tbuckley/cabot-search huggingface dataset:
Linkage to nodal osteoarthritis: quantitative and qualitative analyses of data from a whole-genome screen identify trait-dependent susceptibility loci
Authors: C Greig, K Spreckley, R Aspinwall, E Gillaspy, M Grant, W Ollier, S John, M Doherty, G Wallis
Journal: Annals of the Rheumatic Diseases (2006)

<b>Objective:</b> To identify susceptibility loci for nodal osteoarthritis. <b>Methods:</b> A genome screen at an average marker spacing of 9.29 cM was carried out on 558 people from 202 families, of whom 491 had nodal osteoarthritis. All genotyped people were graded for the incidence and severity of distal interphalangeal (DIP) nodes, and radiographs from 354 people were graded for joint-space narrowing (JSN) and osteophytes (OSTs). Age-regressed indices for DIP nodes, JSN and OSTs were calculated using these phenotypic data. Affected sibling pair (ASP) and quantitative trait analyses were carried out using MERLIN. <b>Results:</b> The data analysis identified suggestive linkage to loci on chromosomes 3 (for JSN and OST), 4 (for JSN), 8 (for DIP), 11 (for radiographic osteoarthritis) and 16 (for JSN). Both the ASP and quantitative analyses identified the loci on chromosomes 4 and 11. The loci on chromosomes 3 and 16 overlap with those previously identified for large-joint osteoarthritis. Of the loci identified by the quantitative analyses with the logarithm of the odds of linkage &gt;1.5, two were linked to more than one trait, whereas nine were linked to single traits: one for DIP, six for JSN and two for OST. <b>Conclusion:</b> The ASP and quantitative analyses of the cohort with nodal osteoarthritis suggest that multiple susceptibility loci for osteoarthritis influence the traits, which combine to form the osteoarthritis phenotype, and that these loci may not act exclusively on the joints of the hand.
Phase I Trial of Systemic Oxaliplatin Combination Chemotherapy With Hepatic Arterial Infusion in Patients With Unresectable Liver Metastases From Colorectal Cancer
Authors: Nancy Kemeny, William Jarnagin, Philip Paty, Mithat Gönen, Lawrence Schwartz, Meroë Morse, Gregory Leonard, Michael D’Angelica, Ronald DeMatteo, Leslie Blumgart, Yuman Fong
Journal: Journal of Clinical Oncology (2005)

Purpose To determine the maximum-tolerated dose (MTD) of concurrent systemic oxaliplatin (Oxal) combinations plus hepatic arterial infusion (HAI) in patients with unresectable hepatic metastases from colorectal cancer. Patients and Methods Thirty-six patients (89% previously treated) with unresectable liver metastases were treated with concurrent HAI and systemic Oxal plus irinotecan (CPT-11; group A) or Oxal, fluorouracil (FU), and leucovorin (LV; group B). Systemic chemotherapy was administered every 2 weeks concurrent with 2 weeks of HAI floxuridine (FUDR) and dexamethasone (Dex) every 28 days. Results The MTD for patients in group A was Oxal 100 mg/m 2 , CPT-11 150 mg/m 2 , and FUDR 0.12 mg/kg × 30 mL divided by pump flow rate. The MTD for group B was Oxal 100 mg/m 2 , LV 400 mg/m 2 , and FU 1,400 mg/m 2 by continuous infusion over 48 hours, with the same FUDR dose as in group A. Grade 3 or 4 toxicities in groups A and B included diarrhea (24% and 20%), neutropenia (10% and 7%), neurotoxicity (24% and 20%), and bilirubin more than 3 mg/mL (5% and 7%, respectively). The complete and partial response rate totaled 90% for group A and 87% for group B. Median survival time was 36 and 22 months for groups A and B, respectively. Seven patients in group A were ultimately able to undergo liver resection. Conclusion Combination therapy with HAI FUDR and Dex plus systemic Oxal combinations may be safely administered to patients with colorectal cancer. The high response rate (88%) and the possibility of conversion to resectability, despite disease progression on prior systemic regimens, suggest that these combinations should be evaluated in larger studies as first- or second-line therapy in patients with hepatic metastases from colorectal cancer.
Modeling Morphogenesis and Oncogenesis in Three-Dimensional Breast Epithelial Cultures
Authors: Christy Hebner, Valerie M. Weaver, Jayanta Debnath
Journal: Annual Review of Pathology Mechanisms of Disease (2008)

