tbuckley/cabot-search huggingface dataset:
Preventing the consequences of Z alpha-1 accumulation in vivo
Authors: Sam Alam, Jicun Wang, Sabina Janciauskiene, Ravi Mahadeva
Journal: European Respiratory Journal (2011)

The Z variant (E342K) of α 1 -antitrypsin (AT) polymerizes and accumulates in hepatocyte endoplasmic reticulum (ER) resulting in neonatal hepatitis and liver cirrhosis. The secretory defect leaves lungs vulnerable to elastolysis and early-onset emphysema. Prevention of Z-AT polymerization can be achieved  in vitro  by targeting strand 4a of the AT molecule. Here we evaluate whether Ac-TTAI-NH 2  (4M) would inhibit Z-AT polymerization  in vivo . HEK293 cells transfected with Z-AT exhibited a significantly reduced AT secretion compared to M-AT cells; p= in vivo , and as such is a major step towards treatment of patients with Z-AT related lung and liver disease.
IgM-rheumatoid factors cross-reactive with IgG and a cell nuclear antigen: immunopathological implications?
Authors: P M Johnson
Journal: Annals of the Rheumatic Diseases (1980)

The cross-reaction of IgM-rheumatoid factors (IgM-RF) with a cell nuclear antigen has been further investigated by immunofluorescence procedures. This reaction appears to be optimal at pH 8-9, and fails to occur at pH 6.5. No evidence was obtained by immunofluorescence that IgM-RF bound to the cell nuclear antigen fixes complement. It would appear that the nuclear reactivity of IgM-RF may be of limited immunopathological significance, though this reaction is of note in understanding the behavioural nature of rheumatoid factors.
Exogenous PDGF-D Is a Potent Mesangial Cell Mitogen and Causes a Severe Mesangial Proliferative Glomerulopathy
Authors: Kelly L. Hudkins, Debra G. Gilbertson, Matthew Carling, Sekiko Taneda, Steven D. Hughes, Matthew S. Holdren, Thomas E. Palmer, Stavros Topouzis, Aaron C. Haran, Andrew L. Feldhaus, Charles E. Alpers
Journal: Journal of the American Society of Nephrology (2004)

ABSTRACT. The PDGF family consists of at least four members, PDGF-A, -B, -C, and -D. All of the PDGF isoforms bind and signal through two known receptors, PDGF receptor-α and PDGF receptor-β, which are constitutively expressed in the kidney and are upregulated in specific diseases. It is well established that PDGF-B plays a pivotal role in the mediation of glomerular mesangial cell proliferation. However, little is known of the roles of the recently discovered PDGF-C and -D in mediating renal injury. In this study, adenovirus constructs encoding PDGF-B, -C, and -D were injected into mice. Mice with high circulating levels of PDGF-D developed a severe mesangial proliferative glomerulopathy, characterized by enlarged glomeruli and a striking increase in glomerular cellularity. The PDGF-B–overexpressing mice had a milder proliferative glomerulopathy, whereas the mice overexpressing PDGF-C and those that received adenovirus alone showed no measurable response. Mitogenicity of PDGF-D and -B for mesangial cells was confirmed in vitro. These findings emphasize the importance of engagement of PDGF receptor-β in transducing mesangial cell proliferation and demonstrate that PDGF-D is a major mediator of mesangial cell proliferation. Finally, this approach has resulted in a unique and potentially valuable model of mesangial proliferative glomerulopathy and its resolution.
Matrix gene expression and decompensated heart failure The aged SHR model
Authors: M Boluyt
Journal: Cardiovascular Research (2000)

