tbuckley/cabot-search huggingface dataset:
The long-term safety of pirfenidone (PFD) in patients with idiopathic pulmonary fibrosis (IPF)
Authors: Dominique Valeyre, Carlo Albera, Williamson Bradford, Ulrich Costabel, Talmadge King, Paul Noble, Steven Sahn, Roland du Bois
Journal: European Respiratory Journal (2012)

Introduction:  PFD is an oral molecule that is approved in Europe and Japan for the treatment of IPF. Long-term safety is being assessed in two open-label (OL) studies in patients with IPF.  Objective:  Further examine the long-term safety of PFD in patients with IPF.   Methods:  All patients receiving PFD 2403 mg/d in the CAPACITY studies or one of two ongoing OL studies of PFD in patients with IPF (Studies 002 and 012) were included in the analysis. Study 002 is a compassionate use study in the U.S.; Study 012 is an OL extension study evaluating PFD in patients who completed CAPACITY.  Results:  A total of 789 patients were included in the analysis. The median duration of exposure to PFD was 2.6 years (range, 1 week–7.7 years); the median daily dose was 2257 mg (range 25–3600). The cumulative total exposure was 2,052 person exposure years (PEY). Consistent with previous studies, almost all patients (99.7%) reported at least one treatment emergent adverse event (AE). Gastrointestinal and skin-related events were the most commonly reported AE9s; these were generally mild to moderate and rarely led to treatment discontinuation. AST/ALT elevations (>3 x ULN) occurred in 21/789 (2.7%) patients; the adjusted incidence of AST/ALT elevations was 1.7 per 100 PEY.  Conclusions:  Analysis of safety data from IPF patients receiving PFD for up to 7.7 years demonstrates that long-term treatment with PFD is safe and generally well tolerated.
Abstract P5-07-06: Exploring the involvement of TTK kinase in centrosome amplification and Her2+ breast cancer
Authors: Jamie L King, Harold I Saavedra
Journal: Cancer Research (2015)

Abstract The centrosome is the cellular organelle responsible for accurate chromosome segregation. In normal cellular function, regulation of the centrosome duplication cycle in concert with the cell cycle is necessary for accurate passage of genetic information. However, when modulators of the cell and/or centrosome duplication cycles are deregulated, this process can result in centrosome amplification (CA, the acquisition of more than two centrosomes), leading to improper segregation of chromosomes and genomic instability. CA generates low-level aneuploidy (which is tolerated) and polyploidy (selected against when checkpoints are present). An integral goal in the field of centrosome biology is to characterize how alterations in modulators of CA influence disease development. In cancer, CA is associated with aggressive tumor types and metastasis and is likely to affect response to treatment. However, the full role of CA in tumorigenesis is poorly understood. Specifically in breast cancer, CA is observed in pre-cancerous lesions, which suggests CA in conjunction with genomic instability is an early contributor to tumorigenesis. In an effort to study mechanisms associated with CA, we are investigating the function of CA in in vitro and in vivo breast cancer models. Our lab and others have detected that TTK (MPS1) kinase, a proposed modulator of centrosome duplication, is overexpressed in Her2+ breast cancer cell lines at the mRNA and protein level compared to non-transformed mammary epithelial cells. We hypothesize that overexpression of TTK leads to CA and that inhibiting TTK expression in cancer cells will prevent active generation of CA and CIN (chromosome instability), leading to suppressed tumorigenic properties and further cancer evolution. Preliminary data shows that transient knockdown of TTK via siRNA attenuates the degree of CA in Her2+ breast cancer cells. Additional preliminary data shows that stable abrogation of TTK via shRNA can inhibit the proliferation of Her2+ breast cancer cells but does not alter expression of some members in the intrinsic apoptotic pathway. Ongoing studies will address the impact of altering TTK expression on CA, CIN, downstream centrosomal duplication signaling and tumorigenic properties of breast cancer cells. The results of these studies will address the mechanistic complexities, such as what centrosomal signaling pathways associated with TTK are underlying CA in breast cancer. We believe this work will help discern how deregulated centrosome regulatory molecules influence mammary tumorigenesis and/or responses to treatment. Citation Format: Jamie L King, Harold I Saavedra. Exploring the involvement of TTK kinase in centrosome amplification and Her2+ breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-07-06.
Three cases of pulmonary aspergilloma in adult patients with cystic fibrosis.
Authors: C P Maguire, J P Hayes, M Hayes, J Masterson, M X FitzGerald
Journal: Thorax (1995)

