tbuckley/cabot-search huggingface dataset:
Repeatability of Spirometry in 18,000 Adult Patients
Authors: Paul L. Enright, Kenneth C. Beck, Duane L. Sherrill
Journal: American Journal of Respiratory and Critical Care Medicine (2003)

The objective of this study was to determine the limits for repeatability of FEV1, FVC, and PEF during spirometry test sessions in adult outpatients. A retrospective chart review of 18,000 consecutive patients, aged 20 to 90 years, referred to a large outpatient pulmonary function laboratory for testing was performed. Measurements included the differences between the highest and second-highest FVC (dFVC), FEV1 (dFEV1), and PEF (dPEF), from prebronchodilator spirometry, and anthropometric factors. Ninety percent of the patients were able to reproduce FEV1 within 120 ml (6.1%), FVC within 150 ml (5.3%), and PEF within 0.80 L (12%). Patient characteristics, such as sex, age, height, smoking status, and FEV1 (% predicted), had very little effect on repeatability, explaining only 2 to 4% of the variation in repeatability (expressed in milliliters). We conclude that the ability of patients to meet or exceed spirometry repeatability goals does not depend on patient characteristics when testing is performed by experienced personnel. The current American Thoracic Society repeatability goal of 200 ml for FEV1 and FVC may be too lenient.
Phase I Study of Bosutinib, a Src/Abl Tyrosine Kinase Inhibitor, Administered to Patients with Advanced Solid Tumors
Authors: Adil I. Daud, Smitha S. Krishnamurthi, Mansoor N. Saleh, Barbara J. Gitlitz, Mitesh J. Borad, Philip J. Gold, Elena G. Chiorean, Gregory M. Springett, Richat Abbas, Shefali Agarwal, Nathalie Bardy-Bouxin, Poe-Hirr Hsyu, Eric Leip, Kathleen Turnbull, Charles Zacharchuk, Wells A. Messersmith
Journal: Clinical Cancer Research (2011)

Bosutinib, a potent ATP-competitive, quinolinecarbonitrile Src/Abl kinase inhibitor, was tested in this first-in-human phase I trial in patients with advanced solid tumor malignancies.This trial was conducted in 2 parts. In part 1 (dose escalation), increasing oral bosutinib doses were administered using a 3 + 3 design. In part 2 (dose expansion), approximately 30 patients each with refractory colorectal, pancreas, or non-small cell lung cancer were treated at the recommended phase II dose (RP2D). Primary efficacy endpoints for part 2 were median progression-free survival (colorectal and non-small cell lung) and median overall survival (pancreas).In part 1, dose-limiting toxicities of grade 3 diarrhea (two patients) and grade 3 rash occurred with bosutinib 600 mg/day and the maximum tolerated dose identified was 500 mg/day. However, the majority of patients treated with 500 mg/day had grade 2 or greater gastrointestinal toxicity, and 400 mg/day was identified as the RP2D. The most common bosutinib-related adverse events were nausea (60% patients), diarrhea (47%), vomiting (40%), fatigue (38%), and anorexia (36%). Bosutinib had a mean half-life of 19 to 20 hours at the RP2D. A partial response (breast) and unconfirmed complete response (pancreas) were observed; 8 of 112 evaluable patients had stable disease for 22 to 101 weeks. However, the primary efficacy endpoints for part 2 were not met.Bosutinib was generally well tolerated in patients with solid tumors, with the main toxicity being gastrointestinal. The RP2D was 400 mg/day orally. Further study of bosutinib is planned in combination regimens.
P242 Bone density and testosterone levels in male cystic fibrosis patients
Authors: B. Marson, C. Valsalakumari, L. Speight, J. Platts, L. George, R. I. Ketchell, J. Duckers
Journal: Thorax (2011)

