in mitochondrial control of apoptosis.  Results: Western blot analysis of IPF lung homogenates revealed significantly increased expression of Bcl-xL when compared to donor lungs, and a similar observation was made in bleomycin versus saline treated murine lungs. In human IPF, much less in donor lungs, Bcl-xL protein is highly expressed in hyperplastic alveolar epithelial type II cells, basal cells, bronchial epithelial ciliated and non-ciliated cells. Furthermore, Bcl-xL expression co-localized with specific HGF receptor cMet. In vitro data shows decreased expression of Bcl-xL in murine epithelial MLE12/15 cells in response to oxidative stress-induced apoptosis. Under these conditions, HGF treatment resulted in increased survival of cells that correlated with increased Bcl-xL expression. The very same effect of HGF is seen after treatment of cells with the potent  ER-stress inducer thapsigargin.  We conclude that HGF has protective effect on epithelial cells under oxidative- and ER-stress conditions. We speculate that Bcl-xL protein may be the downstream target of HGF in prosurvival signaling pathway. Thus, it may play pivotal role in pathogenesis of IPF.
HEMODYNAMIC CHANGES DURING THIOPENTAL ANESTHESIA IN HUMANS: CARDIAC OUTPUT, STROKE VOLUME, TOTAL PERIPHERAL RESISTANCE, AND INTRATHORACIC BLOOD VOLUME 12
Authors: Benjamin Etsten, T. H. Li
Journal: Journal of Clinical Investigation (1955)

Thiopental, monosodium 5-ethyl-5-(1-methyl- butyl) -thiobarbiturate, is extensively used in clinical anesthesia either as a primary anesthetic agent for short surgical procedures or as a sup- plementary drug in conjunction with other anes- thetics.Fatalities have been attributed to its use (1, 2) and cardiac arrest has occurred following its administration to patients under spinal anes- thesia (3).Most of the information concerning the cardio- circulatory effects of thiopental has been derived from animal experimentation (4, 5).Although there have been numerous clinical reports de- scribing changes in blood pressure, pulse rate and respiration during its administration, quanti- tative investigations on the effect of this agent on the cardiocirculatory dynamics in man are meagre (6, 7).In view of its extensive use and the com- plications ascribed to its administration, a critical analysis of the hemodynamic changes which occur at various levels of thiopental narcosis in patients prior to surgery will form the basis of this com- munication. METHODCardiac output and related hemodynamic determina- tions were obtained on 14 patients prior to surgery.These subjects were in good physical condition and had no discernible cardiovascular or pulmonary disease (average age-41 years; range 14 to 60 years).The pre- anesthetic dosage of morphine and scopolamine varied according to the age, weight, and physical status.Ninety minutes after a subcutaneous administration of morphine (5.4 to 8.0 mgm.) and scopolamine (0.26 to 0.43 mgm.),
Functional dyspepsia, delayed gastric emptying, and impaired quality of life
Authors: N J Talley
Journal: Gut (2005)

It remains controversial as to whether delayed gastric emptying in functional dyspepsia is associated with a specific symptom pattern, and it is unknown if gastric emptying in functional dyspepsia is a driver of impaired health related quality of life (HRQOL). We aimed to evaluate the relationship between functional dyspepsia symptoms, gastric emptying, and HRQOL.US patients (n=864; mean age 44 years (range 18-82); 74% female) with functional dyspepsia, as defined by Rome II criteria, were enrolled into one of four clinical trials. All patients had a baseline scintigraphic assessment of gastric emptying of an egg substitute meal, and the trials were stratified on this assessment. Delayed gastric emptying was defined as having at least 6.3% residual volume at four hours. A total of 290 (34%) patients had delayed gastric emptying. HRQOL was assessed by the SF 36 and Nepean dyspepsia index (NDI).Postprandial fullness was independently associated with delayed gastric emptying but the association was weak (odds ratio (OR) 1.98 (95% confidence interval (CI) 1.02, 3.86); p=0.04). No independent association was seen with epigastric pain, early satiety, nausea, or bloating. Mean SF 36 physical composite score (PCS) was 42.3 (95% CI 41.6, 43.0) and the mean SF 36 mental composite score (MCS) was 46.8 (95% CI 46.0, 47.5); both mean scores were significantly lower than age and sex adjusted national norms of 50 (p<.0001). Female sex, increasing age, and higher symptom scores for fullness, epigastric pain, and nausea were each independently associated with decreased PCS scores (all p<0.05). Higher baseline nausea symptom score, lower gastric emptying rates at one hour, and lower body mass index were associated with decreased MCS (all p<0.05). Female sex, epigastric pain, and nausea, but not gastric emptying, were associated with an impaired score on the NDI. However, the magnitude of the significant associations were all small.In patients with functional dyspepsia selected for a clinical trial programme, gastric emptying did not usefully stratify them symptomatically. Quality of life of patients with functional dyspepsia enrolled in this clinical trial programme was significantly impaired but this was not explained by delayed gastric emptying.
T Cells Localize with Proliferating Smooth Muscle α-Actin<sup>+</sup> Cell Compartments in Asthma
Authors: David Ramos-Barbón, Rebeca Fraga-Iriso, Nadia S. Brienza, Carmen Montero-Martínez, Héctor Verea-Hernando, Ron Olivenstein, Catherine Lemiere, Pierre Ernst, Qutayba A. Hamid, James G. Martin
Journal: American Journal of Respiratory and Critical Care Medicine (2010)

