tbuckley/cabot-search huggingface dataset:
ERAD-Derived Preprotein Transport across the Second Outermost Plastid Membrane of Diatoms
Authors: F. Hempel, L. Bullmann, J. Lau, S. Zauner, U. G. Maier
Journal: Molecular Biology and Evolution (2009)

The diatom Phaeodactylum tricornutum harbors a plastid that is surrounded by four membranes and evolved by way of secondary endosymbiosis. Like land plants, most of its plastid proteins are encoded as preproteins on the nuclear genome of the host cell and are resultantly redirected into the organelle. Because two more membranes are present in diatoms than the one pair surrounding primary plastids, the targeting situation is obviously different and more complex. In this work, we focus on preprotein transport across the second outermost plastid membrane—an issue that was experimentally inaccessible until now. We provide first indications that our hypothesis of an ERAD (ER-associated degradation)-derived preprotein transport system might be correct. Our data demonstrate that the symbiont-specific Der1 proteins, sDer1-1 and sDer1-2, form an oligomeric complex within the second outermost membrane of the complex plastid. Moreover, we present first evidence that the complex interacts with transit peptides of preproteins being transported across this membrane into the periplastidal compartment but not with transit peptides of stromal-targeted proteins. Thus, the sDer1 complex might have an additional role in discriminating preproteins that are transported across the two outermost membranes from preproteins directed across all four membranes of the complex plastid. Altogether, our studies of the symbiont-specific ERAD-like machinery of diatoms suggest that a preexisting cellular machinery was recycled to fulfill a novel function during the transition of a former free-living eukaryote into a secondary endosymbiont.
Hyperhomocysteinemia and Low Pyridoxal Phosphate
Authors: Killian Robinson, Ellen L. Mayer, Dave P. Miller, Ralph Green, Frederick van Lente, Anjan Gupta, Kandice Kottke-Marchant, Susan R. Savon, Jacob Selhub, Steven E. Nissen, Michael Kutner, Eric J. Topol, Donald W. Jacobsen
Journal: Circulation (1995)

Background High plasma homocysteine is associated with premature coronary artery disease in men, but the threshold concentration defining this risk and its importance in women and the elderly are unknown. Furthermore, although low B vitamin status increases homocysteine, the link between these vitamins and coronary disease is unclear. Methods and Results We compared 304 patients with coronary disease with 231 control subjects. Risk factors and concentrations of plasma homocysteine, folate, vitamin B12, and pyridoxal 5′-phosphate were documented. A homocysteine concentration of 14 μmol/L conferred an odds ratio of coronary disease of 4.8 ( P &lt;.001), and 5-μmol/L increments across the range of homocysteine conferred an odds ratio of 2.4 ( P &lt;.001). Odds ratios of 3.5 in women and of 2.9 in those 65 years or older were seen ( P &lt;.05). Homocysteine correlated negatively with all vitamins. Low pyridoxal 5′-phosphate (&lt;20 nmol/L) was seen in 10% of patients but in only 2% of control subjects ( P &lt;.01), yielding an odds ratio of coronary disease adjusted for all risk factors, including high homocysteine, of 4.3 ( P &lt;.05). Conclusions Within the range currently considered to be normal, the risk for coronary disease rises with increasing plasma homocysteine regardless of age and sex, with no threshold effect. In addition to a link with homocysteine, low pyridoxal-5′-phosphate confers an independent risk for coronary artery disease.
Targeting therapeutics to arthritic joints by antibody specific to post-translationally modified collagen type II
Authors: Chris Hughes, Bjarne Faurholm, Francesco Dell'Accio, Antonio Manzo, Michael Seed, N M Eltawil, Alessandra Amarrelli, Adam Al-Kashi, Paul G Winyard, Yuti Chernajovsky, Ahuva Nissim
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Background</h3> The aim of our study is to target anti-inflammatory proteins to arthritic joints, in order to improve efficacy and reduce side-effects of current therapies. <h3>Methods</h3> The authors chose type II collagen (CII) as a target as it is uniquely present in cartilage. In the arthritic joint, CII is damaged by reactive oxidant species (ROS) generated in the inflammation process. The authors used ROS-modified CII to select a human single chain fragment variable (scFv) specific to ROS-CII. In order to target therapeutic proteins to the inflamed joints, the authors have fused anti-ROS-CII scFv to anti-inflammatory proteins via an MMP cleavage site linker. MMPs are up-regulated in arthritis, and therefore when the fusion protein is localised to inflamed areas by the scFv, the therapeutic is liberated, and is free to engage its target. <h3>Results</h3> The authors were able to demonstrate binding of anti-ROS modified CII scFv,1-11E to damaged cartilage from rheumatoid arthritis (RA) and osteoarthritis (OA) patients but not to intact cartilage. Accordingly, imaging studies have shown that fluorescently labelled 1-11E scFv localises specifically to inflamed joints in arthritic mice. 1-11E fused to mTNFR2-Fc is able to bind modified CII in ELISA, and is cleaved at the linker site by incubation with MMP-1. Biological activity of mTNFR2 was also demonstrated in vitro. Moreover, the authors show that by fusing mTNFR2-Fc to 1-11E, the therapeutic efficacy in arthritic mice is enhanced. <h3>Conclusion</h3> The authors have a proof of principle that therapeutics targeted by anti-ROS-CII to the joints have augmented anti-inflammatory properties. Future work will involve optimising the fusion proteins with a view to development towards the clinic, including targeting alternative therapeutic molecules.
Evidence that two distinct crypt cell types secrete chloride and potassium in human colon
Authors: John Linley, Arun Loganathan, Shashikala Kopanati, Geoffrey I Sandle, Malcolm Hunter
Journal: Gut (2013)