Impaired functional performance despite hypertrophic enlargement, and an excessive accumulation of extracellular matrix, are hallmarks of the decompensated failing heart. Age is the leading risk factor for heart failure, and there is evidence suggesting that a number of age-associated changes in the cardiac phenotype predispose the heart to failure. The spontaneously hypertensive rat (SHR) exhibits compensated cardiac hypertrophy followed by a transition to heart failure in the last quartile of the lifespan, and thus provides a useful model of the transition from stable compensated hypertrophy to decompensated heart failure in the context of aging. The transition to failure in the SHR is accompanied by marked changes in the expression of an array of genes in the heart, including increased expression of a number of genes associated with the extracellular matrix. Drug treatments that prevent or reverse matrix gene expression in the SHR heart improve myocardial function and survival. The aged SHR model of decompensated heart failure has provided insight into the role of the extracellular matrix in the transition to failure, and can be useful to further investigate the mechanistic bases of heart failure, as well as to evaluate the potential efficacy of novel therapeutic approaches to the treatment of heart failure.
HIV-2/LAV-2 IN PORTUGUESE MAN WITH AIDS (PARIS, 1978) WHO HAD SERVED IN ANGOLA IN 1968-74
Authors: A.G. Saimot, J.P. Coulaud, D. Mechali, S. Matheron, M.C. Dazza, M.A. Rey, F. Brun-Vezinet, J. Leibowitch
Journal: The Lancet (1987)
Individualized image-based lymph node irradiation for prostate cancer
Authors: Hanneke J. M. Meijer, Oscar A. Debats, Emile N. J. Th. van Lin, Marco van Vulpen, J. Alfred Witjes, Wim J. G. Oyen, Jelle O. Barentsz, Johannes H. A. M. Kaanders
Journal: Nature Reviews Urology (2013)
Localisation of divalent metal transporter 1 (DMT1) to the microvillus membrane of rat duodenal enterocytes in iron deficiency, but to hepatocytes in iron overload
Authors: D Trinder
Journal: Gut (2000)

<h3>BACKGROUND</h3> The mechanism of iron absorption by the intestine and its transfer to the main iron storage site, the liver, is poorly understood. Recently an iron carrier was cloned and named DMT1 (divalent metal transporter 1). <h3>AIMS</h3> To determine the level of DMT1 gene expression and protein distribution in duodenum and liver. <h3>METHODS</h3> A DMT1 cRNA and antibody were produced and used in in situ hybridisation and immunohistochemistry, respectively, in rats in which the iron stores were altered by feeding diets with normal, low, and high iron content. <h3>RESULTS</h3> Duodenal DMT1 mRNA was low in crypts and increased at the crypt-villus junction in iron deficient and control rats; it fell in the iron loaded state. Staining for DMT1 protein was not detected in crypts. In villus enterocytes, protein staining was localised to the microvillus membrane in iron deficiency, in the cytoplasm and to a lesser extent in the membrane in controls, and entirely in the cytoplasm of iron loaded animals. Liver DMT1 mRNA was distributed evenly across hepatocytes. DMT1 protein staining was observed on hepatocyte plasma membranes, with highest values in the iron loaded state, lower values in control animals, and none after iron depletion. <h3>CONCLUSIONS</h3> Results are consistent with a role for DMT1 in the transmembrane transport of non-transferrin bound iron from the intestinal lumen and from the portal blood.
Endometrial thickness and pregnancy rates after IVF: a systematic review and meta-analysis
Authors: Annemieke Kasius, Janine G. Smit, Helen L. Torrance, Marinus J.C. Eijkemans, Ben Willem Mol, Brent C. Opmeer, Frank J.M. Broekmans
Journal: Human Reproduction Update (2014)

BACKGROUNDThin endometrium on ultrasound in the course of ovarian hyperstimulation has been thought to be associated with poor success rates after IVF, even in the absence of prior intrauterine surgery or infection. To assess the clinical significance of endometrial thickness (EMT) for IVF outcome, we performed a systematic review and meta-analysis.
A yeast-based genomic strategy highlights the cell protein networks altered by FTase inhibitor peptidomimetics
Authors: Giampiero Porcu, Cathal Wilson, Daniele Di Giandomenico, Antonella Ragnini-Wilson
Journal: Molecular Cancer (2010)