Three-dimensional (3D) epithelial culture systems recreate the cardinal features of glandular epithelium in vivo and represent a valuable tool for modeling breast cancer initiation and progression in a structurally appropriate context. 3D models have emerged as a powerful method to interrogate the biological activities of cancer genes and oncogenic pathways, and recent studies have poignantly illustrated their utility in dissecting the emerging role of tensional force in regulating epithelial tissue homeostasis. We review how 3D models are being used to investigate fundamental cellular and biophysical mechanisms associated with breast cancer progression that have not been readily amenable to traditional genetic or biochemical analysis.
Depletion of Endothelial Progenitor Cells in the Peripheral Blood of Patients With Rheumatoid Arthritis
Authors: Johannes Grisar, Daniel Aletaha, Carl W. Steiner, Theresa Kapral, Sabine Steiner, Daniela Seidinger, Günter Weigel, Ilse Schwarzinger, Wolfgang Wolozcszuk, Günter Steiner, Josef S. Smolen
Journal: Circulation (2005)

Rheumatoid arthritis (RA) is characterized by increased cardiovascular morbidity and mortality that cannot be explained solely by traditional cardiovascular risk factors. Cardiovascular morbidity is related to disease activity and can be normalized by effective therapy. Because the quantity of endothelial progenitor cells (EPCs) in the peripheral blood is correlated inversely with cardiovascular risk, we studied whether such abnormalities could also be observed in patients with RA.EPCs were determined in 52 RA patients and in 16 healthy referents (HRs) by fluorescence-activated cell-sorting (FACS) analysis. Patients were divided into groups characterized by active disease (n=36) and low disease activity (n=16). Cells that were positive by flow cytometry for CD34/KDR/AC133 within the lymphocyte population were characterized as EPCs. Furthermore, in subgroups of patients, circulating EPCs were also quantified by a colony-forming unit (CFU) and a circulating angiogenic cell (CAC) assay. EPCs were significantly decreased in RA patients suffering from active disease compared with those from HRs, as measured by FACS analysis (0.026+/-0.002% versus 0.045+/-0.008%, respectively, P<0.05), CFU assay (mean of 5+/-2 versus 18+/-5 CFU/well in HRs, P<0.05), and CAC assay (mean of 7+/-2 versus 52+/-16 positive cells/high-power field, P<0.005). In contrast, the frequency of circulating EPCs from patients with low disease activity was comparable to that of healthy individuals (0.052+/-0.006% by FACS analysis), CFU assay (10+/-5 CFU/well), and CAC assay (mean of 25+/-5 positive cells). Moreover, EPC quantities in peripheral blood were correlated inversely with disease activity as assessed by the disease activity score (r=-0.38, P<0.01).Our observations indicate that active RA is associated with a depletion of circulating EPCs. This might be one of several factors contributing to the increased cardiovascular risk in RA.
Apoptotic Sensitivity of Colon Cancer Cells to Histone Deacetylase Inhibitors Is Mediated by an Sp1/Sp3-Activated Transcriptional Program Involving Immediate-Early Gene Induction
Authors: Andrew J. Wilson, Anderly C. Chueh, Lars Tögel, Georgia A. Corner, Naseem Ahmed, Sanjay Goel, Do-Sun Byun, Shannon Nasser, Michele A. Houston, Minaxi Jhawer, Helena J.M. Smartt, Lucas B. Murray, Courtney Nicholas, Barbara G. Heerdt, Diego Arango, Leonard H. Augenlicht, John M. Mariadason
Journal: Cancer Research (2010)

Abstract Histone deacetylase inhibitors (HDACi) induce growth arrest and apoptosis in colon cancer cells and are being considered for colon cancer therapy. The underlying mechanism of action of these effects is poorly defined with both transcription-dependent and -independent mechanisms implicated. We screened a panel of 30 colon cancer cell lines for sensitivity to HDACi-induced apoptosis and correlated the differences with gene expression patterns induced by HDACi in the five most sensitive and resistant lines. A robust and reproducible transcriptional response involving coordinate induction of multiple immediate-early (fos, jun, egr1, egr3, atf3, arc, nr4a1) and stress response genes (Ndrg4, Mt1B, Mt1E, Mt1F, Mt1H) was selectively induced in HDACi sensitive cells. Notably, a significant percentage of these genes were basally repressed in colon tumors. Bioinformatics analysis revealed that the promoter regions of the HDACi-induced genes were enriched for KLF4/Sp1/Sp3 transcription factor binding sites. Altering KLF4 levels failed to modulate apoptosis or transcriptional responses to HDACi treatment. In contrast, HDACi preferentially stimulated the activity of Spl/Sp3 and blocking their action attenuated both the transcriptional and apoptotic responses to HDACi treatment. Our findings link HDACi-induced apoptosis to activation of a Spl/Sp3-mediated response that involves derepression of a transcriptional network basally repressed in colon cancer. Cancer Res; 70(2); 609–20
Novel Use of Glucagon in a Closed-Loop System for Prevention of Hypoglycemia in Type 1 Diabetes
Authors: Jessica R. Castle, Julia M. Engle, Joseph El Youssef, Ryan G. Massoud, Kevin C.J. Yuen, Ryland Kagan, W. Kenneth Ward
Journal: Diabetes Care (2010)