<h3>Background</h3> Human colon may secrete substantial amounts of water secondary to chloride (Cl<sup>−</sup>) and/or potassium (K<sup>+</sup>) secretion in a variety of diarrhoeal diseases. Ion secretion occurs via Cl<sup>−</sup> and K<sup>+</sup> channels, which are generally assumed to be co-located in the colonocyte apical membrane, although their exact cellular sites remain unclear. <h3>Objective</h3> &nbsp;To investigate the location of apical Cl<sup>−</sup> (CFTR) and apical K<sup>+</sup> (large conductance; BK) channels within human colonic epithelium. <h3>Design</h3> Whole-cell patch clamp recordings were obtained from intact human colonic crypts. Specific blockers of K<sup>+</sup> channels and CFTR identified different types of K<sup>+</sup> channel and CFTR under resting conditions and after stimulating intracellular cAMP with forskolin. The BK channel β<sub>3</sub>-subunit was localised by immunostaining. <h3>Results</h3> Two types of crypt cells were identified. One (73% of cells) had whole-cell currents dominated by intermediate conductance (IK) K<sup>+</sup> channels under resting conditions, which developed large CFTR-mediated currents in response to increasing intracellular cAMP. The other (27% of cells) had resting currents dominated by BK channels inhibited by the BK channel blocker penitrem A, but insensitive to both forskolin and the IK channel blocker clotrimazole. Immunostaining showed co-localisation of the BK channel β<sub>3</sub>-subunit and the goblet cell marker, MUC2. <h3>Conclusions</h3> In human colon, Cl<sup>−</sup> secretion originates from the dominant population of colonocytes expressing apical CFTR, whereas K<sup>+</sup> secretion is derived from a smaller population of goblet cells expressing apical BK channels. These findings provide new insights into the pathophysiology of secretory diarrhoea and should be taken into account during the development of anti-diarrhoeal drugs.
Breast cancer estrogen and progesterone receptor values: their distribution, degree of concordance, and relation to number of positive axillary nodes.
Authors: B Fisher, D L Wickerham, A Brown, C K Redmond
Journal: Journal of Clinical Oncology (1983)

Increasing evidence indicates the importance of ascertaining the quantitative estrogen receptor (ER) and progesterone receptor (PR) content (in femtomoles per milligram cytosol protein) of primary breast cancers. Those values obtained from the tumors of 1,887 patients participating in National Surgical Adjuvant Breast and Bowel Project protocol B-09 have been analyzed to define (1) the distribution of tumor ER or PR according to patient age, (2) the distribution of tumor PR within a specific ER interval, and (3) the concordance of tumor ER and PR levels. The present findings indicate how predictive the knowledge of the amount of one receptor (e.g., ER) may be for estimating the amount of the other (PR), when the latter is unknown.
Colorectal cancer screening with odour material by canine scent detection
Authors: H. Sonoda, S. Kohnoe, T. Yamazato, Y. Satoh, G. Morizono, K. Shikata, M. Morita, A. Watanabe, M. Morita, Y. Kakeji, F. Inoue, Y. Maehara
Journal: Gut (2011)