<h3>Background</h3> Cystic Fibrosis (CF) is the commonest inherited life threatening condition in the UK and is a multisystem disease. CF related low bone mineral density (BMD) is defined as a Z score 2 SDs below the age and gender matched mean reference value and has been reported in 13% of CF patients.1 Its aetiology is multifactorial with hypogonadism being a potential factor. CF Trust guidelines<sup>2</sup> suggest BMD should be measured and addressed regularly and testosterone levels measured annually in adult males. <h3>Aim</h3> To assess the prevalence of low BMD and testosterone in male CF patients attending the All Wales CF Centre. <h3>Methods</h3> Annual review records (2008–2009) of BMD derived from DEXA scans and testosterone levels were reviewed retrospectively. <h3>Results</h3> 65 male patients (age 18–51 years) were included of whom 60 had a recorded testosterone and BMD. 12 patients (20%) had CF related low BMD (at hip or lumbar spine) of whom three had a low testosterone (&lt;8.0 nmol/l). 12 (20%) patients had low testosterone levels. Of these twelve, three had low leutinising hormone (LH) and nine normal LH and all had normal levels of follicle stimulating hormone. <h3>Discussion</h3> CF related low BMD occurs commonly in men with CF with a quarter of those with low BMD also having low testosterone levels. Low testosterone levels per se also occur frequently in this population and recent CF Trust guidelines2 have suggested an endocrinology opinion should be sought where testosterone is found to be low.
Glioblastoma: From Molecular Pathology to Targeted Treatment
Authors: Timothy F. Cloughesy, Webster K. Cavenee, Paul S. Mischel
Journal: Annual Review of Pathology Mechanisms of Disease (2011)

Glioblastoma (GBM) is one of the most lethal human cancers. Genomic analyses are defining the molecular architecture of GBM, uncovering relevant subsets of patients whose disease may require different treatments. Many pharmacological targets have been revealed, promising to transform patient care through targeted therapies. However, for most patients, clinical responses to targeted inhibitors are either not apparent or not durable. In this review, we address the challenge of developing more effective, molecularly guided approaches for the treatment of GBM patients. We summarize the current state of knowledge regarding molecular classifiers and examine their benefit for stratifying patients for treatment. We survey the molecular landscape of the disease, discussing the challenges raised by acquired drug resistance. Furthermore, we analyze the biochemical features of GBM, suggesting a next generation of drug targets, and we examine the contribution of tumor heterogeneity and its implications. We conclude with an analysis of the experimental approaches and their potential benefit to patients.
Initial treatment patterns over time for anaplastic oligodendroglial tumors
Authors: K. S. Panageas, F. M. Iwamoto, T. F. Cloughesy, K. D. Aldape, A. L. Rivera, A. F. Eichler, D. N. Louis, N. A. Paleologos, B. J. Fisher, L. S. Ashby, J. G. Cairncross, G. B. Roldan Urgoiti, P. Y. Wen, K. L. Ligon, D. Schiff, H. I. Robins, B. G. Rocque, M. C. Chamberlain, W. P. Mason, S. A. Weaver, R. M. Green, F. G. Kamar, L. E. Abrey, L. M. DeAngelis, S. C. Jhanwar, M. K. Rosenblum, A. B. Lassman
Journal: Neuro-Oncology (2012)