OBJECTIVE To minimize hypoglycemia in subjects with type 1 diabetes by automated glucagon delivery in a closed-loop insulin delivery system. RESEARCH DESIGN AND METHODS Adult subjects with type 1 diabetes underwent one closed-loop study with insulin plus placebo and one study with insulin plus glucagon, given at times of impending hypoglycemia. Seven subjects received glucagon using high-gain parameters, and six subjects received glucagon in a more prolonged manner using low-gain parameters. Blood glucose levels were measured every 10 min and insulin and glucagon infusions were adjusted every 5 min. All subjects received a portion of their usual premeal insulin after meal announcement. RESULTS Automated glucagon plus insulin delivery, compared with placebo plus insulin, significantly reduced time spent in the hypoglycemic range (15 ± 6 vs. 40 ± 10 min/day, P = 0.04). Compared with placebo, high-gain glucagon delivery reduced the frequency of hypoglycemic events (1.0 ± 0.6 vs. 2.1 ± 0.6 events/day, P = 0.01) and the need for carbohydrate treatment (1.4 ± 0.8 vs. 4.0 ± 1.4 treatments/day, P = 0.01). Glucagon given with low-gain parameters did not significantly reduce hypoglycemic event frequency (P = NS) but did reduce frequency of carbohydrate treatment (P = 0.05). CONCLUSIONS During closed-loop treatment in subjects with type 1 diabetes, high-gain pulses of glucagon decreased the frequency of hypoglycemia. Larger and longer-term studies will be required to assess the effect of ongoing glucagon treatment on overall glycemic control.
Comment on: ‘Spondyloarthritis: may the force be with you?’, the Editorial by McGonagle<i>et al</i>
Authors: Leonie van Duivenvoorde, Dominique Baeten
Journal: Annals of the Rheumatic Diseases (2014)

We read with great interest the editorial by McGonagle et al 1 on the recent study by Jacques et al. 2 Jacques et al describe a series of elegant experiments in TNFΔARE mice demonstrating that mechanical unloading by tail suspension alleviates peripheral arthritis and explore the molecular mechanisms underlying this phenomenon.

McGonagle et al begin their editorial by stating that Jacques et al demonstrated that experimental spondyloarthritis (SpA) might be a biomechanically triggered process. This conclusion is surprising as Jacques et al did not perform any experiments supporting this suggestion. On the contrary, their experiments used the opposite approach and indicated that mechanical unloading alleviates tumour necrosis factor (TNF)-induced arthritis. This is emphasised …
Elevated carboxy terminal cross linked telopeptide of type I collagen in alcoholic cirrhosis: relation to liver and kidney function and bone metabolism
Authors: S Møller, M Hansen, J Hillingsø, J-E B Jensen, J H Henriksen
Journal: Gut (1999)

The carboxy terminal cross linked telopeptide of type I collagen (ICTP) has been put forward as a marker of bone resorption. Patients with alcoholic liver disease may have osteodystrophy.To assess circulating and regional concentrations of ICTP in relation to liver dysfunction, bone metabolism, and fibrosis.In 15 patients with alcoholic cirrhosis and 20 controls, hepatic venous, renal venous, and femoral arterial concentrations of ICTP, and bone mass and metabolism were measured.Circulating ICTP was higher in patients with cirrhosis than in controls. No overall significant hepatic disposal or production was found in the patient or control groups but slightly increased production was found in a subset of patients with advanced disease. Significant renal extraction was observed in the controls, whereas only a borderline significant extraction was observed in the patients. Measurements of bone mass and metabolism indicated only a mild degree of osteodystrophy in the patients with cirrhosis. ICTP correlated significantly in the cirrhotic patients with hepatic and renal dysfunction and fibrosis, but not with measurements of bone mass or metabolism.ICTP is highly elevated in patients with cirrhosis, with no detectable hepatic net production or disposal. No relation between ICTP and markers of bone metabolism was identified, but there was a relation to indicators of liver dysfunction and fibrosis. As the cirrhotic patients conceivably only had mild osteopenia, the elevated ICTP in cirrhosis may therefore primarily reflect liver failure and hepatic fibrosis.
Small Molecule XIAP Inhibitors Enhance TRAIL-Induced Apoptosis and Antitumor Activity in Preclinical Models of Pancreatic Carcinoma
Authors: Meike Vogler, Henning Walczak, Dominic Stadel, Tobias L. Haas, Felicitas Genze, Marjana Jovanovic, Umesh Bhanot, Cornelia Hasel, Peter Möller, Jürgen E. Gschwend, Thomas Simmet, Klaus-Michael Debatin, Simone Fulda
Journal: Cancer Research (2009)

