tbuckley/cabot-search huggingface dataset:
Glomerular Monocyte-Macrophage Features in ANCA-Positive Renal Vasculitis and Cryoglobulinemic Nephritis
Authors: MARIA PIA RASTALDI, FRANCO FERRARIO, ANDOR CRIPPA, GIACOMO DELL'ANTONIO, DONATELLA CASARTELLI, CARLO GRILLO, GIUSEPPE D'AMICO
Journal: Journal of the American Society of Nephrology (2000)

Abstract. Although it is widely known that many macrophages are present in glomeruli of antineutrophil cytoplasmic antibody (ANCA)-positive renal vasculitis (ANCA + RV) and are believed to contribute to necrotizing extracapillary damage, their precise role is not yet completely understood, especially in humans. The goal of this study was to provide evidence of glomerular macrophage properties in human vasculitis. Twenty-five renal biopsies of ANCA + RV and 18 cases of cryoglobulinemic glomerulonephritis (cryoGN), a disease characterized by massive glomerular macrophage infiltration but absence of necrotizing extracapillary lesions, were selected, and macrophage number, adhesion, acute activation, proliferation, and apoptosis were analyzed by immunohistochemistry and in situ hybridization. Accumulation of macrophages in ANCA + RV was found in areas of glomerular active lesions, whereas in cryoGN, they homogeneously occupied the entire glomerular tuft. Considering the areas of accumulation, comparable macrophage numbers were detected in both diseases. Glomerular vascular cell adhesion molecule-1 was found only in ANCA + RV and only in areas of active lesions. Acute macrophage activation (HLA class II, 27E10) and proinflammatory cytokine production (tumor necrosis factor-α, interleukin-1α) were prominent in ANCA + RV, whereas in cryoGN, 30% of glomerular macrophages seemed activated and cytokine expression was limited to a few glomerular cells ( P = 0.01). Moreover, only in ANCA + RV proliferative markers were shown on glomerular macrophages and apoptotic macrophages were found. From the data, it seems that ANCA + RV and cryoGN differ profoundly in macrophage properties, namely adhesion, proliferation, and apoptotic clearance. Moreover, acute activation and cytokine production seem to be present in a greater number of macrophages in ANCA + RV, giving this disease a stronger severity that could be taken into account for therapeutic strategies.
Quality assurance measures in rectal cancer: caveat utilitor
Authors: R Kennelly, D C Winter
Journal: Gut (2009)

The delivery of surgery has never been more focussed on quality. Patients deserve consistent standards regardless of where they live or are treated. The pursuit of excellence requires the definition of standards and the search is on to find what parameters best guarantee equal patient outcome and care. In a recent paper in Gut , the careful work by Morris et al highlights how wide variation in outcome can occur and shows the importance of population-based audit to monitor trends.1 Certainly, while sphincter preservation is often considered a patient priority Morris et al illustrate that operative choice can profoundly affect quality of care and therefore careful monitoring can indicate room for improvement. A separate area of controversy is the role of lymph node evaluation as a marker of quality assurance. Undoubtedly lymph node evaluation is important but opinions differ as to the exact role that lymph nodes play in rectal cancer management.

In the early 1980s local recurrence of rectal cancer was 20–40%.2 In an attempt to address this issue a more radical local excision was trialled to assess whether careful removal of the whole of the mesorectum would cause a beneficial effect. This work, performed at Basingstoke and now known as total mesorectal excision, revolutionised rectal cancer, reducing local recurrence to 5–10%.3 It was postulated at that time that radical local excision resulted in eradication of disease prior to systemic spread, therefore …
Sequential mitoxantrone/prednisone followed by docetaxel/estramustine in patients with hormone refractory metastatic prostate cancer: results of a phase II study
Authors: A. Font, A. Murias, F.R. García Arroyo, C. Martin, J. Areal, J.J. Sanchez, J.A. Santiago, M. Constenla, J.M. Saladie, R. Rosell
Journal: Annals of Oncology (2005)
Long-Term Mortality of Patients With Acute Myocardial Infarction in the United States and Canada
Authors: Padma Kaul, Paul W. Armstrong, Wei-Ching Chang, C. David Naylor, Christopher B. Granger, Kerry L. Lee, Eric D. Peterson, Robert M. Califf, Eric J. Topol, Daniel B. Mark
Journal: Circulation (2004)