Anaplastic oligodendroglial tumors are rare neoplasms with no standard approach to treatment. We sought to determine patterns of treatment delivered over time and identify clinical correlates of specific strategies using an international retrospective cohort of 1013 patients diagnosed from 1981–2007. Prior to 1990, most patients received radiotherapy (RT) alone as initial postoperative treatment. After 1990, approximately 50% of patients received both RT and chemotherapy (CT) sequentially and/or concurrently. Treatment with RT alone became significantly less common (67% in 1980–1984 vs 5% in 2005–2007, P < .0001). CT alone was more frequently administered in later years (0% in 1980–1984 vs 38% in 2005–2007; P < .0001), especially in patients with 1p19q codeleted tumors (57% of codeleted vs 4% with no deletion in 2005–2007; P < .0001). Temozolomide replaced the combination of procarbazine, lomustine, and vincristine (PCV) among patients who received CT alone or with RT (87% vs 2% in 2005–2007). In the most recent time period, patients with 1p19q codeleted tumors were significantly more likely to receive CT alone (with temozolomide), whereas RT with temozolomide was a significantly more common treatment strategy than either CT or RT alone in cases with no deletion (P < .0001). In a multivariate polytomous logistic regression model, the following were significantly associated with type of treatment delivered: date (5-year interval) of diagnosis (P < .0001), 1p19q codeletion (P < .0001), pure anaplastic oligodendroglioma histology (P < .01), and frontal lobe predominance (P < .05). Limited level 1 evidence is currently available to guide treatment decisions, and ongoing phase III trials will be critical to understanding the optimal therapy.
Prevention of sport injury II: a systematic review of clinical science research
Authors: Kellen McBain, Ian Shrier, Rebecca Shultz, Willem H Meeuwisse, Martin Klügl, Daniel Garza, Gordon O Matheson
Journal: British Journal of Sports Medicine (2011)

Objective To characterise the nature of the sport injury prevention literature by reviewing published articles that evaluate specific clinical interventions designed to reduce sport injury risks. Data sources PubMed, Cinahl, Web of Science and Embase. Main results Only 139 of 2525 articles retrieved met the inclusion criteria. Almost 40% were randomised controlled trials and 30.2% were cohort studies. The focus of the study was protective equipment in 41%, training in 32.4%, education in 7.9%, rules and regulations in 4.3%, and 13.3% involved a combination of the above. Equipment research studied stability devices (42.1%), head and face protectors (33.3%), attenuating devices (17.5%) as well as other devices (7%). Training studies often used a combination of interventions (eg, balance and stretching); most included balance and coordination (63.3%), with strength and power (36.7%) and stretching (22.5%) being less common. Almost 70% of the studies examined lower extremity injuries, and a majority of these were joint (non-bone)-ligament injuries. Contact sports were most frequently studied (41.5%), followed by collision (39.8%) and non-contact (20.3%). Conclusion The authors found only 139 publications in the existing literature that examined interventions designed to prevent sports injury. Of these, the majority investigated equipment or training interventions whereas only 4% focused on changes to the rules and regulations that govern sport. The focus of intervention research is on acute injuries in collision and contact sports whereas only 20% of the studies focused on non-contact sports.
Primary Structure of Mouse and Rat Nephrin cDNA and Structure and Expression of the Mouse Gene
Authors: HELI PUTAALA, KIRSI SAINIO, HANNU SARIOLA, KARL TRYGGVASON
Journal: Journal of the American Society of Nephrology (2000)

Abstract. Nephrin is a central component of the glomerular podocyte slit diaphragm and is essential for the normal renal filtration process. This study describes the complete structure of the mouse nephrin gene, which was shown to be homologous to the human gene, the major difference being 30 exons in the mouse gene as opposed to 29 in human. The complete primary structure of mouse and rat nephrins was also determined. The sequence identity between the mouse and rat proteins was shown to be 93%, while both rodent proteins have only about 83% sequence identity with human nephrin. The availability of the three mammalian sequences is significant for the interpretation of sequence variants and mutations in the nephrin gene in patients with congenital nephrotic syndrome. In situ hybridization analyses of whole mouse embryos and tissues revealed high expression of nephrin in kidney glomeruli and, surprisingly, an intense and highly restricted expression in a set of cells in hindbrain and spinal cord. No expression was observed elsewhere. This expression pattern may explain occasionally occurring neural symptoms caused by inactivating mutations in the nephrin gene in patients with congenital nephrotic syndrome.
Involvement of the Fibroblast Growth Factor System in Adaptive and Chemokine-Induced Arteriogenesis
Authors: Elisabeth Deindl, Imo E. Hoefer, Borja Fernandez, Miroslav Barancik, Matthias Heil, Monika Strniskova, Wolfgang Schaper
Journal: Circulation Research (2003)