Evasion of apoptosis is a characteristic feature of pancreatic cancer, a prototypic cancer that is refractory to current treatment approaches. Hence, there is an urgent need to design rational strategies that counter apoptosis resistance. To explore X-linked inhibitor of apoptosis (XIAP) as a therapeutic target in pancreatic cancer, we analyzed the expression of XIAP in pancreatic tumor samples and evaluated the effect of small molecule XIAP inhibitors alone and in combination with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) against pancreatic carcinoma in vitro and in vivo. Here, we report that XIAP is highly expressed in pancreatic adenocarcinoma samples compared with normal pancreatic ducts. Small molecule XIAP inhibitors synergize with TRAIL to induce apoptosis and to inhibit long-term clonogenic survival of pancreatic carcinoma cells. In contrast, they do not reverse the lack of toxicity of TRAIL on nonmalignant cells in vitro or normal tissues in vivo, pointing to a therapeutic index. Most importantly, XIAP inhibitors cooperate with TRAIL to trigger apoptosis and suppress pancreatic carcinoma growth in vivo in two preclinical models, i.e., the chorioallantoic membrane model and a mouse xenograft model. Parallel immunohistochemical analysis of tumor tissue under therapy reveals that the XIAP inhibitor acts in concert with TRAIL to cause caspase-3 activation and apoptosis. In conclusion, our findings provide, for the first time, evidence in vivo that XIAP inhibitors prime pancreatic carcinoma cells for TRAIL-induced apoptosis and potentiate the antitumor activity of TRAIL against established pancreatic carcinoma. These findings build the rationale for further (pre)clinical development of XIAP inhibitors and TRAIL against pancreatic cancer.
Polypharmacy in patients hospitalised for acute exacerbation of COPD
Authors: Jesús Díez-Manglano, José Barquero-Romero, Pedro Almagro Mena, Jesús Recio-Iglesias, Javier Cabrera-Aguilar, Francisco López-García, Ramón Boixeda Viu, Joan B. Soriano
Journal: European Respiratory Journal (2014)

To the Editor: 

Chronic obstructive pulmonary disease (COPD) imposes a great burden on health systems, and the expense will increase in the years to come [1]. Medication represents a large proportion of COPD-related costs [2], and has increased by 170% over the past 20 years [3]. Inpatients with an acute exacerbation of COPD and more than four diagnoses after admission are prescribed significantly more drugs and present with polypharmacy more frequently [4]. It is well known that polypharmacy is associated with greater occurrence of adverse effects [5] and worse treatment adherence [6]. It also contributes to greater healthcare expense [7].

This study seeks to determine the prevalence of polypharmacy in patients hospitalised with an acute exacerbation of COPD, as well as the factors associated with its occurrence.

The ECCO study is an observational, cross-sectional and multicentre study, with participation from 26 Internal Medicine Departments throughout Spain. Detailed features of the study have been reported elsewhere [8]. Each researcher included, consecutively, every patient admitted for an acute exacerbation of COPD they attended between January 1, 2007 and December 31, 2008. COPD was diagnosed using spirometry [9] in a stable condition prior to admission. Information gathered included age, sex, smoking history, previous admissions for COPD and number of acute exacerbations of COPD over the previous 12 months. The Charlson index was used to assess associated comorbidities, but other conditions prevalent in COPD not included in that index were also noted. Basal dyspnoea prior to admission was assessed using the modified (five point) Medical Research Council (mMRC) scale. Polypharmacy was defined as the chronic concurrent use, more than 3 …
PCPH/ENTPD5 Expression Enhances the Invasiveness of Human Prostate Cancer Cells by a Protein Kinase Cδ–Dependent Mechanism
Authors: Joaquín Villar, María Isabel Arenas, Caitlin M. MacCarthy, María José Blánquez, Oscar M. Tirado, Vicente Notario
Journal: Cancer Research (2007)