<h3>Objective</h3> Early detection and early treatment are of vital importance to the successful treatment of various cancers. The development of a novel screening method that is as economical and non-invasive as the faecal occult blood test (FOBT) for early detection of colorectal cancer (CRC) is needed. A study was undertaken using canine scent detection to determine whether odour material can become an effective tool in CRC screening. <h3>Design</h3> Exhaled breath and watery stool samples were obtained from patients with CRC and from healthy controls prior to colonoscopy. Each test group consisted of one sample from a patient with CRC and four control samples from volunteers without cancer. These five samples were randomly and separately placed into five boxes. A Labrador retriever specially trained in scent detection of cancer and a handler cooperated in the tests. The dog first smelled a standard breath sample from a patient with CRC, then smelled each sample station and sat down in front of the station in which a cancer scent was detected. <h3>Results</h3> 33 and 37 groups of breath and watery stool samples, respectively, were tested. Among patients with CRC and controls, the sensitivity of canine scent detection of breath samples compared with conventional diagnosis by colonoscopy was 0.91 and the specificity was 0.99. The sensitivity of canine scent detection of stool samples was 0.97 and the specificity was 0.99. The accuracy of canine scent detection was high even for early cancer. Canine scent detection was not confounded by current smoking, benign colorectal disease or inflammatory disease. <h3>Conclusions</h3> This study shows that a specific cancer scent does indeed exist and that cancer-specific chemical compounds may be circulating throughout the body. These odour materials may become effective tools in CRC screening. In the future, studies designed to identify cancer-specific volatile organic compounds will be important for the development of new methods for early detection of CRC.
Cyclosporin A in psoriatic arthritis: an open study.
Authors: K Steinsson, I Jonsdottir, H Valdimarsson
Journal: Annals of the Rheumatic Diseases (1990)

Eight patients with psoriatic arthritis entered an open study to determine the efficacy of oral cyclosporin A for their treatment. The starting dose was 3.5 mg/kg daily. Findings after the first six months are reported. One patient withdrew from the study after five months because of tremors, general malaise, and lack of improvement. Seven patients continued through the study, and marked improvement was found after two months in all clinical indices. The skin lesions improved in a parallel fashion. The cyclosporin A dose had to be reduced temporarily by 25% in three patients because of an increase in serum creatinine of more than 50%. A rise in diastolic blood pressure in three patients responded to treatment. The study suggests that cyclosporin A effectively treats arthritic manifestations of psoriasis as well as psoriatic skin lesions.
Dendritic cells, Fc receptors, and Toll-like receptors: potential allies in the battle against rheumatoid arthritis
Authors: T R D J Radstake, A W T van Lieshout, P L C M van Riel, W B van den Berg, G J Adema
Journal: Annals of the Rheumatic Diseases (2005)

Recent findings suggest an important role for Fcgamma receptors and Toll-like receptors expressed by dendritic cells (DC) in the pathogenesis of rheumatoid arthritis (RA). Possibly, DC behaviour might be tuned to counteract the misbalanced immune system in RA. Understanding the precise mechanisms that determine the skewed immune response in RA may provide new clues for the therapeutic use of DC in RA.
Confirmation of Linkage to and Localization of Familial Colon Cancer Risk Haplotype on Chromosome 9q22
Authors: Courtney Gray-McGuire, Kishore Guda, Indra Adrianto, Chee Paul Lin, Leanna Natale, John D. Potter, Polly Newcomb, Elizabeth M. Poole, Cornelia M. Ulrich, Noralane Lindor, Ellen L. Goode, Brooke L. Fridley, Robert Jenkins, Loic Le Marchand, Graham Casey, Robert Haile, John Hopper, Mark Jenkins, Joanne Young, Daniel Buchanan, Steve Gallinger, Mark Adams, Susan Lewis, Joseph Willis, Robert Elston, Sanford D. Markowitz, Georgia L. Wiesner
Journal: Cancer Research (2010)

