tbuckley/cabot-search huggingface dataset:
IL-22 <sup>+</sup> CD4 <sup>+</sup> T Cells Are Associated with Therapeutic <i>Trichuris trichiura</i> Infection in an Ulcerative Colitis Patient
Authors: Mara J. Broadhurst, Jacqueline M. Leung, Vikram Kashyap, Joseph M. McCune, Uma Mahadevan, James H. McKerrow, P’ng Loke
Journal: Science Translational Medicine (2010)

Ulcerative colitis, a type of inflammatory bowel disease, is less common in countries endemic for helminth infections, suggesting that helminth colonization may have the potential to regulate intestinal inflammation in inflammatory bowel diseases. Indeed, therapeutic effects of experimental helminth infection have been reported in both animal models and clinical trials. Here, we provide a comprehensive cellular and molecular portrait of dynamic changes in the intestinal mucosa of an individual who infected himself with Trichuris trichiura to treat his symptoms of ulcerative colitis. Tissue with active colitis had a prominent population of mucosal T helper (T(H)) cells that produced the inflammatory cytokine interleukin-17 (IL-17) but not IL-22, a cytokine involved in mucosal healing. After helminth exposure, the disease went into remission, and IL-22-producing T(H) cells accumulated in the mucosa. Genes involved in carbohydrate and lipid metabolism were up-regulated in helminth-colonized tissue, whereas tissues with active colitis showed up-regulation of proinflammatory genes such as IL-17, IL-13RA2, and CHI3L1. Therefore, T. trichiura colonization of the intestine may reduce symptomatic colitis by promoting goblet cell hyperplasia and mucus production through T(H)2 cytokines and IL-22. Improved understanding of the physiological effects of helminth infection may lead to new therapies for inflammatory bowel diseases.
Cockroach Allergen Bla g 2
Authors: ANNA POMÉS, MARTIN D. CHAPMAN, LISA D. VAILES, TOM L. BLUNDELL, VENUGOPAL DHANARAJ
Journal: American Journal of Respiratory and Critical Care Medicine (2002)

Exposure to German cockroach (Blattella germanica) allergens is associated with the development of chronic respiratory diseases, especially asthma. The mechanism by which allergic patients develop specific immunoglobulin E (IgE) responses to environmental allergens is unknown. However, recent reports provided evidence that enzyme activity, especially proteolytic activity, was a major contributor to allergenicity. Bla g 2 is one of the most potent cockroach allergens (prevalence of IgE responses of 60 to 80%) and shows homology to the aspartic proteinase family of enzymes. We investigated whether the allergenicity of Bla g 2 was linked to its putative enzymatic function. A molecular model of Bla g 2, based on the high resolution crystal structures of pepsin and chymosin, showed that the overall three-dimensional structure of Bla g 2 was similar to that of aspartic proteinases with a well-defined binding pocket. However, critical amino acid substitutions in the catalytic triads and in the "flap" region of the molecule suggested that Bla g 2 was inactive and homologous to mammalian pregnancy-associated glycoproteins. This was confirmed experimentally by enzyme assay. The results show dissociation between enzymatic activity and allergenicity for Bla g 2 and suggest that other genetic and environmental factors are important determinants of sensitization.
Lupus thrombocytopenia: clinical implications and prognostic significance
Authors: P D Ziakas
Journal: Annals of the Rheumatic Diseases (2005)

To clarify clinical manifestations, association with disease activity, and prognostic impact of thrombocytopenia using simple and reliable indices.632 patients were reviewed retrospectively. Fifty patients with thrombocytopenia were included as cases and matched with 100 control patients. Clinical manifestations at first thrombocytopenic episode were recorded. Classification criteria at diagnosis, basic immunological profiles, disease activity (ECLAM), and end organ damage (SLICC) were recorded.29/50 (58%) had thrombocytopenia at diagnosis of lupus. Haemorrhagic manifestations were associated with the degree of thrombocytopenia (p<0.001). Anticardiolipin antibodies were not related to the degree of thrombocytopenia or the severity of haemorrhagic manifestations. Megakaryocytes were normal or increased in 26/28 (93%) bone marrow specimens, indicating peripheral platelet destruction. Patients with high disease activity were more thrombocytopenic than controls (OR = 2.61, 95% CI 1.13 to 5.96, p = 0.009). Patients with low C3 or CH50 were more likely to be thrombocytopenic (OR = 2.36, 95% CI 1.05 to 5.26, p = 0.029). Median SLICC for lupus patients with thrombocytopenia was 2 (range 0-11) compared with 1 (range 0-12) for controls (p<0.001). No deaths occurred during thrombocytopenic episodes.Thrombocytopenia is not directly associated with end organ damage and mortality, but defines a subgroup of patients with higher morbidity and is thus a major complication of systemic lupus erythematosus, affecting overall prognosis.
How to treat women with antiphospholipid antibodies in pregnancy?
Authors: R H W M DERKSEN
Journal: Annals of the Rheumatic Diseases (2001)

