tbuckley/cabot-search huggingface dataset:
PTU-116 Functional immune restoration correlates with HBSAG decline and may predict treatment response on sequential NUC therapy in CHB
Authors: US Gill, D Peppa, L Micco, HD Singh, GR Foster, MK Maini, PTF Kennedy
Journal: Gut (2015)

<h3>Introduction</h3> Sequential/combined therapeutic approaches comprising Pegylated-Interferon (Peg-IFNα) and nucleot (s)ide analogues (NUC) are being given greater consideration as treatment strategies for chronic hepatitis B (CHB) to achieve HBsAg loss. We demonstrated boosting of NK cells in eAg- patients treated with Peg-IFNα <i>(Micco <i>et al</i>, <i>J. Hepatol</i>, 2013),</i>and postulated this effect could be maintained with sequential NUC therapy. Differential NK cell responses in patients receiving sequential NUCs were analysed and correlated with HBsAg response, to elucidate a possible treatment advantage with Peg-IFNα exposure. <h3>Method</h3> PBMC from 18eAg+ patients during Peg-IFNα therapy were utlised. 9/18 patients considered Peg-IFNα non-responders after 48-weeks therapy progressed to sequential NUCs and were followed until virally suppressed. Phenotypic and functional analysis of NK cell subsets was performed by multicolour flow-cytometry and findings correlated with on-therapy HBsAg changes. <h3>Results</h3> Peg-IFNα expanded CD56<sup>bright </sup>NK cells by 3-fold (p = 0.0001) which was maintained on sequential therapy. NK cell receptor expression was analysed. All receptors, except NKG2C, were maintained on sequential NUCs, with marked augmentation in the expression of NKp30 and NKp46 on CD56<sup>bright</sup>NK cells (p = &lt;0.05). These NK cells maintained their ability to degranulate and produce IFNγ during sequential therapy, functional restorations not seen on NUCs alone (p = 0.0001&amp;0.002 respectively). TRAIL expression was analysed; this decreased on sequential NUCs, but remained higher than baseline. 6/9 patients had significant declines in HBsAg (&gt;0.5 log<sub>10</sub>IU/ml) on sequential NUCs. We noted that only these patients showed the ability to increase the proportion of functional NK cells (IFNγ+&amp;CD107<sup>+</sup>) on sequential NUCs. Additionally only these responders demonstrated a reduction in TRAIL expression on sequential NUCs, compared to those without HBsAg decline, who showed the reverse. <h3>Conclusion</h3> Restoration of NK cell cytotoxic/effector functions is seen on sequential therapy, but only in those patients with HBsAg decline. Lower expression of TRAIL also correlates with treatment response, in line with our finding that TRAIL+ NK cells can delete antiviral T-cells (<i>Peppa <i>et al</i>, <i>JEM</i>2013</i>). IFNγ, CD107 and TRAIL expression on NK cells may predict those patients who are likely to demonstrate HBsAg decline on sequential therapy. Thus we have identified a phenotype of TRAIL<sup>low</sup>IFNγ/CD107<sup>hi</sup>NK cells which may act as a biomarker in predicting treatment response in this setting. Given these findings, the TRAIL pathway may be a potential future target in order to improve treatment outcomes in CHB. <h3>Disclosure of interest</h3> None Declared.
PWE-209 Orai inhibition prevents cytosolic ca2+ overload and acute pancreatitis
Authors: L Wen, S Voronina, MA Javed, M Awais, P Szatmary, D Latawiec, M Chvanov, D Collier, J Barrett, M Begg, K Stauderman, M Dunn, A Tepikin, D Criddle, R Sutton
Journal: Gut (2015)