Background— In a previous substudy of the GUSTO-I trial, we observed better functional and quality-of-life outcomes among patients in the United States (US patients) compared with patients in Canada. Rates of invasive therapy were significantly higher in the United States and were associated with a small mortality benefit (0.4%, adjusted P =0.02). We sought to determine whether Canadian–US differences in practice patterns in GUSTO-I had an impact on 5-year mortality. Methods and Results— Mortality data for 23 105 US and 2898 Canadian patients enrolled in GUSTO-I were obtained from national mortality databases. Median follow-up was 5.46 years in the US and 5.33 years in the Canadian cohort. Five-year mortality rate was 19.6% among US and 21.4% among Canadian patients ( P =0.02). After baseline adjustment, enrollment in Canada was associated with a higher hazard of death (1.17; 95% confidence interval, 1.07 to 1.28, P =0.001). Revascularization rates during the index hospitalization in the United States were almost 3 times those in Canada: 30.5% versus 11.4% for angioplasty and 13.1% versus 4.0% for bypass surgery ( P &lt;0.01 for both). After accounting for revascularization status as a time-dependent covariate, country was no longer a significant predictor of long-term mortality. These results were confirmed in a propensity-matched analysis. Conclusions— Our results suggest, for the first time, that the more conservative pattern of care with regard to early revascularization in Canada for ST-segment elevation acute myocardial infarction may have a detrimental effect on long-term survival. Our results have important policy implications for cardiac care in countries and healthcare systems wherein use of invasive procedures is similarly conservative.
Interdigital lesions and frequency of acute dermatolymphangioadenitis in lymphoedema in a filariasis-endemic area
Authors: T. McPherson, S. Persaud, S. Singh, M.P. Fay, D. Addiss, T.B. Nutman, R. Hay
Journal: British Journal of Dermatology (2006)

Lymphatic filariasis (LF) is a mosquito-borne nematode infection that causes permanent lymphatic dysfunction in virtually all infected individuals and clinical disease in a subset of these. One major sequel of infection is lymphoedema of the limbs. Lymphoedema of the leg affects an estimated 15 million persons in LF-endemic areas worldwide. Acute dermatolymphangioadenitis (ADLA) in people with filarial lymphoedema causes acute morbidity and increasingly severe lymphoedema. Episodes of ADLA are believed to be caused by bacteria, and it has been shown that entry lesions in the skin play a causative role. Clinical observations suggest that interdigital skin lesions of the feet, often assumed to be fungal, may be of particular importance.To investigate the epidemiology and aetiology of interdigital lesions (IDL) of the feet in filarial lymphoedema.The frequency and mycological aetiology of IDL in 73 patients with filarial lymphoedema were compared with 74 individuals without lymphoedema in a region of Guyana highly endemic for Wuchereria bancrofti.More than 50% of patients with lymphoedema had one or more IDL (odds ratio 2.69; 95% confidence interval 1.31-5.66; P<0.005 compared with controls). The number of lesions was the strongest predictor of frequency of ADLA. Only 18% of the lesions had positive microscopy or culture for fungi (dermatophytes and Scytalidium).These findings highlight the importance of interdigital entry lesions as risk factors for episodes of ADLA and have implications for the control of morbidity from filarial lymphoedema.
Molecular Evolution and Phylogenetic Utility of the petD Group II Intron: A Case Study in Basal Angiosperms
Authors: Cornelia Löhne, Thomas Borsch
Journal: Molecular Biology and Evolution (2004)