Genetic risk factors are important contributors to the development of colorectal cancer. Following the definition of a linkage signal at 9q22-31, we fine mapped this region in an independent collection of colon cancer families. We used a custom array of single-nucleotide polymorphisms (SNP) densely spaced across the candidate region, performing both single-SNP and moving-window association analyses to identify a colon neoplasia risk haplotype. Through this approach, we isolated the association effect to a five-SNP haplotype centered at 98.15 Mb on chromosome 9q. This haplotype is in strong linkage disequilibrium with the haplotype block containing HABP4 and may be a surrogate for the effect of this CD30 Ki-1 antigen. It is also in close proximity to GALNT12, also recently shown to be altered in colon tumors. We used a predictive modeling algorithm to show the contribution of this risk haplotype and surrounding candidate genes in distinguishing between colon cancer cases and healthy controls. The ability to replicate this finding, the strength of the haplotype association (odds ratio, 3.68), and the accuracy of our prediction model (approximately 60%) all strongly support the presence of a locus for familial colon cancer on chromosome 9q.
Cutaneous solitary fibrous tumour with myxoid stroma
Authors: S-E. Chang, G-Y. Bae, J-H. Choi, K-J. Sung, K-C. Moon, J-K. Koh, M-W. Lee, J.S. Silverman
Journal: British Journal of Dermatology (2002)

Sir, Solitary fibrous tumour (SFT) is a distinctive CD34‐positive spindle cell neoplasm of probable mesenchymal origin that generally arises in the pleura.1–5 Rare cases of SFT arising in the skin have recently been reported, reinforcing the notion that SFT may arise in non‐serosal sites.4, 5 We report an additional case by describing a shelled‐out lesion of SFT with abundant myxoid change. A 42‐year‐old Korean woman presented in April 1998 with an asymptomatic, slowly enlarging lesion on the thigh. The lesion was first noted 5 years previously. Examination showed a solitary, about 1‐cm diameter, well‐demarcated, skin‐coloured, round, smooth‐surfaced, non‐tender nodule on the right upper posterior thigh (Fig. 1a). Lymph nodes were not palpable. Under a clinical diagnosis of epidermal cyst, incision and tumour enucleation were performed to minimize scarring. The spindle cell tumour was located in the dermis and subcutis, and had a smooth border. It was surrounded by a thin rim of normal tissue like a pseudoencapsulation, thus making the tumour easily shelled out. There were peripheral foci of entrapped normal adipocytes (Fig. 1b). The tumour cells appeared fibroblastic, with a weakly alcianophilic, fibrillar fibromyxoid stroma, and were in a patternless swirling and focally storiform arrangement. The tumour exhibited alternating hypercellular and hypocellular areas. The tumour cells had an elongate, dendritic spindle cell morphology and the nuclei were bland (Figs 1c,d). The mucinous stroma was positive to alcian blue (Fig. 1d) and colloidal iron, but negative to periodic acid–Schiff with diastase and toluidine blue. Immunohistochemical markers for smooth muscle actin, desmin, lysozyme, CD68, S‐100 protein, epithelial membrane antigen, cytokeratin, CD117 and factor XIIIa were negative, but diffuse positivity for CD34 was characteristic (Fig. 1c). For differential diagnosis of dermatofibrosarcoma protuberans (DFSP), reverse transcription–polymerase chain reaction assay for the DFSP‐specific COL1A1‐PDGFB chimeric fusion transcripts using eight of the possible 51 break points in the COL1A1 gene was negative. SFT was a final diagnosis. Two years later, there were no recurrences.
Refractory hypoxaemia after pneumonectomy: diagnosis by transoesophageal echocardiography.
Authors: L Berry, S Braude, J Hogan
Journal: Thorax (1992)

A patient with normal oxygenation before operation became very breathless and hypoxaemic after a right pneumonectomy. Transoesophageal echocardiography showed right to left interatrial shunting due to a patent foramen ovale. Transoesophageal echocardiography should be included in the assessment of patients who became inappropriately dyspnoeic after pneumonectomy.
Oocyte activation, phospholipase C zeta and human infertility
Authors: J. Kashir, B. Heindryckx, C. Jones, P. De Sutter, J. Parrington, K. Coward
Journal: Human Reproduction Update (2010)