<h3>Introduction</h3> Cytosolic calcium overload triggers pancreatic acinar injury induced by pancreatitis toxins. Sustained Ca<sup>2+</sup>elevation depends on Ca<sup>2+</sup>entry through store-operated Ca<sup>2+</sup>entry (SOCE) channel Orai1, but the role of which in experimental acute pancreatitis (EAP) and human pancreatic acinar cell injury has not been determined. <h3>Method</h3> Confocal and patch clamp technology were used to examine the effects of GSK-7975A and CM_128, inhibitors of SOCE channel Orai1 on bile acid-, hystimulation-, thapsigargin-, or cyclopiazonic acid-induced calcium entry into murine and human pancreatic acinar as well as human Orai1/STIM1-transfected HEK 293 cells. The effects of GSK-7975A and CM_128 on human necrotic pancreatic acinar cell death pathway activation induced by bile acid were monitored. EAP was induced by seven hourly intraperitoneal cerulein injections (50 mg/kg), retrograde pancreatic ductal TLCS infusion (50 mL 3 mM) or two hourly intraperitoneal injections of 150 mg/kg palmitoleic acid and 1.35g/kg ethanol. Different doses of either compound were tested in three diverse clinical representative models of EAP, begun at different time point after disease induction. EAP severity was assessed by standard biochemical parameters and blinded histopathology. <h3>Results</h3> GSK-7975A and CM_128 inhibited toxin-induced SOCE and/or Ca<sup>2+</sup>release-activated Ca<sup>2+</sup>currents in a concentration-dependent manner up to &gt;90% of control in all cells tested and significantly inhibited murine and human necrotic pancreatic acinar cell death pathway activation (p &lt; 0.05). Administration of GSK-7975A or CM_128 after induction of EAP had pronounced inhibitory effects on all local and systemic disease parameters in all three models (all p &lt; 0.05), demonstrating both dose- and time-dependency, with significantly greater effectiveness in a range of parameters when given one hour rather than six hours after disease induction. <h3>Conclusion</h3> This study confirms the pivotal role of cytosolic calcium overload in the pathogenesis of acute pancreatitis and provides robust preclinical validation for Orai inhibition as a treatment for acute pancreatitis. <h3>Disclosure of interest</h3> L. Wen: None Declared, S. Voronina: None Declared, M. Javed: None Declared, M. Awais: None Declared, P. Szatmary: None Declared, D. Latawiec: None Declared, M. Chvanov: None Declared, D. Collier: None Declared, J. Barrett Employee of: GlaxoSmithKline, M. Begg Employee of: GlaxoSmithKline, K. Stauderman Employee of: CalciMedica, M. Dunn Employee of: CalciMedica, A. Tepikin: None Declared, D. Criddle: None Declared, R. Sutton: None Declared.
Sulfolane (a metabolite of busulfan) Levels Could Predict Occurrence Of Hemorrhagic Cystitis In Children Receiving Busulfan Based Myeloablative Conditioning Before Hematopoietic Stem Cell Transplantation
Authors: Chakradhara Rao S Uppugunduri, Mohamed Aziz Rezgui, Yves Theoret, Patricia Huezo Diaz, Anuj Kumar Tyagi, Samira Mezziani, Marie-France Vachon, Catherine Desjean, Michel Duval, Henrique Bittencourt, Maja Krajinovic, Marc Ansari
Journal: Blood (2013)
Pharmacotherapy of bulimia nervosa with fluoxetine: assessment of clinically significant attitudinal change
Authors: D S Goldbloom, M P Olmsted
Journal: American Journal of Psychiatry (1993)

The authors used an individual change model to examine the clinically significant effect of pharmacotherapy with fluoxetine on the attitudes and beliefs characteristic of bulimia nervosa.Three hundred eighty-two women meeting DSM-III-R criteria for bulimia nervosa participated in a multicenter, double-blind, randomized clinical trial of placebo, 20 mg of fluoxetine, and 60 mg of fluoxetine for 8 weeks. Behavioral change was assessed with self-monitored measures of binge eating and purging, and psychological change was measured with the self-rating Eating Disorder Inventory and the Hamilton Rating Scale for Depression. A specific statistical method was used to determine clinically significant change in psychological measures.On the majority of psychological measures, more of the subjects receiving active drug than those receiving placebo showed clinically significant change. Behavioral improvement was significantly associated with the likelihood of demonstrating clinically significant psychological change. The observed effect of pharmacotherapy on attitudinal change was not related to the presence of depression at baseline. These results compare favorably with other interventions for bulimia nervosa.Measures of change in treatment studies should reflect clinical as well as statistical significance. In the short-term, treatment of bulimia nervosa with fluoxetine appears to produce clinically significant attitudinal and behavioral changes.
Extracting a low-dimensional description of multiple gene expression datasets reveals a potential driver for tumor-associated stroma in ovarian cancer
Authors: Safiye Celik, Benjamin A. Logsdon, Stephanie Battle, Charles W. Drescher, Mara Rendi, R. David Hawkins, Su-In Lee
Journal: Genome Medicine (2016)

Patterns in expression data conserved across multiple independent disease studies are likely to represent important molecular events underlying the disease. We present the INSPIRE method to infer modules of co-expressed genes and the dependencies among the modules from multiple expression datasets that may contain different sets of genes. We show that INSPIRE infers more accurate models than existing methods to extract low-dimensional representation of expression data. We demonstrate that applying INSPIRE to nine ovarian cancer datasets leads to a new marker and potential driver of tumor-associated stroma, HOPX, followed by experimental validation. The implementation of INSPIRE is available at http://inspire.cs.washington.edu .
Design of Cancer Assays for Pharmaceutical Agents
Authors: J L Ciminera, J F Heyse, N Mantel, P C Pitot
Journal: JNCI Journal of the National Cancer Institute (1984)