Abstract Previous reports showed that PCPH is mutated or deregulated in some human tumors, suggesting its participation in malignant progression. Immunohistochemical analyses showed that PCPH is not expressed in normal prostate, but its expression increases along cancer progression stages, being detectable in benign prostatic hyperplasia, highly expressed in prostatic intraepithelial neoplasia, and remaining at high levels in prostate carcinoma. Experiments designed to investigate the contribution of PCPH to the malignant phenotype of prostate cancer cells showed that PCPH overexpression in PC-3 cells, which express nearly undetectable PCPH levels, increased collagen I expression and enhanced invasiveness, whereas shRNA-mediated PCPH knockdown in LNCaP cells, which express high PCPH levels, down-regulated collagen I expression and decreased invasiveness. PCPH regulated invasiveness and collagen I expression by a mechanism involving protein kinase Cδ (PKCδ): (a) PCPH knockdown in LNCaP cells decreased PKCδ levels relative to control cells; (b) PKCδ knockdown in LNCaP cells recapitulated all changes caused by PCPH knockdown; and (c) forced expression of PKCδ in cells with knocked down PCPH reverted all changes provoked by PCPH down-regulation and rescued the original phenotype of LNCaP cells. These results strongly suggested that the expression level and/or mutational status of PCPH contributes to determine the invasiveness of prostate cancer cells through a mechanism involving PKCδ. Data from immunohistochemical analyses in serial sections of normal, premalignant, and malignant prostate specimens underscored the clinical significance of our findings by showing remarkably similar patterns of expression for PCPH and PKCδ, thus strongly suggesting their likely coregulation in human tumors. [Cancer Res 2007;67(22):10859–68]
C–C Chemokines Released by Lipopolysaccharide (LPS)-stimulated Human Macrophages Suppress HIV-1 Infection in Both Macrophages and T Cells
Authors: Alessia Verani, Gabriella Scarlatti, Manola Comar, Eleonora Tresoldi, Simona Polo, Mauro Giacca, Paolo Lusso, Antonio G. Siccardi, Donata Vercelli
Journal: The Journal of Experimental Medicine (1997)

Human immunodeficiency virus-1 (HIV-1) expression in monocyte-derived macrophages (MDM) infected in vitro is known to be inhibited by lipopolysaccharide (LPS). However, the mechanisms are incompletely understood. We show here that HIV-1 suppression is mediated by soluble factors released by MDM stimulated with physiologically significant concentrations of LPS. LPS-conditioned supernatants from MDM inhibited HIV-1 replication in both MDM and T cells. Depletion of C–C chemokines (RANTES, MIP-1α, and MIP-1β) neutralized the ability of LPS-conditioned supernatants to inhibit HIV-1 replication in MDM. A combination of recombinant C–C chemokines blocked HIV-1 infection as effectively as LPS. Here, we report an inhibitory effect of C–C chemokines on HIV replication in primary macrophages. Our results raise the possibility that monocytes may play a dual role in HIV infection: while representing a reservoir for the virus, they may contribute to the containment of the infection by releasing factors that suppress HIV replication not only in monocytes but also in T lymphocytes.
Effect of ICS 205-930 (a specific 5-HT3 receptor antagonist) on gastric emptying of a solid meal in normal subjects.
Authors: L M Akkermans, A Vos, A Hoekstra, J M Roelofs, M Horowitz
Journal: Gut (1988)

The effects on gastric emptying of a solid meal of the specific 5-HT3-receptor antagonist ICS 205-930, 10 mg and 20 mg intravenously were assessed with a scintigraphic technique in 12 normals. The 50% emptying time was less, the lag phase was shorter and the post lag emptying rate was faster after 20 mg ICS 205-930 (p less than 0.02). After 10 mg ICS 205-930 the lag phase was significantly shorter compared with placebo (p less than 0.04). These results suggest that 5-HT3 receptors may be involved in the regulation of gastric emptying in man.
Absorption of propranolol and practolol in Coeliac disease.
Authors: R L Parsons, C M Kaye, K Raymond, J R Trounce, P Turner
Journal: Gut (1976)

Plasma concentrations of propranolol and practolol were measured in patients with coeliac disease and normal subjects. The mean plasma propranolol concentration in the coeliac patients was higher throughout the period of study, the differences being significant at one, six, and eight hours. The plasma concentration profile of practolol in the coeliacs followed a similar pattern but lagged behind that of the normal subjects. A possible reason for these differences is an alteration in the rate of drug diffusion across the atrophic mucosa of the upper jejunum in coeliac disease. Analysis of the results of the propranolol study suggests that an increase in the rate of absorption combined with saturation of first pass extraction may account for the increased plasma concentrations of unchanged propranolol found in coeliac disease. These abnormalities of drug absorption do not appear to be related to the duration of treatment with a gluten free diet.