The persistent presence in plasma of medium to high levels of IgG and/or IgM class anticardiolipin antibodies (aCL) and/or the lupus anticoagulant (LAC) is associated with both “recurrent pregnancy loss” and venous and arterial thrombosis.1 This clinicoserological entity, first described in the early eighties in patients with systemic lupus erythematosus was termed the antiphospholipid syndrome (APS).1 2 The recognition that APS also occurs in otherwise healthy people led to the term primary antiphospholipid syndrome.3 The classic laboratory markers of APS, aCL, and LAC belong to the family of so-called antiphospholipid antibodies (aPL). Clinical studies indicate that aPL are related to both early pregnancy losses and fetal demise in advanced pregnancy and that placental thrombosis and infarction are common findings in aPL related intrauterine fetal deaths.4 Studies in animal models for APS support a causative role for aPL in pregnancy loss.5 Prospective clinical studies have confirmed that aPL are risk factors for pregnancy loss, both in patients with systemic lupus erythematosus (60% versus 13% pregnancy loss)6 and in healthy nulliparous women (16% versus 7% pregnancy loss).7 In women with a history of three or more consecutive pregnancy losses persistently positive tests for aPL are found in up to 15%,8 and in these, subsequent fetal loss rates up to 60–90% are noted without specific treatment.8 9 Apart from being risk factors for fetal demise, aPL associate with high frequencies of pre-eclampsia, intrauterine growth restriction, fetal distress, and premature delivery.9 10 

aCL are detected with enzyme linked immunosorbent assays (ELISAs), in which the negatively charged phospholipid cardiolipin is coated on plastic plates, whereas LAC refers to antibodies which prolong the clotting time of phospholipid dependent coagulation tests by competing with coagulation factors for binding to the catalytic phospholipid template.11 aCL and antibodies …
Utility of FDG-PET scanning in lymphoma by WHO classification
Authors: Rebecca Elstrom, Liang Guan, Gary Baker, Khozaim Nakhoda, Jo-Anne Vergilio, Hongming Zhuang, Stephanie Pitsilos, Adam Bagg, Lisa Downs, Amit Mehrotra, Scott Kim, Abass Alavi, Stephen J. Schuster
Journal: Blood (2003)
Abstract 105: Characterizing the exomic profile of MSI colorectal cancer
Authors: Johanna K. Kondelin, Alexandra Gylfe, Sari Tuupanen, Heikki Ristolainen, Riku Katainen, Tomas Tanskanen, Heikki Jarvinen, Jukka-Pekka Mecklin, Pia Vahteristo, Lauri A. Aaltonen
Journal: Cancer Research (2012)