Abstract Background Farnesyltransferase inhibitors (FTIs) are anticancer agents developed to inhibit Ras oncoprotein activities. FTIs of different chemical structure act via a conserved mechanism in eukaryotic cells. They have low toxicity and are active on a wide range of tumors in cellular and animal models, independently of the Ras activation state. Their ultimate mechanism of action, however, remains undetermined. FTase has hundred of substrates in human cells, many of which play a pivotal role in either tumorigenesis or in pro-survival pathways. This lack of knowledge probably accounts for the failure of FTIs at clinical stage III for most of the malignancies treated, with the notable exception of haematological malignancies. Understanding which cellular pathways are the ultimate targets of FTIs in different tumor types and the basis of FTI resistance is required to improve the efficacy of FTIs in cancer treatment. Results Here we used a yeast-based cellular assay to define the transcriptional changes consequent to FTI peptidomimetic administration in conditions that do not substantially change Ras membrane/cytosol distribution. Yeast and cancer cell lines were used to validate the results of the network analysis. The transcriptome of yeast cells treated with FTase inhibitor I was compared with that of untreated cells and with an isogenic strain genetically inhibited for FTase activity ( Δram1 ). Cells treated with GGTI-298 were analyzed in a parallel study to validate the specificity of the FTI response. Network analysis, based on gene ontology criteria, identified a cell cycle gene cluster up-regulated by FTI treatment that has the Aurora A kinase IPL1 and the checkpoint protein MAD2 as hubs. Moreover, TORC1-S6K-downstream effectors were found to be down-regulated in yeast and mammalian FTI-treated cells. Notably only FTIs, but not genetic inhibition of FTase, elicited up-regulation of ABC/transporters. Conclusions This work provides a view of how FTIs globally affect cell activity. It suggests that the chromosome segregation machinery and Aurora A association with the kinetochore as well as TORC1-S6K downstream effectors are among the ultimate targets affected by the transcriptional deregulation caused by FTI peptidomimetics. Moreover, it stresses the importance of monitoring the MDR response in patients treated with FTIs.
Mid‐regional pro‐adrenomedullin as a novel predictor of mortality in patients with chronic heart failure
Authors: Stephan von Haehling, Gerasimos S. Filippatos, Jana Papassotiriou, Mariantonietta Cicoira, Ewa A. Jankowska, Wolfram Doehner, Piotr Rozentryt, Corrado Vassanelli, Joachim Struck, Waldemar Banasiak, Piotr Ponikowski, Dimitrios Kremastinos, Andreas Bergmann, Nils G. Morgenthaler, Stefan D. Anker
Journal: European Journal of Heart Failure (2010)
Tobamovirus evolution: gene overlaps, recombination, and taxonomic implications
Authors: R. T. Lartey, T. C. Voss, U. Melcher
Journal: Molecular Biology and Evolution (1996)

Tobamoviruses, mostly isolated from solanaceous plants, may represent ancient virus lineages that have codiverged with their hosts. Recently completed nucleotide sequences of six nonsolanaceous tobamoviruses allowed assessment of the codivergence hypothesis and support a third subgroup within tobamoviruses. The genomic sequences of 12 tobamoviruses and the partial sequences of 11 others have been analyzed. Comparisons of the predicted protein sequences revealed three clusters of tobamoviruses, corresponding to those infecting solanaceous species (subgroup 1), those infecting cucurbits and legumes (subgroup 2), and those infecting crucifers. The orchid-infecting odontoglossum ringspot tobamovirus was associated with subgroup 1 genomes by its coat and movement protein sequences, but with the crucifer-pathogenic tobamoviruses by the remainder of its genome, suggesting that it is the progeny of a recombinant. For four of five genomic regions, subgroup 1 and 3 genomes were equidistant from a subgroup 2 genome chosen for comparison, suggesting uniform rates of evolution. A phylogenetic tree of plant families based on the tobamoviruses they harbor was congruent with that based on rubisco sequences but had a different root, suggesting that codivergence was tempered by rare events of viruses of one family colonizing another family. The proposed subgroup 3 viruses probably have an origin of virion assembly in the movement protein gene, a large (25-codon) overlap of movement and coat protein open reading frames, and a comparably shorter genome. Codon-position-dependent base compositions and codon prevalences suggested that the coat protein frame of the overlap region was ancestral. Bootstrapped parsimony analysis of the nucleotides in the overlap region and of the sequences translated from the -1 frame (the subgroup 3 movement protein frame) of this region produced trees inconsistent with those deduced from other regions. The results are consistent with a model in which a no or short overlap organization was ancestral. Despite encoding of subgroup 2 and 3 movement protein C-termini by nonhomologous nucleotides, weak similarities between their amino acid sequences suggested convergent sequence evolution.
Combined bronchoalveolar lavage and transbronchial lung biopsy: safety and yield in ventilated patients
Authors: P.A. Bulpa, A.M. Dive, L. Mertens, M.A. Delos, J. Jamart, P.A. Evrard, M.R. Gonzalez, E.J. lnstallé
Journal: European Respiratory Journal (2003)