Fibroblast growth factors (FGFs) have been applied in a variety of therapeutic and experimental studies to improve collateral blood flow. However, the pathophysiological role and the temporospatial expression of the FGFs and their receptors during arteriogenesis have never been elucidated in vivo. Here, we report that collateral artery growth in its early phase is associated with an increased expression of FGF receptor-1 (FGFR-1) and syndecan-4 on mRNA and protein levels as well as with an increased kinase activity of FGFR-1 in a rabbit model of arteriogenesis. However, the mRNA levels of FGF-1 and -2 remained constant. Our data suggest that these growth factors are supplied by endothelial attracted monocytes that, in turn, produce and deliver the FGFs to growing collateral arteries. Monocyte chemoattractant protein-1-stimulated arteriogenesis was strongly reduced in rabbits by application of the FGF inhibitor polyanetholesulfonic acid, indicating that the monocyte-related arteriogenesis (as well as the unstimulated adaptation proper) is promoted by FGFs. In summary, this study shows that arteriogenesis is associated with an increased expression of the FGFRs at the site of the vessel, whereas the growth-promoting ligands are supplied by monocytes in a paracrine way.
MyD88-Dependent Signaling Decreases the Antitumor Efficacy of Epidermal Growth Factor Receptor Inhibition in Head and Neck Cancer Cells
Authors: Adam T. Koch, Laurie Love-Homan, Madelyn Espinosa-Cotton, Aditya Stanam, Andrean L. Simons
Journal: Cancer Research (2015)

Abstract EGFR is upregulated in the majority of head and neck squamous cell carcinomas (HNSCC). However, many patients with HNSCC respond poorly to the EGFR inhibitors (EGFRI) cetuximab and erlotinib, despite tumor expression of EGFR. Gene expression analysis of erlotinib-treated HNSCC cells revealed an upregulation of genes involved in MyD88-dependent signaling compared with their respective vehicle-treated cell lines. We therefore investigated whether MyD88-dependent signaling may reduce the antitumor efficacy of EGFRIs in HNSCC. Erlotinib significantly upregulated IL6 secretion in HNSCC cell lines, which our laboratory previously reported to result in reduced drug efficacy. Suppression of MyD88 expression blocked erlotinib-induced IL6 secretion in vitro and increased the antitumor activity of erlotinib in vivo. There was little evidence of Toll-like receptor or IL18 receptor involvement in erlotinib-induced IL6 secretion. However, suppression of IL1R signaling significantly reduced erlotinib-induced IL6 production. A time-dependent increase of IL1α but not IL1β was observed in response to erlotinib treatment, and IL1α blockade significantly increased the antitumor activity of erlotinib and cetuximab in vivo. A pan-caspase inhibitor reduced erlotinib-induced IL1α secretion, suggesting that IL1α was released because of cell death. Human HNSCC tumors showed higher IL1α mRNA levels compared with matched normal tissue, and IL1α was found to be negatively correlated with survival in patients with HNSCC. Overall, the IL1α/IL1R/MYD88/IL6 pathway may be responsible for the reduced antitumor efficacy of erlotinib and other EGFRIs, and blockade of IL1 signaling may improve the efficacy of EGFRIs in the treatment of HNSCC. Cancer Res; 75(8); 1657–67. ©2015 AACR.
Association of Oral Sodium Phosphate Purgative Use with Acute Kidney Injury
Authors: Frank P. Hurst, Erin M. Bohen, Eric M. Osgard, David K. Oliver, Nealanjon P. Das, Sam W. Gao, Kevin C. Abbott
Journal: Journal of the American Society of Nephrology (2007)