Abstract Colorectal cancer (CRC) is the third most common cancer in Western countries. Of all CRC tumors, 15% display microsatellite instability (MSI) caused by defective cellular mismatch repair. Cells displaying MSI accumulate a high number of mutations throughout the genome, especially in short repeat areas called microsatellites. Also point mutations occur in excess in these tumors. Sporadic MSI CRCs are caused by biallelic inactivation of the MLH1 gene, usually by promoter hypermethylation. The MSI tumors have a genetic and clinopathological profile that significantly differs from microsatellite stable (MSS) CRC. Overall, MSI tumors have been studied much less than MSS tumors, mainly due to the high number of mutations in MSI tumors, which makes data analysis and identification of relevant mutations challenging. To date, several genes have been proposed as MSI target genes based on targeted searches of their mutation frequency in microsatellite areas. A few systematic sequencing studies on colorectal cancer have been published, but none of them focus on MSI tumors, making this study first of a kind. In this study, the exome of 25 sporadic MSI tumors and corresponding normal samples are sequenced to identify changes of somatic origin. Bioinformatical tools are used to rank the genes and identify true driver genes based on clustering of missense mutations. The most interesting findings will be validated by direct Sanger sequencing. In addition to corresponding normal specimens, samples from healthy Finnish blood donors as well as data from other ongoing sequencing projects and sequence databases are used as controls to exclude polymorphisms. The data of all the 25 tumors has been analyzed and validation of the potential clusters of missense mutations is in process. The pathological nature of the changes will be confirmed by possible functional studies. This way we wish to identify new driver genes in MSI CRC. A detailed understanding of the molecular background of this tumor type is important for the development of more efficient screening methods and personalized treatments. By characterizing changes typical for different MSI tumors, we wish to identify subtypes within the MSI tumor category that could be exploited in treatment. Such understanding of MSI tumors could improve the treatment and hence prognosis of patients diagnosed with MSI type CRC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 105. doi:1538-7445.AM2012-105
Mitochondrial Regulation of Sarcoplasmic Reticulum Ca <sup>2+</sup> Content in Vascular Smooth Muscle Cells
Authors: Damon Poburko, Chiu-Hsiang Liao, Cornelis van Breemen, Nicolas Demaurex
Journal: Circulation Research (2008)

Subplasmalemmal ion fluxes have global effects on Ca 2+ signaling in vascular smooth muscle. Measuring cytoplasmic and mitochondrial [Ca 2+ ]and [Na + ], we previously showed that mitochondria buffer both subplasmalemmal cytosolic [Ca 2+ ] and [Na + ] in vascular smooth muscle cells. We have now directly measured sarcoplasmic reticulum [Ca 2+ ] in aortic smooth muscle cells, revealing that mitochondrial Na + /Ca 2+ exchanger inhibition with CGP-37157 impairs sarcoplasmic reticulum Ca 2+ refilling during purinergic stimulation. By overexpressing hFis1 to remove mitochondria from the subplasmalemmal space, we show that the rate and extent of sarcoplasmic reticulum refilling is augmented by a subpopulation of peripheral mitochondria. In ATP-stimulated cells, hFis-1–mediated relocalization of mitochondria impaired the sarcoplasmic reticulum refilling process and reduced mitochondrial [Ca 2+ ] elevations, despite increased cytosolic [Ca 2+ ] elevations. Reversal of plasmalemmal Na + /Ca 2+ exchange was the primary Ca 2+ entry mechanism following ATP stimulation, based on the effects of KB-R7943. We propose that subplasmalemmal mitochondria ensure efficient sarcoplasmic reticulum refilling by cooperating with the plasmalemmal Na + /Ca 2+ exchanger to funnel Ca 2+ into the sarcoplasmic reticulum and minimize cytosolic [Ca 2+ ] elevations that might otherwise contribute to hypertensive or proliferative vasculopathies.
Effect of omeprazole on intragastric bacterial counts, nitrates, nitrites, and N-nitroso compounds.
Authors: E Verdu, F Viani, D Armstrong, R Fraser, H H Siegrist, B Pignatelli, J P Idstrom, C Cederberg, A L Blum, M Fried
Journal: Gut (1994)

Previous studies have suggested that profound inhibition of gastric acid secretion may increase exposure to potentially carcinogenic N-nitroso compounds. The aim of this study was to find out if the proton pump inhibitor omeprazole (20 mg daily) is associated with increased concentrations of potentially carcinogenic N-nitroso compounds in gastric juice. The volume of gastric contents, number of bacteria, and concentrations of nitrates, nitrites, and N-nitroso compounds was determined in gastric aspirates obtained after an overnight fast in 14 healthy volunteers (7M:7F) after one week of treatment with placebo, and one and two weeks9 treatment with omeprazole. Median bacterial concentrations were 1.0 x 10(4) (range 5.0 x 10(3)-5.0 x 10(6)) colony forming units (CFU)/ml after one weeks9 treatment with placebo and increased significantly to 4.0 x 10(5) (0-3.3 x 10(7)) CFU/ml after two weeks9 treatment with omeprazole (p &lt; 0.05). A similar increase was seen in the concentration of nitrate reducing bacteria. There was no difference in the volume of gastric aspirates after treatment with omeprazole when compared with placebo (65 (29-155) ml v 42 (19-194) ml). The concentration of N-nitroso compounds was 0.13 (0-1.0) mumol/l after two weeks of omeprazole, which was not significantly different from that seen with placebo (0.15 (0-0.61) mumol/l). There was also no increase in the concentrations of nitrates or nitrites. It is concluded that omeprazole (20 mg once daily) for two weeks in healthy volunteers is associated with gastric bacterial proliferation but does not increase concentrations of N-nitroso compounds.
P53 Our experience of avoiding unnecessary bronchoscopies by use of sputum induction for the investigation of suspected tuberculosis
Authors: T. Gorsuch, L. Wilson, J. L. Hoyle
Journal: Thorax (2011)