The aim of this study was to evaluate the safety and diagnostic yield of bedside bronchoalveolar lavage (BAL) combined with fibrescopic transbronchial lung biopsy (TBLB) in determining the aetiology of pulmonary infiltrates in mechanically ventilated patients. The records of 38 mechanically ventilated patients who underwent BAL/TBLB to investigate unexplained pulmonary infiltrates were retrospectively reviewed. Patients were divided into two groups: immunocompetent (group 1: n=22; group 1a: n=11, late acute respiratory distress syndrome (ARDS); group 1b: n=11, no ARDS) and immunocompromised (group 2, n=16). The procedure allowed a diagnosis in 28 patients (74%), inducing therapeutic modification in 24 (63%) and confirmation of clinical diagnosis in four (11%). In groups 1a, 1b and 2, diagnosis was obtained in 11 out of 11 (fibroproliferation), seven out of 11 and 10 out of 16 patients, and therapy changed in 11 out of 11 (administration of steroids), six out of 11 and seven out of 16 patients, respectively. Pneumothorax occurred in nine patients (four of group 1a), bleeding in four (&lt;35 mL), and transient hypotension in two. No fatalities were procedure-related. Combined bronchoalveolar lavage/transbronchial lung biopsy is of diagnostic and therapeutic value in mechanically ventilated patients with unexplained pulmonary infiltrates, excluding those with late acute respiratory distress syndrome. Although complications are to be expected, the benefits of the procedure appear to exceed the risks in patients in whom a histological diagnosis is deemed necessary.
Liver Cell Adenoma and Oral Contraceptives
Authors: Kristina Antoniades
Journal: JAMA (1975)

A POSSIBLE association between liver cell adenoma and oral contraceptives has been indicated in recent reports.<sup>1-10</sup>Although histologically benign, these tumors can be complicated by rupture, bleeding, hemoperitoneum, and shock. Death has occurred in eight of 24 cases reported to date. It is likely that an increasing number of these tumors will manifest themselves in the future. To our knowledge, this is the first report of a case in which completely separate tumors of the liver were found simultaneously in a patient taking oral contraceptives. This is the second case involving liver cell adenoma seen within a year at our institution.<sup>10</sup> <h3>Report of a Case</h3> A 32-year-old woman, gravida 3, para 3, had been taking oral contraceptives (a mixture of norethindrone and mestranol [Ortho-Novum], 2 mg) for six years. She was admitted to our hospital with upper abdominal pain associated with nausea and vomiting of a few days'
The clinical relevance of antibodies to ribosomal-P common epitope in two targeted systemic lupus erythematosus populations: a large cohort of consecutive patients and patients with active central nervous system disease
Authors: A G Tzioufas
Journal: Annals of the Rheumatic Diseases (2000)

To develop an enzyme linked immunosorbent assay (ELISA) using as substrate a synthetic 22-aminoacid peptide, corresponding to the ribosomal P0, P1 and P2 common epitope. To study the specificity and sensitivity of the method and evaluate the frequency and clinical associations of anti-P antibodies in two groups of systemic lupus erythematosus (SLE) patients: (a) unselected SLE patients and (b) SLE patients with central nervous system (CNS) involvement.The C-terminal 22 aminoacid peptide of the ribosomal P proteins (Lys-Lys-Glu-Glu-Lys-Lys-Glu-Glu-Lys-Ser-Glu-Glu-Glu-Asp-Glu-Asp-Met- Gly-Phe-Gly-Leu-Phe-Asp) was synthesised according to Merrifield's solid phase procedure. Purification of the peptide was performed by preparative high performance liquid chromatography and confirmed by amino acid analysis. Using this peptide, in a concentration 5 microg/ml, an ELISA was developed. The presence of anti-P antibodies was evaluated by western blot using purified ribosomal proteins from rat liver. Sera from 178 consecutive patients with SLE and 28 patients with SLE and CNS manifestations were tested. Sera from 58 patients with rheumatoid arthritis and 57 patients with primary Sjögren's syndrome were used as controls. The cut off point of the assay was defined using 124 normal sera.The specificity of the assay was evaluated by homologous inhibition. Pretreatment of positive sera with soluble 22mer peptide of the ribosomal P proteins resulted in 88% inhibition. The concordance between the peptide assay and western blot was found to be 83%. Thirty three of 178 (18. 6%) of the unselected SLE patients had antibodies to P-protein common epitope. Their presence was associated with more active disease (European Consensus Lupus Activity Measurement, ECLAM scoring system) (p<0.001), higher levels of anti-ds DNA antibodies (p<0.05) and lower levels of the C4 component of complement (p<0.01). Eleven of 28 (39.3%) patients with SLE and active CNS involvement had antibodies to P-protein. The overall prevalence of anti-P antibodies in active CNS disease patients was statistically significantly higher, as compared with unselected SLE patients (chi(2)=6.04, p<0.05). These antibodies were found in a high proportion of patients without anticardiolipin antibodies (52.4%) and they were associated with diffuse CNS involvement (psychiatric disorders (71%) and epilepsy (75%)).A synthetic analogue of the common epitope of ribosomal P-proteins can be use as an antigen for the detection of anti-P antibodies. These antibodies are associated with active SLE and CNS involvement particularly in patients without anticardiolipin antibodies.
DKK2 Mediates Osteolysis, Invasiveness, and Metastatic Spread in Ewing Sarcoma
Authors: Kristina Hauer, Julia Calzada-Wack, Katja Steiger, Thomas G.P. Grunewald, Daniel Baumhoer, Stephanie Plehm, Thorsten Buch, Olivia Prazeres da Costa, Irene Esposito, Stefan Burdach, Günther H.S. Richter
Journal: Cancer Research (2012)