Pulmonary aspergillomas usually occur when Aspergillus fungi colonise lung tissue previously damaged by disease. Pulmonary aspergillomas in three adult patients with cystic fibrosis are reported--an association not previously described. At the time of diagnosis all three patients had previous long term colonisation with Aspergillus fumigatus and severe advanced destructive lung disease with lung function less than 25% of the predicted normal values. It is likely that, with increasing survival in cystic fibrosis, more adult patients will develop aspergillomas during the protracted phase of end stage lung disease that characterises the terminal years of this condition.
Cost-Effectiveness of Alternative Thresholds of the Fasting Plasma Glucose Test to Identify the Target Population for Type 2 Diabetes Prevention in Adults Aged ≥45 Years
Authors: Xiaohui Zhuo, Ping Zhang, Henry S. Kahn, Edward W. Gregg
Journal: Diabetes Care (2013)

OBJECTIVE The study objective was to evaluate the cost-effectiveness of alternative fasting plasma glucose (FPG) thresholds to identify adults at high risk for type 2 diabetes for diabetes preventive intervention. RESEARCH DESIGN AND METHODS We used a validated simulation model to examine the change in lifetime quality-adjusted life years (QALYs) and medical costs when the FPG threshold was progressively lowered in 5-mg/dL decrements from 120 to 90 mg/dL. The study sample includes nondiabetic adults aged ≥45 years in the United States using 2006–2010 data from the National Health and Nutrition Examination Survey. High-risk individuals were assumed to receive a lifestyle intervention, as that used in the Diabetes Prevention Program. We calculated cost per QALY by dividing the incremental cost by incremental QALY when lowering the threshold to the next consecutive level. Medical costs were assessed from a health care system perspective. We conducted univariate and probabilistic sensitivity analyses to assess the robustness of the results using different simulation scenarios and parameters. RESULTS Progressively lowering the FPG threshold would monotonically increase QALYs, cost, and cost per QALY. Reducing (in 5-mg/dL decrements) the threshold from 120 to 90 mg/dL cost $30,100, $32,900, $42,300, $60,700, $81,800, and $115,800 per QALY gained, respectively. The costs per QALY gained were lower for all thresholds under a lower-cost and less-effective intervention scenario. CONCLUSIONS Lowering the FPG threshold leads to a greater health benefit of diabetes prevention but reduces the cost-effectiveness. Using the conventional benchmark of $50,000 per QALY, a threshold of 105 mg/dL or higher would be cost effective. A lower threshold could be selected if the intervention cost could be lowered.
Expression of leukocyte integrins and tissue factor in mononuclear phagocytes
Authors: B Nakstad, T Haugen, OH Skjonsberg, T Lyberg
Journal: European Respiratory Journal (1998)

Coagulation is intimately involved in the pathology of inflammation. The leukocyte beta2-integrins have several functions, including serving as receptors for coagulation factor X and fibrinogen. Tissue factor (TF) is a receptor for factor VII and a very potent trigger of coagulation. The intention of this study was to examine a possible coexpression of beta2-integrins (CD11b/CD18 and CD11c/CD18) and the procoagulant TF in alveolar macrophages (AM) and blood monocytes, i.e. cells of the same differentiation lineage. The expression of beta2-integrins in human AM isolated by bronchoalveolar lavage and in blood monocytes was analysed by flow cytometry, whereas TF activity was analysed in a one-stage clotting assay. In monocytes, TF activity, CD11b and CD11c expression were highly inducible by lipopolysaccharide (LPS), with a 13-, 19- and four-fold increase, respectively. In AM, TF and beta2-integrins were all constitutively expressed, but the expression could not be further enhanced by LPS stimulation. CD11b and CD11c expression varied inversely with the cell size of AM, in contrast to TF activity which is known to be proportional to AM cell size. In vitro expression of beta2-integrins and tissue factor in lipopolysaccharide-stimulated blood monocytes seems to be intimately coregulated, whereas the expression of these receptors in alveolar macrophages seems to be unresponsive to lipopolysaccharide. These results indicate that blood monocytes and alveolar macrophages have different roles and use different mechanisms in cell-induced fibrin formation.
Prevalence of metronidazole resistant Helicobacter pylori strains among Chinese peptic ulcer disease patients and normal controls in Hong Kong.
Authors: C K Ching, K P Leung, R W Yung, S K Lam, B C Wong, K C Lai, C L Lai
Journal: Gut (1996)