<h3>Introduction</h3> The majority of cases of pulmonary tuberculosis (pTB) are diagnosed by microscopy and culture of sputum. When a patient is unable to produce sputum spontaneously, further procedures are required to obtain suitable samples for examination. There is debate about the relative merits of sputum induction (SI) and fiberoptic bronchoscopy (FOB; Brown M <i>et al</i>, 2007, Anderson C <i>et al</i>, 1995). SI is less invasive, cheaper, and unlikely to cause cross-infection, whereas FOB allows visualisation of the bronchial tree and other pathologies—especially cancer. At our hospitals, a diagnostic algorithm was devised to reduce the need for FOB for the diagnosis of pTB. Clinicians only requested bronchoscopy when three induced sputum samples were negative, unsuccessful, or contraindicated. <h3>Method</h3> A retrospective cohort study, from 1 January 2008 to 31 December 2010. Patients undergoing SI for suspected pTB were identified from physiotherapy records, and the bronchoscopy database was interrogated for mycobacterial requests. <h3>Results</h3> 521 induced sputum samples were sent from 214 patients. In total, 28 patients were diagnosed with pTB, 16 (57%) of whom were smear-positive. Non-tuberculous mycobacteria (NTM) were grown from four patients. Microbiological results of SI are listed in Abstract P53 table 1. Tuberculosis was diagnosed on the first sample in 25 cases (89%), the second in one (4%) case, and the third in two cases (7%). However, only 57% had at least three samples taken. Of 472 patients who underwent SI or FOB, 14 (3.0%) had both. Of those 14, three (21%) had positive samples for mycobacteria, two of which were <i>Mycobacterium tuberculosis</i>. All 14 had concordant culture results, whereas one case had a discordant smear result. In this case <i>Mycobacterium malmoense</i> was grown at both FOB and SI, although only the FOB sample was smear-positive. <h3>Comment</h3> In this cohort, FOB carried out after SI did not increase the diagnostic yield. Fewer than 2% of those undergoing SI went on to have FOB, which suggests that clinicians were satisfied with SI and did not feel that bronchoscopy was required. However a systematic review and meta-analysis, and a larger, prospective study would be desirable.
NHS reform: the risks of jumping on the spot again
Authors: Alan Maynard
Journal: Journal of the Royal Society of Medicine (2013)

Tragic events in hospitals in Mid-Staffordshire and Morecambe Bay, together with another round of structural ‘re-disorganization’ have fuelled speculation about the long-term viability of the National Health Service (NHS).

Elected to have no ‘top down’ reform of the NHS the coalition government has implemented radical evidence-free reforms focused on the creation of a quango, NHS England, with responsibility for strategic system management and the commissioning of specialist services. One hundred and fifty-two primary care trusts have been replaced by 210 clinical commissioning groups managed by general practitioners transmogrified into managers of 60% of the NHS budget.

The legislation underpinning these changes is complex and has created speculation that healthcare provision and perhaps its finance may be privatized. Privatization is likely to sustain the inefficiencies of the NHS, with potentially much greater inequity in access to patient care. Let's compare the actual performance of each system, while bearing in mind the ideals of each of the protagonists.1 In both the provision and finance of healthcare, public and private systems often have common failings.
Critics remain unconvinced that 180 amendments have improved the health bill
Authors: A. O'Dowd
Journal: BMJ (2011)

The revised Health and Social Care Bill, which will usher in substantial changes in the NHS, is still floundering without majority support from the medical profession despite many changes.

Opposition to the reforms is building despite the government’s revisions to the bill in the form of 180 amendments made after recommendations from the NHS Future Forum, the body appointed to review the government’s plans.

The BMJ , having spoken to several informed sources, has found that although some believe the bill to be slightly improved from its original form, many others consider that the bill’s basic aims are intact and have not changed.

