tbuckley/cabot-search huggingface dataset:
Does ispaghula husk stimulate the entire colon in diverticular disease?
Authors: H A Thorburn, K B Carter, J A Goldberg, I G Finlay
Journal: Gut (1992)

The effect of ispaghula husk on colonic motility of the right and left side was examined in 10 patients with left sided diverticular disease using an untethered pressure sensitive radiotelemetry capsule. After treatment, ispaghula husk reduced mouth to rectum transit by a median of 8.8 hours and the time to midtransverse colon by five hours. In the right colon there was an increase in the median percentage activity of 7% and the median number of pressure waves greater than 5 mm Hg/hour rose by 35.3. Motility changes in the left colon were less pronounced. Five of the seven patients with abdominal pain and six of the nine patients with altered bowel habit responded to treatment. These results suggest that it is ispaghula husk9s action on the right unaffected colon which alleviates the symptoms of left sided diverticular disease.
TL1A–DR3 interaction regulates Th17 cell function and Th17-mediated autoimmune disease
Authors: Bhanu P. Pappu, Anna Borodovsky, Timothy S. Zheng, Xuexian Yang, Ping Wu, Xingwen Dong, Shawn Weng, Beth Browning, Martin L. Scott, Li Ma, Lihe Su, Qiang Tian, Pascal Schneider, Richard A. Flavell, Chen Dong, Linda C. Burkly
Journal: The Journal of Experimental Medicine (2008)

T helper type 17 (Th17) cells play an important pathogenic function in autoimmune diseases; their regulation, however, is not well understood. We show that the expression of a tumor necrosis factor receptor family member, death receptor 3 (DR3; also known as TNFRSF25), is selectively elevated in Th17 cells, and that TL1A, its cognate ligand, can promote the proliferation of effector Th17 cells. To further investigate the role of the TL1A–DR3 pathway in Th17 regulation, we generated a TL1A-deficient mouse and found that TL1A−/− dendritic cells exhibited a reduced capacity in supporting Th17 differentiation and proliferation. Consistent with these data, TL1A−/− animals displayed decreased clinical severity in experimental autoimmune encephalomyelitis (EAE). Finally, we demonstrated that during EAE disease progression, TL1A was required for the optimal differentiation as well as effector function of Th17 cells. These observations thus establish an important role of the TL1A–DR3 pathway in promoting Th17 cell function and Th17-mediated autoimmune disease.
Calpain-I induced alterations in the cytoskeletal structure and impaired mechanical properties of single myocytes of rat heart
Authors: Z Papp
Journal: Cardiovascular Research (2000)

Objective: The involvement of Calpain-I mediated proteolysis has been implicated in myofibrillar dysfunction of reperfused myocardium following ischemia (stunning). This study addresses the question whether ultrastructural alterations might be responsible for the depressed contractility. Methods: Mechanical properties and protein composition of isolated myocytes after Calpain-I exposure (1.25 U/ml; 10 min; 15°C; pCa 5.0) and of ischemic rat hearts following reperfusion were characterized. Results: Maximal isometric force (44±5 kN/m2) at pCa 4.5 (pCa=−log[Ca2+]) decreased by 42.5% in Triton permeabilized myocytes (n=11) after Calpain-I treatment. Force (and consequent myofilament disarrangement) during Calpain-I treatment was prevented by 40 mM BDM. The contractile force of Calpain-I exposed myocytes was significantly higher at submaximal levels of activation (pCa 5.5, 5.4 and 5.3) before maximal force development (pCa 4.5) than after maximal force development. The pCa50 value (5.40±0.02) determined from these initial test contractures did not differ significantly from that of untreated controls (5.44±0.03). However, after full activation Ca2+-sensitivity of force production in Calpain-I treated myocytes was significantly reduced (pCa50 5.34±0.02). This change in pCa50 was positively correlated with the reduction in maximal isometric force and was accompanied by sarcomere disorder. These findings imply that at least part of the Calpain-I induced mechanical alterations are dependent on force history. Measurements of the rate of force redevelopment after unloaded shortening suggested that Calpain-I did not affect cross-bridge kinetics. SDS gel electrophoresis and Western immunoblotting of Calpain-I treated myocytes revealed desmin degradation. The desmin content of postischemic myocardium was also reduced. Conclusion: Our results indicate that ultrastructural alterations may play an important role in the Calpain-I mediated cardiac dysfunction.
MEDICINE IN NORTHERN IRELAND
Authors: S.D. Clarke, J. Cleland, C.A. Gleadhill, D.S. Gordon, J.W.S. Irwin, G.W. Johnston, T. Kennedy, R.H. Livingston, J.H. Lowry, P.J. Molloy, E. Morrison, H.W. Rodgers, T.B. Smiley, H.M. Stevenson, R.I. Wilson, W. Wilson, J.A. Weaver, John Andress, J.D.A. Robb
Journal: The Lancet (1972)
Supported employment: cost‐effectiveness across six European sites
Authors: Martin Knapp, Anita Patel, Claire Curran, Eric Latimer, Jocelyn Catty, Thomas Becker, Robert E. Drake, Angelo Fioritti, Reinhold Kilian, Christoph Lauber, Wulf Rössler, Toma Tomov, Jooske van Busschbach, Adelina Comas‐Herrera, Sarah White, Durk Wiersma, Tom Burns
Journal: World Psychiatry (2013)