Ewing sarcoma, an osteolytic malignancy that mainly affects children and young adults, is characterized by early metastasis to lung and bone. In this study, we identified the pro-metastatic gene DKK2 as a highly overexpressed gene in Ewing sarcoma compared with corresponding normal tissues. Using RNA interference, we showed that DKK2 was critical for malignant cell outgrowth in vitro and in an orthotopic xenograft mouse model in vivo. Analysis of invasion potential in both settings revealed a strong correlation of DKK2 expression to Ewing sarcoma invasiveness that may be mediated by the DKK effector matrix metalloproteinase 1 (MMP1). Furthermore, gene expression analyses established the ability of DKK2 to differentially regulate genes such as CXCR4, PTHrP, RUNX2, and TGFβ1 that are associated with homing, invasion, and growth of cancer cells in bone tissue as well as genes important for osteolysis, including HIF1α, JAG1, IL6, and VEGF. DKK2 promoted bone infiltration and osteolysis in vivo and further analyses defined DKK2 as a key factor in osteotropic malignancy. Interestingly, in Ewing sarcoma cells, DKK2 suppression simultaneously increased the potential for neuronal differentiation while decreasing chondrogenic and osteogenic differentiation. Our results provide strong evidence that DKK2 is a key player in Ewing sarcoma invasion and osteolysis and also in the differential phenotype of Ewing sarcoma cells.
Orthotopic Liver Transplantation in Two Adults with Niemann-Pick and Gaucher's Diseases: Implications for the Treatment of Inherited Metabolic Disease
Authors: Elizabeth J. Smanik, Anthony S. Tavill, Gretta H. Jacobs, Irwin A. Schafer, Lou Farquhar, Fredrick L. Weber, James T. Mayes, James A. Schulak, Mary Petrelli, Gregory C. Zirzow, Katharine L. Oliver, STEPHEN P. F. Miller, Roscoe O. Brady
Journal: Hepatology (1993)

Two adults were seen with cirrhosis caused by different lipid storage diseases. A 42-yr-old woman with Niemann-Pick disease type B had marked hepatomegaly, ascites and recent variceal bleeding. Her evaluation showed chronic bilateral pulmonary infiltrates, multiple stigmata of chronic liver disease including the recent cessation of menses, diuretic-resistant sterile ascites, hepatic encephalopathy and variceal bleeding. Five percent of normal sphingomyelinase activity was measured in peripheral leukocytes. A 42-yr-old man with Gaucher's disease and a history of bilateral hip replacements presented with hepatomegaly, jaundice, refractory ascites and renal insufficiency. His evaluation showed 20% to 23% of normal glucocerebrosidase activity in peripheral leukocytes. Both patients underwent orthotopic liver transplantation with resolution of all aspects of decompensated liver function. Assessment of the underlying metabolic defect before and 6 to 14 mo after transplantation showed that after transplantation the patient with Niemann-Pick disease had above normal hepatic sphingomyelinase activity, a less-marked increase in peripheral leukocyte enzyme activity and lower than normal hepatic sphingomyelin and cholesterol content. In contrast, the patient with Gaucher's disease had only a 61% increase in hepatic glucocerebrosidase activity but had an elevated hepatic glucocerebroside content that was only 15% of the pretransplant level and decreased peripheral leukocyte enzyme levels. These findings suggest that variable relationships may exist between posttransplant hepatic and peripheral leukocyte enzyme activities in the different lipidoses, which may have implications for recurrence of glycolipid-induced liver damage.