A study was conducted to evaluate the prevalence of metronidazole resistant Helicobacter pylori strains among the Chinese in Hong Kong. The efficacy of the triple therapy that contains metronidazole as one of the anti-microbial agents in eradication of the metronidazole susceptible and the metronidazole resistant strains was also assessed.Culture for H pylori was attempted from antral biopsy specimens of 70 peptic ulcer and 51 control subjects. Successfully cultured H pylori strains were tested for metronidazole susceptibility. Twenty six peptic ulcer disease subjects who had received a course of triple therapy were also reassessed four to six weeks later for successful eradication of H pylori infection.H pylori was successfully cultured from antral biopsy specimens in 69 of 80 (86%) of the infected subjects. The overall metronidazole resistance rate was 53.5% (37 of 69). There was a significantly higher metronidazole resistance rate among H pylori isolates from the asymptomatic controls (20 of 25) than the peptic ulcer disease subjects (17 of 44) (p = 0.0007). Twenty three of 32 (73%) women and 14 of 37 (38%) men harboured the metronidazole resistant strains. There was no sex or age difference as far as the prevalence of metronidazole resistant strains were concerned within each study group. Pre-treatment metronidazole susceptible H pylori were significantly more likely to respond to the triple therapy used than those with the metronidazole resistant ones (14 of 15 v five of 10) (p = 0.021).
Noninvasive mechanical ventilation in patients with acute respiratory failure due to H1N1 infection
Authors: Eva Tonveronachi, Ilaria Valentini, Andrea Fabiani, Rosanna Vaschetto, Antonina Pigna, Riccardo Maviglia, Gabriela Sangiorgi, Massimo Gorini, Marco Adversi, Gianfranco Di Nino, Stefano Faenza, Massimo Antonelli, Paolo Navalesi, Stefano Nava
Journal: European Respiratory Journal (2011)

We evaluated the clinical outcomes of consecutive patients positive for H1N1 and admitted to 6 Intensive Care Units in Italy for severe Acute Respiratory Failure and requiring non-invasive mechanical ventilation (NIV). 29/54 (54%) patients admitted to the ICUs needed immediate intubation for gasping, coma or respiratory arrest. The remaining 25 patients (mean age 49.8±12) underwent an NIV trial as a first line treatment using the helmet (n.19 patients) or a total face mask (n.6). Arterial Blood Gases (ABGs) at enrolment were: pH=7,41±0.02, PaO 2 /FiO 2 =117±64 and PaCO 2 =40,5±9. At the first ABGs control (between 309 and 909) PaO 2 /FiO 2  significantly (p 2  to 36.4±9. Mean duration of NIV was 49.8±33 hrs. 10/25 (40%) of the patients required intubation after 20.3 hrs. Overall mortality rate was 7/25 (28%), with all the deaths occurring in the NIV failure group. NIV failure had a lower PaO 2 /FiO 2  at admission (78.6±21 vs 152.4±32 p
Down-regulation of ZIP4 by RNA Interference Inhibits Pancreatic Cancer Growth and Increases the Survival of Nude Mice with Pancreatic Cancer Xenografts
Authors: Min Li, Yuqing Zhang, Uddalak Bharadwaj, Qihui (Jim) Zhai, Charlotte H. Ahern, William E. Fisher, F. Charles Brunicardi, Craig D. Logsdon, Changyi Chen, Qizhi Yao
Journal: Clinical Cancer Research (2009)

Zinc levels have been correlated with cancer risk, although the role of zinc and zinc transporters in cancer progression is largely unknown. We recently found that a zinc transporter, ZIP4, is overexpressed in pancreatic cancer. In this study, we further deciphered the role that ZIP4 plays in a pancreatic cancer mouse model by silencing ZIP4.ZIP4 stable silencing was established in pancreatic cancer cell lines ASPC-1 (ASPC-shZIP4) and BxPC-3 (BxPC-shZIP4) by short hairpin RNA using retrovirus vectors. The stable cells were characterized in vitro and in vivo using a nude mouse xenograft model.Silencing of ZIP4 was associated with decreased cell proliferation, migration, and invasion. Both ASPC-shZIP4 and BxPC-shZIP4 cells showed a significant reduction in tumor volume and weight in the s.c. model, and decreased primary tumor weight in the orthotopic model compared with the vector control cells (ASPC-shV and BxPC-shV). Silencing of ZIP4 also caused reduced incidence of tumor metastasis in the mice and downsized the tumor grade. More importantly, silencing of ZIP4 significantly increased the survival rate of nude mice with orthotopic xenografts (P = 0.005). All ASPC-shZIP4-injected mice (100%) remained alive up to 32 days after tumor implantation, whereas only 30% of the ASPC-shV mice were alive at the same time point. CyclinD1 expression was decreased in the ASPC-shZIP4 xenografts.These results identify a previously uncharacterized role of ZIP4 in pancreatic cancer progression, and indicate that knocking down ZIP4 by short hairpin RNA might be a novel treatment strategy for pancreatic cancers with ZIP4 overexpression.
Dopamine regulates endothelial progenitor cell mobilization from mouse bone marrow in tumor vascularization
Authors: Debanjan Chakroborty, Uttio Roy Chowdhury, Chandrani Sarkar, Rathindranath Baral, Partha Sarathi Dasgupta, Sujit Basu
Journal: Journal of Clinical Investigation (2008)