Airway remodeling in asthma comprises increased airway smooth muscle (ASM), an alteration linked to airway hyperresponsiveness and disease severity. Experimental studies showed that T cells adhere to ASM through vascular cell adhesion molecule-1 (VCAM-1) and drive ASM growth through direct contact between the T cells and smooth muscle alpha-actin (alpha-SMA)(+) cells.To support the hypothesis of a T-cell/alpha-SMA(+) cell contact mechanism of ASM remodeling in asthma, using bronchial biopsies.We performed quantitative morphology on T cells, proliferating cell nuclear antigen (PCNA), alpha-SMA, and VCAM-1 on biopsies from subjects with moderate and severe asthma and healthy control subjects.We demonstrate ASM cell proliferation and infiltration by T cells in proportion to severity in the subjects with asthma. T cells localized with alpha-SMA(+)PCNA(+) cells, suggesting direct intercellular contact and a relationship with alpha-SMA(+) cell proliferation. Furthermore, the subjects with asthma developed a proliferating compartment of subepithelial alpha-SMA(+), nonorganized airway contractile elements (NOACE), suggesting a phenotype gradient from undifferentiated cells to smooth muscle-like cells. T-cell juxtaposition events were also observed in this compartment and correlated to its mass. The subjects with asthma showed VCAM-1 expression in postcapillary venules and clusters of VCAM-1 immunoreactivity in ASM and NOACE, consistent with a role of VCAM-1 in T-cell/alpha-SMA(+) cell interaction.T cells may induce alpha-SMA(+) cell proliferation through direct intercellular contact. NOACE may in part contribute to ASM growth through differentiation and translocation of alpha-SMA(+) cells. The findings support the role of the T cell in ASM remodeling in asthma.
Uremic pruritus treated with ultraviolet light
Authors: B. C. Schultz
Journal: JAMA (1980)

This study evaluated the treatment of uremic pruritus with ultraviolet B light in patients with chronic renal failure and severe pruritus not attributed to other skin or internal disease. Eight of ten patients responded with complete relief of itching. Photoinactivation of a yet unidentified substance could explain the success of this treatment.
Comparison of Mortality Between Private For-Profit and Private Not-For-Profit Hemodialysis Centers
Authors: P. J. Devereaux, Holger J. Schünemann, Nikila Ravindran, Mohit Bhandari, Amit X. Garg, Peter T.-L. Choi, Brydon J. B. Grant, Ted Haines, Christina Lacchetti, Bruce Weaver, John N. Lavis, Deborah J. Cook, David R. S. Haslam, Terrence Sullivan, Gordon H. Guyatt
Journal: JAMA (2002)

ContextPrivate for-profit and private not-for-profit dialysis facilities provide the majority of hemodialysis care in the United States. There has been extensive debate about whether the profit status of these facilities influences patient mortality.ObjectiveTo determine whether a difference in adjusted mortality rates exists between hemodialysis patients receiving care in private for-profit vs private not-for-profit dialysis centers.Data SourcesWe searched 11 bibliographic databases, reviewed our own files, and contacted experts in June 2001–January 2002. In June 2002, we also searched PubMed using the "related articles" feature, SciSearch, and the reference lists of all studies that fulfilled our eligibility criteria.Study SelectionWe included published and unpublished observational studies that directly compared the mortality rates of hemodialysis patients in private for-profit and private not-for-profit dialysis centers and provided adjusted mortality rates. We masked the study results prior to determining study eligibility, and teams of 2 reviewers independently evaluated the eligibility of all studies. Eight observational studies that included more than 500 000 patient-years of data fulfilled our eligibility criteria.Data ExtractionTeams of 2 reviewers independently abstracted data on study characteristics, sampling method, data sources, and factors controlled for in the analyses. Reviewers resolved disagreements by consensus.Data SynthesisThe studies reported data from January 1, 1973, through December 31, 1997, and included a median of 1342 facilities per study. Six of the 8 studies showed a statistically significant increase in adjusted mortality in for-profit facilities, 1 showed a nonsignificant trend toward increased mortality in for-profit facilities, and 1 showed a nonsignificant trend toward decreased mortality in for-profit facilities. The pooled estimate, using a random-effects model, demonstrated that private for-profit dialysis centers were associated with an increased risk of death (relative risk, 1.08; 95% confidence interval, 1.04-1.13; P<.001). This relative risk suggests that there are annually 2500 (with a plausible range of 1200-4000) excessive premature deaths in US for-profit dialysis centers.ConclusionsHemodialysis care in private not-for-profit centers is associated with a lower risk of mortality compared with care in private for-profit centers.
Diverse Gene Expression and DNA Methylation Profiles Correlate with Differential Adaptation of Breast Cancer Cells to the Antiestrogens Tamoxifen and Fulvestrant
Authors: Meiyun Fan, Pearlly S. Yan, Cori Hartman-Frey, Lei Chen, Henry Paik, Samuel L. Oyer, Jonathan D. Salisbury, Alfred S.L. Cheng, Lang Li, Phillip H. Abbosh, Tim H-M. Huang, Kenneth P. Nephew
Journal: Cancer Research (2006)