Oral sodium phosphate (OSP) is a commonly used purgative before colonoscopy. There have been numerous reports of acute phosphate nephropathy attributed to the use of OSP. This study evaluated the association between the use of OSP and acute kidney injury (AKI) in an observational, retrospective, cohort study. Of 9799 patients who underwent colonoscopy and had serum creatinine values recorded within 365 days before and after the procedure, AKI, defined as > or =50% increase in baseline serum creatinine, was identified in 114 (1.16%). After adjustment for significant covariates in a multiple logistic regression model, the use of OSP was associated with increased risk for AKI (odds ratio 2.35; 95% confidence interval 1.51 to 3.66; P < 0.001) with an adjusted number need to harm of 81. Age was also independently associated with AKI in this cohort; therefore, until larger, prospective studies define the population at risk for acute phosphate nephropathy, the use of polyethylene glycol-based purgatives should be considered for older patients and possibly for those with comorbid medical conditions.
Cyclic adenosine monophosphate–responsive element modulator alpha overexpression impairs function of hepatic myeloid‐derived suppressor cells and aggravates immune‐mediated hepatitis in mice
Authors: Linda Hammerich, Klaudia Theresa Warzecha, Martina Stefkova, Matthias Bartneck, Kim Ohl, Nikolaus Gassler, Tom Luedde, Christian Trautwein, Klaus Tenbrock, Frank Tacke
Journal: Hepatology (2014)

Molecular factors driving immune‐mediated inflammation in the liver are incompletely understood. The transcription factor, cyclic adenosine monophosphate‐responsive element modulator alpha (CREMα) can endorse differentiation of T lymphocytes toward T‐helper (Th)17 cells, thereby promoting autoimmunity in systemic lupus erythematosus or lung inflammation. To investigate the role of CREMα in liver disease, we subjected transgenic (Tg) mice overexpressing CREMα under control of the CD2 promoter (crem tg mice), which restrains expression mainly to lymphocytes (T, natural killer [NK], and NKT cells), to acute and chronic liver injury models. Already in steady state, Tg CREMα overexpression broadly reduced hepatic immune cell numbers by decreasing their viability, but did not affect immune cell migration or the fibrogenic response to chronic liver injury. Strikingly, crem tg mice developed more severe immune‐mediated hepatitis with a higher mortality rate, compared to wild‐type (wt) mice, upon concanavalin A (ConA) administration. Unlike in T cells from spleen, CREMα overexpression did not induce a predominant Th17 response in intrahepatic T cells, given that hepatic crem tg CD4 + T cells expressed less interleukin (IL)‐17 than wt T cells. Reconstitution of Rag1−/− mice with Crem−/− T cells did not ameliorate ConA hepatitis. Overexpression of CREMα did not influence NK and NKT‐cell effector functions either. Interestingly, a subset of monocytic myeloid‐derived suppressor cells (MDSCs) also expressed CD2 and CREMα. Crem tg MDSCs isolated from liver expressed reduced inducible nitric oxide synthase and arginase 1 and displayed a reduced T‐cell suppressive activity. The adoptive transfer of wt MDSCs was capable of reducing the fulminant immune‐mediated liver damage in crem tg mice to wt level. Conclusion : These results suggest compartmental differences of T cell activation pathways between liver and other organs in autoimmunity and define a functional role of CREMα in hepatic monocytic MDSCs for the pathogenesis of immune‐mediated liver disease. (H epatology 2015;61:990–1002)
Effect on Quality of Life Of Multidisciplinary Psycho-educational Group Interventions - A Randomized Controlled Trial
Authors: L. Fernandes, J.A. Fonseca, A. Costa-pereira, L. Delgado, S. Martins, A. Moreira, A. Feteira, V. Abreu, M. Vaz, M. Castel-Branco
Journal: Journal of Allergy and Clinical Immunology (2006)
T cell clones from an X-linked hyper-immunoglobulin (IgM) patient induce IgE synthesis in vitro despite expression of nonfunctional CD40 ligand.
Authors: P Life, J F Gauchat, V Schnuriger, S Estoppey, G Mazzei, A Durandy, A Fischer, J Y Bonnefoy
Journal: The Journal of Experimental Medicine (1994)