Design of Cancer Assays for Pharmaceutical Agents JNCI: Journal of the National Cancer Institute, Volume 72, Issue 6, June 1984, Page 1212, https://doi.org/10.1093/jnci/72.6.1212 Published: 01 June 1984
Bioluminescent reporters to monitor killer cell–mediated delivery of granzymes inside target cells
Authors: Stefanie A. H. de Poot, Elisabeth A. van Erp, Jan Meeldijk, Roel Broekhuizen, Roel Goldschmeding, Marjolein C. Olthof, Elisabeth M. P. Steeghs, Niels Bovenschen
Journal: Blood (2015)
Contradicting Cochrane
Authors: R. F O'Connor, R. Moloney
Journal: BMJ (2009)

<h3>Introduction</h3> Atrial fibrillation (AF) in patients with ischaemic ocular events is often under-investigated. We aimed to determine the prevalence of AF in these patients. <h3>Setting</h3> University College Hospital London daily TIA clinic, main referral centre for North-Central London. Consecutive records for all patients with transient or permanent ischaemic visual loss were reviewed, January 2014-September 2016. Electrocardiograms (ECG), cardiac monitoring reports and previous AF were recorded. <h3>Results</h3> Of 395 patients, 220 (55.4%) male, mean age 64 years (SD=15.1), 261 (66%) had transient and 134 (34%) permanent events. ECG was performed in 360 (91%) but only 236 (60%) had cardiac monitoring; 386 (91.1%) had carotid imaging. 8% (31) had AF and 8% (31) symptomatic carotid disease (CAS). Median ABCD2 in AF was 3, similar to non-AF patients. Only 51.6% with known AF were anticoagulated. Hypertension (p=0.012), previous TIA (p&lt;0.001) and stroke (p=0.014) were more common in AF patients; diabetes (p=0.793), smoking (p=0.653) and hypercholesterolaemia (p=0.144) were not. 90 day recurrence of stroke/TIA/ocular ischaemia was 10.1%. This was higher in AF patients (16.1%, mean 12.3 days), comparable to CAS patients (18.9%). AF patients were more likely to represent with stroke (HR=5.74, 95%CI=[0.54,61.6], p=0.239). <h3>Conclusion</h3> 8% of patients with ischaemic ocular events had AF, same as CAS; this is probably an underestimate, as these patients are often under-investigated with only 60% undergoing cardiac monitoring.
AB0975 The Heart in Rheumatic Fever: Frequency and Severity in Our Series
Authors: F. Cuoco, G. Di Landro, S. Torreggiani, M.M. D'Errico, A. Petaccia, F. Corona
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Background</h3> Rheumatic fever (RF) is an autoimmune phenomenon that occurs after infection with group A streptococcus. Inflammation of the joints, heart and brain results in the common clinical manifestation of arthritis, carditis and chorea. The major morbidity and mortality result from rheumatic heart disease (RHD). <h3>Objectives</h3> To retrospectively evaluate the demographic features, clinical characteristics and outcome among RF/RHD cases admitted in our Hospital in the last 35 years. <h3>Methods</h3> Clinical and instrumental data of 359 RF cases observed between 1980 and 2014 were retrospectively evaluated. The clinical features of RF were classified according to the revised Jones criteria. Of these patients (201 males and 158 females with mean age at onset of RF 8.4±2.6 years), 325 had acute RF (ARF), while 34 were an exception to the Jones criteria. Patients with acute RHD (ARHD) were divided into 2 groups: 218 aged &gt;5 years and 21 aged &lt;5 years, comparing the clinical characteristics and echocardiographic parameters. Valvular disease was studied by echocardiographic assessment with classification of severity in 3 degrees: mild, moderate and severe according to a qualitative and semi-quantitative assessment of the colour flow Doppler. We compared the follow-up for mitral regurgitation (MR) and aortic regurgitation (AR), either as isolated lesion or in combined mitral-aortic regurgitation (MAR), in order to assess their severity, the time course and the eventual resolution of valvular lesion. <h3>Results</h3> The majority of patient is Caucasian born in Italy (93.9%). Commonest major clinical manifestation among RF patients was carditis (72.1%) followed by arthritis (57.9%), p&lt;0.05. Commonest valvular lesion among RHD patients was MR (48.3%), followed by MAR (44.4%) and AR (6.2%). No patient aged &lt;5 years presented AR. Higher severity of ARHD was observed in children aged &lt;5 years (66.7% of moderate-severe carditis compared to 48.2% of children &gt;5 years, p&lt;0.05) and a slower healing (Graph I). <h3>Conclusions</h3> The study evidenced that carditis is the most common major clinical manifestation in our population. The prevalence of ARHD in preschool age is significant (8.8%) and higher than reported in the literature (2.5% - 5%). The valvulopathy was more severe in younger children, explaining the slower resolution time. <h3>References</h3> WHO Expert Consultation on Rheumatic Fever and Rheumatic Heart Disease (2001: Geneva Switzerland). Rheumatic fever and rheumatic heart disease: report of a WHO Expert Consultation, Geneva, October 29–November 1, 2001. WHO Technical Report Series; 923. Geneva: World Health Organization; 2004. Tani LY et al. Rheumatic fever in children younger than 5 years: is the presentation different? Pediatrics 2003; 112: 1065-8. Canter B et al. Rheumatic fever in children under 5 years old. Pediatrics 2004; 114: 329-30. <h3>Disclosure of Interest</h3> None declared
SAT0372 Ectopically Secreted Mucins Might Perpetuate the Inflammation in Salivary Glands of SjÖgren's Syndrome Patients
Authors: M.-J. Barrera, S. Aguilera, E. Veerman, J. Cortés, S. González, D. Díaz-Jiménez, I. Castro, C. Molina, V. Bahamondes, C. Leyton, M. Hermoso, M.-J. González
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Background</h3> Loss of apico-basal polarity in acinar cells is a characteristic of labial salivary glands (LSG) of Sjögren9s syndrome (SS) patients (1). In these glands, the ectopic presence of salivary mucins in the extracellular matrix has been described (1). The structure of mucins consists of a protein backbone with large number of O-linked oligosaccharides covalently attached. In SS-patients, ectopic mucin oligosaccharides might be recognized as not-self antigens by innate immunity receptors, inducing or increasing a pro-inflammatory response. <h3>Objectives</h3> To determine whether exogenous salivary mucins or mucin oligosaccharides induce the expression of pro-inflammatory cytokines, to evaluate if the Toll-like receptor-4 (TLR4) is involved in this response and if pro-inflammatory cytokines are able to induce the expression of salivary mucins. <h3>Methods</h3> Human submandibular gland (HSG) cells were stimulated with mucin from bovine submaxillary glands (BSM), Sulfo-Lewis (SO<sub>3</sub>-3Galβ1-3GlcNAc) oligosaccharide and human recombinant TNF-α or IFN-γ at different concentrations and for different periods of time. For TLR4 signaling assays, HSG cells were pre-treated with the TIRAP inhibitory peptide TBX2 or with an anti-TLR4 blocking antibody and then stimulated with BSM. The mRNA expression of mucins and cytokines was determined by real time PCR. <h3>Results</h3> Mucins and Sulfo-Lewis induced a significant increase in CXCL8, TNF-α, IFN-α, IFN-β, IL-6 and IL-1β mRNA levels. The induction of cytokines was mediated by TLR4 as shown by reversion of the effect using TBX2 or the anti-TLR4 antibody. TNF-α and IFN-γ induced <i>in vitro</i> the expression of salivary mucins such as MUC1Y/ and MUC1/SEC, which are overexpressed in LSG of SS-patients. <h3>Conclusions</h3> Salivary mucins and mucin oligosaccharides were recognized by TLR4 in epithelial cells initiating a pro-inflammatory response that could attract inflammatory cells. The overexpression and aberrant localization of mucins in LSG of SS-patients and their induction upon stimulation with pro-inflammatory cytokines support a self-perpetuating mucin-cytokine signaling loop that may facilitate the maintenance of the inflammatory environment leading to disruption of salivary gland homeostasis in SS-patients. <h3>References</h3> Barrera MJ, Bahamondes V, Sepúlveda D, Quest AFG, Castro I, Cortés J, Aguilera S, Urzúa U, Molina C, Pérez P, Ewert P, Alliende C, Hermoso MA, González S, Leyton C and González MJ. Sjögren9s Syndrome: J Autoimmun. 2013 May;42:7-18. <h3>Acknowledgements</h3> Fondecyt 1120062 (MJG, SA, CM, SG) and PhD fellowship Conicyt-Chile (MJB and JC). <h3>Disclosure of Interest</h3> None declared
The psychiatrist as medical backup: ambiguity in the delegation of clinical responsibility
Authors: R G Vasile, T G Gutheil
Journal: American Journal of Psychiatry (1979)