MPs on the parliamentary Health and Social Care Bill Committee, which was reconvened to scrutinise the changes to the bill, agreed the revised version on 14 July. It will return to the House of Commons in September and pass on to the Lords later in the year on its way to becoming law.

Several important concerns remain, however, such as competition between providers with more scope for the private sector to provide NHS services; more central control of clinician led commissioning; and a tripling of the statutory bodies in the NHS, …
MiR-145, a new regulator of the DNA Fragmentation Factor-45 (DFF45)-mediated apoptotic network
Authors: Jianjun Zhang, Haiyan Guo, Guanxiang Qian, Shengfang Ge, Huifeng Ji, Xiaobo Hu, Wantao Chen
Journal: Molecular Cancer (2010)

MicroRNA-145 (miR-145) is considered to play key roles in many cellular processes, such as proliferation, differentiation and apoptosis, by inhibiting target gene expression. DNA Fragmentation Factor-45 (DFF45) has been found to be the substrate of Caspase-3, and the cleavage of DFF45 by caspase-3 during apoptosis releases DFF40 that degrades chromosomal DNA into nucleosomal fragments. There are currently no in-depth studies on the relationship between miR-145 and the DFF45 gene.In this study, we identified DFF45 as a novel target of miR-145. We demonstrated that miR-145 targets a putative binding site in the coding sequence (CDS) of DFF45, and its abundance is inversely associated with DFF45 expression in colon cancer cells. Using a luciferase reporter system, we found that miR-145 suppresses the expression of the luciferase reporter gene fused to the putative binding site of DFF45. The level of DFF45 protein, but not DFF45 mRNA, was decreased by miR-145, suggesting a mechanism of translational regulation. Furthermore, we demonstrate that this specific silencing of DFF45 by miR-145 accounts, at least in part, for the staurosporine-induced tumor cell apoptosis in vitro.Our study reveals a previously unrecognized function of miR-145 in DFF45 processing, which may underlie crucial aspects of cancer biology.
Standard Treatments Induce Antigen-Specific Immune Responses in Prostate Cancer
Authors: Nancy J. Nesslinger, Robert A. Sahota, Brad Stone, Kayli Johnson, Navraj Chima, Caitlin King, Devon Rasmussen, Darcy Bishop, Paul S. Rennie, Martin Gleave, Paul Blood, Howard Pai, Charles Ludgate, Brad H. Nelson
Journal: Clinical Cancer Research (2007)

Abstract Purpose: Prostate tumors express antigens that are recognized by the immune system in a significant proportion of patients; however, little is known about the effect of standard treatments on tumor-specific immunity. Radiation therapy induces expression of inflammatory and immune-stimulatory molecules, and neoadjuvant hormone therapy causes prominent T-cell infiltration of prostate tumors. We therefore hypothesized that radiation therapy and hormone therapy may initiate tumor-specific immune responses. Experimental Design: Pretreatment and posttreatment serum samples from 73 men with nonmetastatic prostate cancer and 50 cancer-free controls were evaluated by Western blotting and SEREX (serological identification of antigens by recombinant cDNA expression cloning) antigen arrays to examine whether autoantibody responses to tumor proteins arose during the course of standard treatment. Results: Western blotting revealed the development of treatment-associated autoantibody responses in patients undergoing neoadjuvant hormone therapy (7 of 24, 29.2%), external beam radiation therapy (4 of 29, 13.8%), and brachytherapy (5 of 20, 25%), compared with 0 of 14 patients undergoing radical prostatectomy and 2 of 36 (5.6%) controls. Responses were seen within 4 to 9 months of initiation of treatment and were equally prevalent across different disease risk groups. Similarly, in the murine Shionogi tumor model, hormone therapy induced tumor-associated autoantibody responses in 5 of 10 animals. In four patients, SEREX immunoscreening of a prostate cancer cDNA expression library identified several antigens recognized by treatment-associated autoantibodies, including PARP1, ZNF707 + PTMA, CEP78, SDCCAG1, and ODF2. Conclusion: We show for the first time that standard treatments induce antigen-specific immune responses in prostate cancer patients. Thus, immunologic mechanisms may contribute to clinical outcomes after hormone and radiation therapy, an effect that could potentially be exploited as a practical, personalized form of immunotherapy.