A high proportion of people with severe mental health problems are unemployed but would like to work. Individual Placement and Support (IPS) offers a promising approach to establishing people in paid employment. In a randomized controlled trial across six European countries, we investigated the economic case for IPS for people with severe mental health problems compared to standard vocational rehabilitation. Individuals (n=312) were randomized to receive either IPS or standard vocational services and followed for 18 months. Service use and outcome data were collected. Cost-effectiveness analysis was conducted with two primary outcomes: additional days worked in competitive settings and additional percentage of individuals who worked at least 1 day. Analyses distinguished country effects. A partial cost-benefit analysis was also conducted. IPS produced better outcomes than alternative vocational services at lower cost overall to the health and social care systems. This pattern also held in disaggregated analyses for five of the six European sites. The inclusion of imputed values for missing cost data supported these findings. IPS would be viewed as more cost-effective than standard vocational services. Further analysis demonstrated cost-benefit arguments for IPS. Compared to standard vocational rehabilitation services, IPS is, therefore, probably cost-saving and almost certainly more cost-effective as a way to help people with severe mental health problems into competitive employment.
P2-12-31: Moderate Immunohistochemical Expression of HER2 (2+) without HER2 Gene-Amplification Is a Negative Prognostic Factor in Early Breast Cancer.
Authors: V Rossi, I Sarotto, F Maggiorotto, Cont N Tomasi, S Redana, M Aglietta, R Ponzone, F Montemurro
Journal: Cancer Research (2011)

Abstract Purpose: We sought to evaluate whether moderate HER2 immunohistochemical (IHC) expression (2+ and no HER2/amplification) identifies early breast cancer (EBC) with a distinct prognostic profile. Methods: A total of 1295 women (median age 58, range 22–94) undergoing surgery for EBC from Jan 1995 to Sept 2009 were retrospectively reviewed. All patients had undergone HER2 testing by the HercepTest and, when needed, by fluorescence in-situ hybridization (FISH). All tests were carried on at our Institutional Surgical Pathology laboratory. The impact of HER2 status on disease-free survival (DFS) was corrected for other clinical and pathological potential covariates by Cox Proportional Regression Analysis. Results: A total of 494 (38%), 486 (38%), 119 (9%) and 196 (15%) of the patients had HER2 0+, 1+ 2+ and positive (3+ or FISH+) tumors, respectively. Sixty-one of 196 patients with HER2−positive EBC received adjuvant trastuzumab. A total of 298 DFS events occurred at median follow-up of 59 months (4-137 months). By using HER2 0+ status as reference, multivariate analysis revealed that HER2 2+ expression was associated with a significant increase in the risk of a DFS event (HR 2.303, 95% C.I. 1.501−3.533, p&amp;lt;0.001), whereas HER2 1+ was not (HR 0.976, 95% C.I. 0.698−1.365, p=0.889). We performed exploratory two-group comparisons by further classifying tumors according to hormone-receptor status (cutoff for ER and PgR positivity ≥10% of stained cells). Results are summarized in the table. HER2 2+ expression was associated with worse prognosis in both ER and/or PgR positive and ER/PgR negative tumors. In the latter group, HER2 2+ expression was associated with a particularly high rate of DFS events, with a 60-month projected DFS of 20%. Furthermore, while DFS curves plateaued at 60 months for HER2−positive tumors (with and without adjuvant trastuzumab) and for ER/PgR negative tumors with HER2 0/1+ expression, hormone receptor positive/HER2 2+ tumors displayed a particularly high rate of late relapses (beyond 60 months). Results did not change using a 1% cutoff to define ER and PgR positivity. Conclusion: Moderate HER2 positivity (IHC 2+/FISH negative) identifies EBC patients at increased risk of a DFS event, regardless of hormone receptor status. Due to suggestions from large randomized trials that the benefits of trastuzumab may not be limited to HER2−positive tumors, patients with HER2 2+ EBC are ideal candidates for studies testing this hypothesis. Multivariate Hazard Ratios, corrected by age, lymph-node status, tumor diameter, tumor grade, proliferation (Ki 67 index) and receipt of adjuvant chemotherapy Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-12-31.
Acute pyelonephritis and renal scarring are caused by dysfunctional innate immunity in mCxcr2 heterozygous mice
Authors: Majlis Svensson, Manisha Yadav, Bo Holmqvist, Nataliya Lutay, Catharina Svanborg, Gabriela Godaly
Journal: Kidney International (2011)