The induction of immunoglobulin E (IgE) switching in B cells requires at least two signals. The first is given by either of the soluble lymphokines interleukin 4 (IL-4) or IL-13, whereas the second is contact dependent. It has been widely reported that a second signal can be provided by the CD40 ligand (CD40L) expressed on the surface of T cells, mast cells, and basophils. A defect in the CD40L has been shown recently to be responsible for the lack of IgE, IgA, and IgG, characteristic of the childhood X-linked immunodeficiency, hyper IgM syndrome (HIGM1). IgE can however be detected in the serum of some HIGM1 patients. In this study, we isolated T cell clones and lines using phytohemagglutinin (PHA) and allergen, respectively, from the peripheral blood of one such patient who expressed a truncated form of CD40L, and investigated their ability to induce IgE switching in highly purified, normal tonsillar B cells in vitro. Unexpectedly, 4 of 12 PHA clones tested induced contact-dependent IgE synthesis in the presence of exogenous IL-4. These clones were also shown to strongly upregulated IL-4-induced germline epsilon RNA and formed dense aggregates with B cells. Of the four helper clones, three were CD8+, of which two were characteristic of the T helper cell 2 (Th2) subtype. Two allergen-specific HIGM1 T cell lines, both of the Th0 subtype, could also drive IgE synthesis when prestimulated using specific allergen. All clones and lines were negative for surface expression of CD40L, and the mutated form of CD40L was confirmed for a representative clone by RNase protection assay and sequencing. The IgE helper activity could not be attributed to membrane tumor necrosis factor alpha (TNF-alpha) although it was strongly expressed on activated clones, and the addition of neutralizing anti-TNF-alpha antibody did not abrogate IgE synthesis. These results therefore suggest the involvement of T cell surface molecules other than CD40L in the induction of IgE synthesis, and that these molecules may also be implicated in other aspects of T-B cell interactions.
Systemic Treatment with Tetra-<i>O</i>-Methyl Nordihydroguaiaretic Acid Suppresses the Growth of Human Xenograft Tumors
Authors: Richard Park, Chih-Chuan Chang, Yu-Chuan Liang, Yousun Chung, Ryan A. Henry, Elaine Lin, David E. Mold, Ru Chih C. Huang
Journal: Clinical Cancer Research (2005)

Abstract Purpose: We have previously shown that the transcriptional inhibitor tetra-O-methyl nordihydroguaiaretic acid (M4N) induces growth arrest in tumor cells and exhibits tumoricidal activity when injected intratumorally into tumor cell explants in mice. The experiments reported here were designed to determine whether M4N can be given systemically and inhibit the growth of five different human xenograft tumors. Experimental Design: Nude (nu/nu) mice bearing xenografts of each of five human tumor types (i.e., hepatocellular carcinoma, Hep 3B; prostate carcinoma, LNCaP; colorectal carcinoma, HT-29; breast carcinoma, MCF7; and erythroleukemia, K-562) were treated with M4N given i.v. or i.p. in a Cremophor EL–based solvent system or orally in a corn oil based diet. Tumors from the treated animals were measured weekly and analyzed for the expression of the Cdc2 and survivin genes, both previously shown to be down-regulated by M4N. Results: Systemic M4N treatment suppressed the in vivo growth of xenografts in each of the five human tumor types. Four of the five tumor models were particularly sensitive to M4N with tumor growth inhibitions (T/C values) of ≤42%, whereas the fifth, HT-29, responded to a lesser extent (48.3%). Growth arrest and apoptosis in both the xenograft tumors and in the tumor cells grown in culture were accompanied by reductions in both Cdc2 and tumor-specific survivin gene expression. Pharmacokinetic analysis following oral and i.v. administration to ICR mice indicated an absolute bioavailability for oral M4N of ∼88%. Minimal drug-related toxicity was observed. Conclusion: These preclinical studies establish that when given systemically, M4N can safely and effectively inhibit the growth of human tumors in nude mice.