When the psychiatrist functions as medical backup, i.e., in a setting of delegated clinical responsibility, a number of problems may arise, originating from factors in the patient, in the physician, in the staff member to whom responsibility is delegated, and in the setting itself. The authors delineate these problem areas through case examples and discuss the implications for multidisciplinary training.
PTU-332 Five-year review of local hepato-pancreatobiliary (hpb) cancer service and its impact on cancer detection in a non-tertiary centre in mersey region: Abstract PTU-332 Table 1
Authors: VPK Lekharaju, A Boon, A Redwood, A Singhal
Journal: Gut (2015)

<h3>Introduction</h3> Management of patients with HPB cancer is complex. This requires close liaison between secondary and tertiary centres. Care of HPB cancer patients is limited by variable expertise of respective clinical teams. We developed a local HPB Cancer Service (HPBCS) in 2008 to improve the quality of care and hereby report 5-year impact on referrals to HPBCS. <h3>Method</h3> <b>Local HPB Service:</b>The HPBCS was launched on the Wirral in June 2008, first such service in a large DGH (catchment population of 360 000) in Merseyside. Patients with suspected HPB cancer were referred to the local HPBCS comprising of 2 HPB consultants and specialist nurse. Patients are identified via 2-week referrals from primary care, acute admissions, ward referrals and radiology flags. All patients are managed as per regional Mersey and Cheshire Cancer Network (MCCN) protocols with discussion at the appropriate MDTs. The team meets weekly to discuss all new referrals, MDT outcomes and care of all sick patients. There are weekly HPB nurse-led outpatient and telephone clinics that provide urgent feedback of MDT decisions, rapid access for symptom control and ensures continuity of care. The demographics, imaging reports and MDT outcomes are prospectively collected and maintained in a database. We reviewed and analysed the data for the last 5 years since the set up of the HPBCS. <h3>Results</h3> There is an year on year increase in cancer detection and referral rates since establishing the local HPBCS. The cohort of patients requiring annual surveillance for IPMN is continously increasing. We are the major feeder hospital to supra-regional MDTs. Table 1summarises the work load and referral numbers. <h3>Conclusion</h3> Since commencement of HPBCS, there is definite increase in number of suspected HPB cancers within the trust. These are referred on to the regional MDTs within 2 weeks, resulting in timely and uniform care as per MCCN guidelines, with local ownership of care. There is consistent rise in diagnosis of hepatocellular cancer which may reflect increasing incidence of chronic liver diseases nationally. Ever increasing pool of surveillance patients and radiology alerts contribute to significant ongoing work load. HPBCS was formally praised in MCCN peer review in 2010 and awarded Wirral Trust Foundation Award in 2011. <h3>Disclosure of interest</h3> None Declared.
Role of gamma-aminobutyric acid in antipanic drug efficacy
Authors: M F Breslow, M P Fankhauser, R L Potter, K E Meredith, J Misiaszek, D G Hope
Journal: American Journal of Psychiatry (1989)

All effective pharmacologic agents used to treat panic disorder augment gamma-aminobutyric acid (GABA) transmission. Anxiolytics and antidepressants that lack GABA activity are not effective in panic disorder. To test the hypothesis that GABA activity is a component of antipanic drug efficacy, the authors treated nine medication-free panic disorder subjects with oral baclofen (30 mg/day for 4 weeks) in a double-blind, placebo-controlled crossover trial. Baclofen, a selective GABA agonist, was significantly more effective than placebo in reducing the number of panic attacks and scores on the Hamilton anxiety scale, Zung scale, and Katz-R nervousness subscale. The authors discuss possible mechanisms of antipanic drug efficacy.
Abstract IA07: Multiple myeloma as a model of bone metastasis.
Authors: Irene Ghobrial
Journal: Clinical Cancer Research (2015)

Abstract The process of cell metastasis is characterized by a multistep process, the invasion-metastasis cascade. This involves cell invasion, intravasation into nearby blood vessels, passage into the circulation, followed by homing into predetermined distant tissues, the formation of new foci of micrometastases, and finally the growth of micrometastasis into macroscopic tumors. Multiple myeloma (MM) represents one of the best models to examine bone metastasis as it is characterized by the presence of multiple myelomatous “omas” throughout the skeleton, indicating that there is continuous trafficking of tumor cells to multiple areas in the bone marrow niches. We will examine intrinsic factors of clonal heterogeneity that mediate cell dissemination, as well as factors present in the bone marrow niche that are permissive for oncogenic proliferation. In addition, we will discuss advances that have been discovered in the complex process of invasion-metastasis in MM, and potential therapeutic agents that target the different steps of cell dissemination and progression. Citation Format: Irene Ghobrial. Multiple myeloma as a model of bone metastasis. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr IA07.