Abstract The development of targeted therapies for antiestrogen-resistant breast cancer requires a detailed understanding of its molecular characteristics. To further elucidate the molecular events underlying acquired resistance to the antiestrogens tamoxifen and fulvestrant, we established drug-resistant sublines from a single colony of hormone-dependent breast cancer MCF7 cells. These model systems allowed us to examine the cellular and molecular changes induced by antiestrogens in the context of a uniform clonal background. Global changes in both basal and estrogen-induced gene expression profiles were determined in hormone-sensitive and hormonal-resistant sublines using Affymetrix Human Genome U133 Plus 2.0 Arrays. Changes in DNA methylation were assessed by differential methylation hybridization, a high-throughput promoter CpG island microarray analysis. By comparative studies, we found distinct gene expression and promoter DNA methylation profiles associated with acquired resistance to fulvestrant versus tamoxifen. Fulvestrant resistance was characterized by pronounced up-regulation of multiple growth-stimulatory pathways, resulting in estrogen receptor α (ERα)–independent, autocrine-regulated proliferation. Conversely, acquired resistance to tamoxifen correlated with maintenance of the ERα-positive phenotype, although receptor-mediated gene regulation was altered. Activation of growth-promoting genes, due to promoter hypomethylation, was more frequently observed in antiestrogen-resistant cells compared with gene inactivation by promoter hypermethylation, revealing an unexpected insight into the molecular changes associated with endocrine resistance. In summary, this study provides an in-depth understanding of the molecular changes specific to acquired resistance to clinically important antiestrogens. Such knowledge of resistance-associated mechanisms could allow for identification of therapy targets and strategies for resensitization to these well-established antihormonal agents. (Cancer Res 2006; 66(24): 11954–66)
OX40 triggering blocks suppression by regulatory T cells and facilitates tumor rejection
Authors: Silvia Piconese, Barbara Valzasina, Mario P. Colombo
Journal: The Journal of Experimental Medicine (2008)

Regulatory T (T reg) cells are the major obstacle to cancer immunotherapy, and their depletion promptly induces conversion of peripheral precursors into T reg cells. We show that T reg cells can be functionally inactivated by OX40 triggering. In tumors, the vast majority of CD4(+) T cells are Foxp3(+) and OX40(bright). However, intratumor injection of the agonist anti-OX40 monoclonal antibody (mAb) OX86, but not anti-CD25 mAb, induces tumor rejection in 80% of mice, an effect that is abrogated by CD8 depletion. Upon intratumor OX40 triggering, increased numbers of infiltrating dendritic cells (DCs) migrate to draining lymph nodes and generate a new wave of tumor-specific cytotoxic T lymphocytes, as detected by tetramer and CD44 staining of node CD8(+) T lymphocytes. Tumor-bearing Rag1-knockout (KO) mice reconstituted with OX40-deficient T reg cells and wild-type (WT) effector T cells, or the reciprocal combination, showed that both T reg and effector T cells must be triggered via OX40 for the tumor to be rejected. Accordingly, WT but not OX40-KO mice receiving intratumor coinjection of OX86 and ovalbumin protein were able to revert tumor-induced tolerization of adoptively transferred OX40-competent OTII T lymphocytes. In conclusion, OX40-mediated inactivation of T reg cell function unleashes nearby DCs, allowing them to induce an adaptive immune response. In addition, the known OX40-dependent delivery of fitness signals to activated T cells is boosted by concurrent T reg cell inhibition. OX40 triggering thus has multiple effects that converge to mediate tumor rejection.
Ror1 Is a Pseudokinase That Is Crucial for Met-Driven Tumorigenesis
Authors: Alessandra Gentile, Luca Lazzari, Silvia Benvenuti, Livio Trusolino, Paolo M. Comoglio
Journal: Cancer Research (2011)