Mobilization of endothelial progenitor cells (EPCs) from the bone marrow and their subsequent participation in neovessel formation are implicated in tumor growth and neovascularization. As the neurotransmitter dopamine (DA) modulates adult endothelial cell function, we hypothesized that DA might have a regulatory role in mobilization of EPCs from the bone marrow niche. We show that there was a significant decrease in bone marrow DA content and an increase in EPC mobilization in tumor-bearing mice associated with tumor neovascularization. DA treatment of tumor-bearing mice inhibited EPC mobilization and tumor growth through its D2 receptors, as DA treatment failed to inhibit EPC mobilization in tumor-bearing mice treated with a specific DA D2 receptor antagonist and in tumor-bearing mice lacking the D2 receptor. In addition, we found that DA, through D2 receptors, exerted its inhibitory effect on EPC mobilization through suppression of VEGFA-induced ERK1/ERK2 phosphorylation and MMP-9 synthesis. These findings reveal a new link between DA and EPC mobilization and suggest a novel use for DA and D2 agents in the treatment of cancer and other diseases involving neovessel formation.
Sphingosine-1-phosphate modulates spiral modiolar artery tone: A potential role in vascular-based inner ear pathologies?
Authors: E SCHERER, D LIDINGTON, E OESTREICHER, W ARNOLD, U POHL, S BOLZ
Journal: Cardiovascular Research (2006)

The mechanisms regulating spiral modiolar artery (SMA) tone are not known, yet their characterization is pivotal for understanding inner ear blood flow regulation. Sphingosine-1-phosphate (S1P), known to stimulate vasoconstriction in several vascular beds, is a candidate regulator of SMA tone with potential pathophysiological relevance.Gerbil SMAs were isolated, cannulated and pressurized (30 mm Hg transmural) for experimentation under near-in vivo conditions. For functional experiments, vascular diameter and intracellular Ca2+ were simultaneously measured. Standard RT-PCR and immunohistochemical techniques were also employed.mRNA transcripts encoding sphingosine kinase, S1P phosphohydrolase and three S1P receptors (S1P(1-3)) were detected in the SMA. S1P induced dose-dependent vasoconstriction of the SMA (EC50 = 115 nmol/L), and enhanced the apparent Ca2+-sensitivity of the contractile apparatus. Noradrenaline did not elicit vasoconstriction. The Rho kinase inhibitor Y27632 (1 micromol/L) reversed S1P-induced vasoconstriction and the S1P-mediated enhancement of Ca2+-sensitivity. RhoA was observed to translocate to the plasma membrane in response to stimulation with 30 micromol/L S1P.We conclude that all key signalling pathway constituents are present at the mRNA level for S1P to act as an endogenous regulator of SMA tone. S1P stimulates potent, RhoA/Rho kinase-dependent SMA vasoconstriction and Ca2+ sensitization. The high sensitivity to S1P suggests that SMA vasoconstriction is likely to occur under pathological conditions that increase intramural S1P concentrations (i.e., inflammation). From a clinical perspective, the present study identifies new potential therapeutic targets for the treatment of vascular-based, "stroke-like" inner ear pathologies: the enzymes responsible for S1P bioavailability and the S1P receptors.
HIV-1 vaccine-induced immunity in the test-of-concept Step Study: a case–cohort analysis
Authors: M Juliana McElrath, Stephen C De Rosa, Zoe Moodie, Sheri Dubey, Lisa Kierstead, Holly Janes, Olivier D Defawe, Donald K Carter, John Hural, Rama Akondy, Susan P Buchbinder, Michael N Robertson, Devan V Mehrotra, Steven G Self, Lawrence Corey, John W Shiver, Danilo R Casimiro
Journal: The Lancet (2008)
CD7 false‐positive acute myelogenous leukemia and promyelocytic leukemia cell line HL‐60: Characterization of CD7 epitopes by four monoclonal antibodies
Authors: Nobutaka Imamura, Hiromi Ota, Atsushi Kuramoto
Journal: American Journal of Hematology (1991)