BACKGROUNDMammalian oocytes are activated by intracellular calcium (Ca2+) oscillations following gamete fusion. Recent evidence implicates a sperm-specific phospholipase C zeta, PLCζ, which is introduced into the oocyte following membrane fusion, as the responsible factor. This review summarizes the current understanding of human oocyte activation failure and describes recent discoveries linking certain cases of male infertility with defects in PLCζ expression and activity. How these latest findings may influence future diagnosis and treatment options are also discussed.
Emerging Concepts in Alzheimer's Disease
Authors: Harry V. Vinters
Journal: Annual Review of Pathology Mechanisms of Disease (2014)

Alzheimer's disease/senile dementia of the Alzheimer type (AD/SDAT) is the most common neuropathologic substrate of dementia. It is characterized by synapse loss (predominantly within neocortex) as well as deposition of certain distinctive lesions (the result of protein misfolding) throughout the brain. The latter include senile plaques, composed mainly of an amyloid (Aβ) core and a neuritic component; neurofibrillary tangles, composed predominantly of hyperphosphorylated tau; and cerebral amyloid angiopathy, a microangiopathy affecting both cerebral cortical capillaries and arterioles and resulting from Aβ deposition within their walls or (in the case of capillaries) immediately adjacent brain parenchyma. In this article, I discuss the hypothesized role these lesions play in causing cerebral dysfunction, as well as CSF and neuroimaging biomarkers (for dementia) that are especially relevant as immunotherapeutic approaches are being developed to remove Aβ from the brain parenchyma. In addition, I address the role of neuropathology in characterizing the sequelae of new AD/SDAT therapies and helping to validate CSF and neuroimaging biomarkers of disease. Comorbidity of AD/SDAT and various types of cerebrovascular disease is a major theme in dementia research, especially as cognitive impairment develops in the oldest old, who are especially vulnerable to ischemic and hemorrhagic brain lesions.
Effect of interleukin-6 receptor blockade on surrogates of vascular risk in rheumatoid arthritis: MEASURE, a randomised, placebo-controlled study
Authors: Iain B McInnes, Liz Thompson, Jon T Giles, Joan M Bathon, Jane E Salmon, Andre D Beaulieu, Christine E Codding, Timothy H Carlson, Christian Delles, Janet S Lee, Naveed Sattar
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Objectives</h3> The interleukin-6 receptor (IL-6R) blocker tocilizumab (TCZ) reduces inflammatory disease activity in rheumatoid arthritis (RA) but elevates lipid concentrations in some patients. We aimed to characterise the impact of IL-6R inhibition on established and novel risk factors in active RA. <h3>Methods</h3> Randomised, multicentre, two-part, phase III trial (24-week double-blind, 80-week open-label), MEASURE, evaluated lipid and lipoprotein levels, high-density lipoprotein (HDL) particle composition, markers of coagulation, thrombosis and vascular function by pulse wave velocity (PWV) in 132 patients with RA who received TCZ or placebo. <h3>Results</h3> Median total-cholesterol, low-density lipoprotein-cholesterol (LDL-C) and triglyceride levels increased in TCZ versus placebo recipients by week 12 (12.6% vs 1.7%, 28.1% vs 2.2%, 10.6% vs −1.9%, respectively; all p&lt;0.01). There were no significant differences in mean small LDL, mean oxidised LDL or total HDL-C concentrations. However, HDL-associated serum amyloid A content decreased in TCZ recipients. TCZ also induced reductions (&gt;30%) in secretory phospholipase A2-IIA, lipoprotein(a), fibrinogen and D-dimers and elevation of paraoxonase (all p&lt;0.0001 vs placebo). The ApoB/ApoA1 ratio remained stable over time in both groups. PWV decreases were greater with placebo than TCZ at 12 weeks (adjusted mean difference 0.79 m/s (95% CI 0.22 to 1.35; p=0.0067)). <h3>Conclusions</h3> These data provide the first detailed evidence for the modulation of lipoprotein particles and other surrogates of vascular risk with IL-6R inhibition. When compared with placebo, TCZ induced elevations in LDL-C but altered HDL particles towards an anti-inflammatory composition and favourably modified most, but not all, measured vascular risk surrogates. The net effect of such changes for cardiovascular risk requires determination.