The human kinome includes Ror1, a poorly characterized orphan receptor. Here we report the findings of an investigation of Ror1 contributions to cancer, undertaken through an integrated screening of 43 cancer cell lines where we measured protein expression, tyrosine phosphorylation, and growth response following RNAi-mediated Ror1 suppression. Ror1 was expressed in approximately 75% of the cancer cell lines without apparent histotype distribution. Gastric carcinoma cells (HS746T) and non-small cell lung carcinoma cells (NCI-H1993) exhibited high levels of Ror1 tyrosine phosphorylation, and Ror1 suppression caused growth inhibition. Biochemical assays revealed unexpectedly that Ror1 is a pseudokinase that is devoid of catalytic activity. Intriguingly, the two cell lines featuring tyrosine-phosphorylated Ror1 both exhibited amplification and activation of the Met oncogene. Ror1 phosphorylation was abrogated by Met inhibition, indicating Met-dependent transphosphorylation of Ror1. Conversely, Ror1 was not transphosphorylated by other constitutively active tyrosine kinases, including EGFR and ErbB2. Constitutive silencing of Ror1 in HS746T and NCI-H1993 carcinoma cells impaired proliferation in vitro and induced a dramatic inhibition of tumorigenesis in vivo. Together, our findings suggest a critical role for Ror1 in malignant phenotypes sustained by the Met oncogene.
P69 A study of the prevalence of hypoxaemia, hypercapnia, hyperoxaemia and acidosis in hospital blood gas specimens (with clinical outcomes)
Authors: F. Simpson, B. R. O'Driscoll
Journal: Thorax (2011)

<h3>Introduction</h3> Some clinicians take an aggressive approach to supplemental oxygen therapy to avoid the dangers of hypoxaemia but many patients, especially those with COPD, are at risk from uncontrolled oxygen therapy. Furthermore, recent publications have suggested an independent association between hyperoxaemia and in-hospital mortality of ICU patients (de Jonge 2008, Kilgannon 2010). <h3>Methods</h3> We studied a 1-year database of 29 587 hospital blood gas specimens including samples from A&amp;E and ICU. Only the first adequate sample from each patient was analysed; (n=7956). Samples were grouped in saturation bands corresponding to the recommended target saturation ranges in the BTS Emergency Oxygen Guideline and saturation bands above, below and between these ranges (Abstract P69 table 1). A random sub-sample of 360 specimens was analysed in more detail for clinical outcomes and the prevalence of risk factors for type 2 respiratory failure. <h3>Results</h3> Excluding A&amp;E cases, only 10% of blood gas samples demonstrated Type 1 respiratory failure with PO<sub>2</sub> &lt;8 kPa (60 mm Hg) and normal CO<sub>2</sub> levels. Thirty per cent of first A&amp;E samples had Type 1 respiratory failure. Of 7965 samples analysed, 22% were hypercapnic with PCO<sub>2</sub> &gt;6 kPa (45 mm Hg) consistent with Type 2 respiratory failure and the oxygen saturation was above 92% in 54% of these hypercapnic patients. 22% of all samples were hyperoxaemic with PO<sub>2</sub>&gt;15 kPa (112 mm Hg) and 26% had saturation &gt;98%. Within the sub-sample of 360 specimens there were 72 in-hospital deaths (20%). The lowest mortality was 8% in the 88–92% saturation range and the highest mortality was 39% in those with saturation &lt;88%. Of 85 patients documented to be at risk of Type 2 respiratory failure, 62 (73%) had oxygen saturations greater than the 88–92% target range recommended in BTS Guidelines. <h3>Conclusions</h3> Despite the introduction of the BTS Guidelines, hyperoxaemia is still a common finding in blood gas specimens in 2011. Type 2 respiratory failure is twice as common as Type 1 failure except for A&amp;E samples but the majority of patients at risk of Type 2 respiratory failure had oxygen saturations above the recommended target range. These results demonstrate the need for a prospective study of the link between oxygen therapy and overall hospital mortality.
Induced Basal Normoglycemia and Altered Platelet Aggregation in Non-insulin-dependent Diabetes
Authors: R J Evans, J Lane, R R Holman, R C Turner
Journal: Diabetes Care (1982)

Non-insulin-dependent diabetic subjects had abnormally raised in vitro platelet aggregation rates to collagen or ristocetin when thought to be "well-controlled" on diet alone but shown to have raised basal plasma glucose levels. Basal normoglycemia, induced with either ultralente insulin or chlorpropamide, was associated with a significant reduction of the enhanced platelet aggregation rates to normal. Some sulfonylurea drugs have been reported to have specific anti-platelet aggregatory properties, but the degree of plasma glucose control is probably more relevant.