Phenotypes of cells from 12 patients with acute myelogenous leukemia (AML) were analysed by means of a fluorescence-activated cell sorter utilizing a panel of monoclonal antibodies (MAbs). A majority of the cells from peripheral blood coexpressed the antigens against MAbs CD11, CD13, and CD33 but did not express the antigens against CD1, CD3, CD4, CD5, CD8, CD19, CD20, CD21, CD41 and 42, and glycophorin A. Three out of the 12 cases expressed CD7 antigen. However, one of them showed no reaction with Tp40 MAb, whereas the others showed reaction with Leu9 and T55. The discrepancy of reactivities between Leu9 and Tp40 MAbs prompted us to study the promyelocytic leukemia cell line HL-60, which showed similar reactions against Leu9 and Tp40 MAbs. Leu9, OKT16, and T55 MAbs reacted strongly with HL60 cells, whereas Tp40 MAb, which reacted strongly with T-cell leukemia cell line Jurkat, showed no reaction. The reactivity of Leu9, OKT16, and T55 MAbs with HL-60 cells was completely inhibited after preincubation with aggregated human immunoglobulin G (AHIG), which clearly shows the existence of nonspecific binding between these 3 MAbs and HL-60 cells via Fc gamma R. On the basis of our experiments, we conclude that HL-60 cells bind nonspecifically with Leu9, OKT16, and T55 MAbs via FcRI, and this is suggestive that de novo AML cells probably behave in the same fashion. Hence, we recommend that the utilization of murine IgG2a and IgG3 MAbs should be avoided especially in cell surface analysis of myeloid leukemic cells.
Audit of computed tomography pulmonary angiogram (CTPA) requesting at Hammersmith hospital
Authors: Martha Purcell, Huw Ellis
Journal: European Respiratory Journal (2014)

Introduction  CTPA is the gold standard for diagnosing pulmonary emboli (PE). CTPA is expensive and involves exposure to high levels of radiation. NICE provides detailed diagnostic pathways to follow when PE is suspected. This guidance involves using Well9s score to differentiate high risk patients in addition to a D-dimer test.  Aims  To determine the proportion of CTPA requests using a Well9s score or D-dimer in accordance with NICE guidance.  Methods  Retrospective data was collected for CTPA scans carried out from 1 st  June to 31 st  August 2013. The requests were examined and details of Well9s scores and D-dimers was extracted. The diagnostic result of each CTPA was recorded.  After initial audit, posters detailing the Well9s score and NICE guidance were placed throughout the hospital. The audit results were presented at various regional meetings.  The audit cycle was completed by collecting data from 1 st  January to 31 st  March 2014.  Results  76 CTPAs were carried out over June and August 2013. Of these, 8 patients were diagnosed with PE, 3 had a Well9s score calculated, while 49 had a D-dimer. A range of other respiratory pathology was identified including consolidation and malignancy.  Re-audit data from January 2014 demonstrated an increased number of Well9s scores being calculated. However, no increase in the number of PE diagnoses was observed.  Conclusions  It is obvious that NICE guidance on CTPA requesting is not being followed to a suitable standard. In addition, the positive yield of PE was only 10.5%. This may indicate the threshold for ordering CTPA is too low and patients are exposed to high doses of radiation unnecessarily. Finally, the results demonstrate inefficient use of funding and resources.
Substantial deletion overlap among divergent Arabidopsis genomes revealed by intersection of short reads and tiling arrays
Authors: Luca Santuari, Sylvain Pradervand, Amelia-Maria Amiguet-Vercher, Jerôme Thomas, Eavan Dorcey, Keith Harshman, Ioannis Xenarios, Thomas E Juenger, Christian S Hardtke
Journal: Genome biology (2010)

Identification of small polymorphisms from next generation sequencing short read data is relatively easy, but detection of larger deletions is less straightforward. Here, we analyzed four divergent Arabidopsis accessions and found that intersection of absent short read coverage with weak tiling array hybridization signal reliably flags deletions. Interestingly, individual deletions were frequently observed in two or more of the accessions examined, suggesting that variation in gene content partly reflects a common history of deletion events.