The CXCR1 receptor and chemokine CXCL8 (IL-8) support neutrophil-dependent clearance of uropathogenic Escherichia coli from the urinary tract. CXCR1 is reduced in children prone to pyelonephritis, and heterozygous hCXCR1 polymorphisms are more common in this patient group than in healthy individuals, strongly suggesting a disease association. Since murine CXCR2 (mCXCR2) is functionally similar to human CXCR1, we determined effects of gene heterozygosity on the susceptibility to urinary tract infection by infecting heterozygous (mCxcr2(+/-)) mice with uropathogenic Escherichia coli. Clearance of infection and tissue damage were assessed as a function of innate immunity in comparison to that in knockout (mCxcr2(-/-)) and wild-type (mCxcr2(+/+)) mice. Acute sepsis-associated mortality was increased and bacterial clearance drastically impaired in heterozygous compared to wild-type mice. Chemokine and neutrophil responses were delayed along with evidence of neutrophil retention and unresolved kidney inflammation 1 month after infection. This was accompanied by epithelial proliferation and subepithelial fibrosis. The heterozygous phenotype was intermediate, between knockout and wild-type mice, but specific immune cell infiltrates that accompany chronic infection in knockout mice were not found. Hence, the known heterozygous CXCR1 polymorphisms may predispose patients to acute pyelonephritis and urosepsis.
Fatal Infusion Reactions to Cetuximab: Role of Immunoglobulin E–Mediated Anaphylaxis
Authors: Yoann Pointreau, Scott P. Commins, Gilles Calais, Hervé Watier, Thomas A.E. Platts-Mills
Journal: Journal of Clinical Oncology (2011)

report a fatal hypersensitivity reaction to cetuximab in a 63-year-old patient with metastatic colon cancer and outlined a 0.1% incidence of death in the literature. We greatly acknowledge the authors’ desire to communicate the risk of fatal anaphylactic reaction with cetuximab. Over the past 2 years in our center in Tours, France, four instances of grade 4 anaphylactic reactions occurred in patients treated for head and neck cancer (locally advanced or metastatic), with one immediately fatal; another patient died within 5 days (unpublished data). Seven lethal anaphylactic reactions were registered in a pharmacovigilance survey in France, based on spontaneous declarations (Grandvuillemin et al, manuscript in preparation). Anaphylaxis to cetuximab is a problem that merits serious clinical attention. In the authors’ words, “the pathogenic mechanisms underlying the development of this phenomenon remain to be elucidated.” 1 They raise the hypothesis of immunoglobulin E (IgE) –independent mechanisms, even in the context of a paradoxic atopic history. Moreover, Tronconi et al suggest that the field “search for reliable risk factors that can facilitate the safe selection of patients as candidates for cetuximabbased treatment.” 1 These comments are quite surprising, because they do not integrate major contributions that have been previously published. Indeed, it has been known for 3 years that anaphylaxis to cetuximab is the result of antidrug IgE antibodies present in patient serum before therapy. 2 These IgE antibodies are directed against galactose--1, 3-galactose (3Gal) residues, present in the Fab portion of this monoclonal antibody. 3 Because humans do not express this glycan, anti3Gal IgM and IgG antibodies spontaneously develop, whereas the appearance of IgE is only occasional. The observation that most of the patients developed reactions to cetuximab during their first infusion supports this hypothesis and is consistent with an IgE-mediated event. Environmental factors, such as bites by ectoparasitic ticks, probably explain the heterogeneous proportion of individuals displaying anti3Gal IgE and the heterogeneous incidence of anaphylactic reactions to cetuximab among studies and geographic areas. 2,4-6 History of atopy, age, race, additional therapy (ie, chemotherapy or radiotherapy), sex, and head and neck cancer (rather than colorectal cancer) have also been proposed as factors favoring anaphylaxis to cetuximab, but they remain controversial. 2,4,5
Children with mild asthma: do they benefit from inhaled corticosteroids?
Authors: H.G.M. Arets, A.W.A. Kamps, H.J.L. Brackel, P.G.H. Mulder, N.A. Vermue, C.K. van der Ent
Journal: European Respiratory Journal (2002)

In children with mild asthma, who show hardly any abnormalities in pulmonary function, objective measurement of the effect of inhaled corticosteroids is difficult. The short term effect of fluticasone propionate (FP) in these children was evaluated, using both subjective and objective parameters. A total of 68 children (5–10 yrs old) were randomly assigned to either FP 250 µg or placebo twice daily as metered-dose inhaler via spacer during 12 weeks. Symptom scores, use of rescue medication, wheezing, parent global evaluation and pulmonary function tests including forced expiratory volume in one second (FEV 1 ), peak expiratory flow (PEF) and bronchial responsiveness (provocation dose of methacholine causing a 20% fall in FEV 1 (PD 20 )) were evaluated. FP-treated versus placebo-treated children showed significant changes in percentage symptom-free days, use of β 2 -mimetics, morning and evening PEF, FEV 1 % pred and wheezing. No significant improvements were found in parent global evaluation, absolute values of FEV 1 nor PD 20 . These findings show that inhaled corticosteroids are effective in children with mild asthma. This effect can be assessed by both objective and subjective parameters. Early start of inhaled corticosteroids should be considered even when pulmonary function is normal.
Increased hyaluronic acid content in idiopathic pulmonary arterial hypertension
Authors: E. Papakonstantinou, F. M. Kouri, G. Karakiulakis, I. Klagas, O. Eickelberg
Journal: European Respiratory Journal (2008)

Idiopathic pulmonary arterial hypertension (IPAH) is a fatal disease characterised by elevated blood pressure in the pulmonary circulation. Initial vasoconstriction, proliferation of pulmonary arterial smooth muscle cells (PASMC) and increased deposition of extracellular matrix (ECM) contribute to pathological remodelling of pulmonary arterioles in IPAH. Glycosaminoglycans (GAGs), components of the ECM, control cellular proliferation and differentiation, but their expression in IPAH remains elusive. In the present study, GAG expression was investigated in the lungs of patients with IPAH or control transplant donors, and expression and localisation of GAG-metabolising enzymes were analysed in vivo and in vitro. A significant increase in the expression of hyaluronic acid (HA) was detected in IPAH lungs, associated with increased hyaluronan synthase (Has)1 and decreased hyaluronoglucosaminidase 1 gene expression, as assessed by quantitative RT-PCR and Western blotting. HAS1 protein localised to PASMC in vivo and increased HA deposition was observed in remodelled pulmonary arteries in IPAH. Transforming growth factor-beta1, a profibrotic growth factor, led to increased HA secretion and HAS1 expression in primary PASMC. The results demonstrate an increased hyaluronic acid content in idiopathic pulmonary arterial hypertension lungs, associated with increased hyaluronan synthase 1 and decreased hyaluronoglucosaminidase 1 gene expression. Synergistic regulation of glycosaminoglycan-metabolising enzymes in favour of accumulation may, thus, regulate pathological vascular remodelling in idiopathic pulmonary arterial hypertension lungs.
Adoptive transfer of genetically modified Wilms' tumor 1–specific T cells in a novel malignant skull base meningioma model
Authors: Kenichiro Iwami, Atsushi Natsume, Masasuke Ohno, Hiroaki Ikeda, Junichi Mineno, Ikuei Nukaya, Sachiko Okamoto, Hiroshi Fujiwara, Masaki Yasukawa, Hiroshi Shiku, Toshihiko Wakabayashi
Journal: Neuro-Oncology (2013)

Meningiomas are the most commonly diagnosed primary intracranial neoplasms. Despite significant advances in modern therapies, the management of malignant meningioma and skull base meningioma remains a challenge. Thus, the development of new treatment modalities is urgently needed for these difficult-to-treat meningiomas. The goal of this study was to investigate the potential of build-in short interfering RNA-based Wilms' tumor protein (WT1)–targeted adoptive immunotherapy in a reproducible mouse model of malignant skull base meningioma that we recently established. We compared WT1 mRNA expression in human meningioma tissues and gliomas by quantitative real-time reverse-transcription polymerase chain reaction. Human malignant meningioma cells (IOMM-Lee cells) were labeled with green fluorescent protein (GFP) and implanted at the skull base of immunodeficient mice by using the postglenoid foramen injection (PGFi) technique. The animals were sacrificed at specific time points for analysis of tumor formation. Two groups of animals received adoptive immunotherapy with control peripheral blood mononuclear cells (PBMCs) or WT1-targeted PBMCs. High levels of WT1 mRNA expression were observed in many meningioma tissues and all meningioma cell lines. IOMM-Lee-GFP cells were successfully implanted using the PGFi technique, and malignant skull base meningiomas were induced in all mice. The systemically delivered WT1-targeted PBMCs infiltrated skull base meningiomas and significantly delayed tumor growth and increased survival time. We have established a reproducible mouse model of malignant skull base meningioma. WT1-targeted adoptive immunotherapy appears to be a promising approach for the treatment of difficult-to-treat meningiomas.
High-Level in Vivo Gene Marking after Gene-Modified Autologous Hematopoietic Stem Cell Transplantation without Marrow Conditioning in Nonhuman Primates
Authors: Kyoji Ueda, Yutaka Hanazono, Hiroaki Shibata, Naohide Ageyama, Yasuji Ueda, Satoko Ogata, Toshiaki Tabata, Takeyuki Nagashima, Masaaki Takatoku, Akihiko Kume, Susumu Ikehara, Masafumi Taniwaki, Keiji Terao, Mamoru Hasegawa, Keiya Ozawa
Journal: Molecular Therapy (2004)

The successful engraftment of genetically modified hematopoietic stem cells (HSCs) without toxic conditioning is a desired goal for HSC gene therapy. To this end, we have examined the combination of intrabone marrow transplantation (iBMT) and in vivo expansion by a selective amplifier gene (SAG) in a nonhuman primate model. The SAG is a chimeric gene consisting of the erythropoietin (EPO) receptor gene (as a molecular switch) and c-Mpl gene (as a signal generator). Cynomolgus CD34+ cells were retrovirally transduced with or without SAG and returned into the femur and humerus following irrigation with saline without prior conditioning. After iBMT without SAG, 2-30% of colony-forming cells were gene marked over 1 year. The marking levels in the peripheral blood, however, remained low (<0.1%). These results indicate that transplanted cells can engraft without conditioning after iBMT, but in vivo expansion is limited. On the other hand, after iBMT with SAG, the peripheral marking levels increased more than 20-fold (up to 8-9%) in response to EPO even at 1 year posttransplant. The increase was EPO-dependent, multilineage, polyclonal, and repeatable. Our results suggest that the combination of iBMT and SAG allows efficient in vivo gene transduction without marrow conditioning.
Noninvasive Detection of Breast Cancer Lymph Node Metastasis Using Carbonic Anhydrases IX and XII Targeted Imaging Probes
Authors: Narges K. Tafreshi, Marilyn M. Bui, Kellsey Bishop, Mark C. Lloyd, Steven A. Enkemann, Alexis S. Lopez, Dominique Abrahams, Bradford W. Carter, Josef Vagner, Stephen R. Grobmyer, Robert J. Gillies, David L. Morse
Journal: Clinical Cancer Research (2011)

Abstract Purpose: To develop targeted molecular imaging probes for the noninvasive detection of breast cancer lymph node metastasis. Experimental Design: Six cell surface or secreted markers were identified by expression profiling and from the literature as being highly expressed in breast cancer lymph node metastases. Two of these markers were cell surface carbonic anhydrase isozymes (CAIX and/or CAXII) and were validated for protein expression by immunohistochemistry of patient tissue samples on a breast cancer tissue microarray containing 47 normal breast tissue samples, 42 ductal carcinoma in situ, 43 invasive ductal carcinomas without metastasis, 46 invasive ductal carcinomas with metastasis, and 49 lymph node macrometastases of breast carcinoma. Targeted probes were developed by conjugation of CAIX- and CAXII-specific monoclonal antibodies to a near-infrared fluorescent dye. Results: Together, these two markers were expressed in 100% of the lymph node metastases surveyed. Selectivity of the imaging probes were confirmed by intravenous injection into nude mice-bearing mammary fat pad tumors of marker-expressing cells and nonexpressing cells or by preinjection of unlabeled antibody. Imaging of lymph node metastases showed that peritumorally injected probes detected nodes harboring metastatic tumor cells. As few as 1,000 cells were detected, as determined by implanting, under ultrasound guidance, a range in number of CAIX- and CAXII-expressing cells into the axillary lymph nodes. Conclusion: These imaging probes have potential for noninvasive staging of breast cancer in the clinic and elimination of unneeded surgery, which is costly and associated with morbidities. Clin Cancer Res; 18(1); 207–19. ©2011 AACR.