Sequences of spacers and group I introns in plant chloroplast genomes have recently been shown to be very effective in phylogenetic reconstruction at higher taxonomic levels and not only for inferring relationships among species. Group II introns, being more frequent in those genomes than group I introns, may be further promising markers. Because group II introns are structurally constrained, we assumed that sequences of a group II intron should be alignable across seed plants. We designed universal amplification primers for the petD intron and sequenced this intron in a representative selection of 47 angiosperms and three gymnosperms. Our sampling of taxa is the most representative of major seed plant lineages to date for group II introns. Through differential analysis of structural partitions, we studied patterns of molecular evolution and their contribution to phylogenetic signal. Nonpairing stretches (loops, bulges, and interhelical nucleotides) were considerably more variable in both substitutions and indels than in helical elements. Differences among the domains are basically a function of their structural composition. After the exclusion of four mutational hotspots accounting for less than 18% of sequence length, which are located in loops of domains I and IV, all sequences could be aligned unambiguously across seed plants. Microstructural changes predominantly occurred in loop regions and are mostly simple sequence repeats. An indel matrix comprising 241 characters revealed microstructural changes to be of lower homoplasy than are substitutions. In showing Amborella first branching and providing support for a magnoliid clade through a synapomorphic indel, the petD data set proved effective in testing between alternative hypotheses on the basal nodes of the angiosperm tree. Within angiosperms, group II introns offer phylogenetic signal that is intermediate in information content between that of spacers and group I introns on the one hand and coding sequences on the other.
Neuropilin-1 Suppresses Tumorigenic Properties in a Human Pancreatic Adenocarcinoma Cell Line Lacking Neuropilin-1 Coreceptors
Authors: Michael J. Gray, Jane S. Wey, Anna Belcheva, Marya F. McCarty, Jose G. Trevino, Douglas B. Evans, Lee M. Ellis, Gary E. Gallick
Journal: Cancer Research (2005)

Abstract Neuropilin-1 (NRP-1) was first described as a coreceptor implicated in neuronal guidance that bound members of the semaphorin/collapsin family. NRP-1 is also expressed in endothelial cells and is believed to promote angiogenesis by acting as a coreceptor with vascular endothelial growth factor (VEGF) receptor 2. Recent studies suggest that NRP-1 can function through both a VEGF-dependent and VEGF-independent fashion. Expression of NRP-1 has been shown in many human tumors, including pancreatic adenocarcinomas. The exact role of NRP-1 in tumor cells is unknown, particularly in cells that lack the NRP-1 coreceptors VEGF receptor 2 and Plexin-A1. To discern the regulatory role(s) of NRP-1 in pancreatic adenocarcinoma that lack these coreceptors, we overexpressed both full-length NRP-1 and a deletion form of NRP-1 that does not interact with semaphorin or VEGF. Overexpression of either isoform reduced several key tumorigenic properties, including anchorage-independent cell growth and migration in vitro, and resulted in reduced tumor incidence and tumor volume in vivo. Conversely, reduction of NRP-1 expression by small interfering RNA targeting led to enhanced tumor growth. Thus, NRP-1 may play distinct growth regulatory roles in different tumor types, and altering NRP-1 expression or function may be a means of influencing the growth of pancreatic cancers.
Susceptibility loci for intracranial aneurysm in European and Japanese populations
Authors: Kaya Bilguvar, Katsuhito Yasuno, Mika Niemelä, Ynte M Ruigrok, Mikael von und zu Fraunberg, Cornelia M van Duijn, Leonard H van den Berg, Shrikant Mane, Christopher E Mason, Murim Choi, Emília Gaál, Yasar Bayri, Luis Kolb, Zulfikar Arlier, Sudhakar Ravuri, Antti Ronkainen, Atsushi Tajima, Aki Laakso, Akira Hata, Hidetoshi Kasuya, Timo Koivisto, Jaakko Rinne, Juha Öhman, Monique M B Breteler, Cisca Wijmenga, Matthew W State, Gabriel J E Rinkel, Juha Hernesniemi, Juha E Jääskeläinen, Aarno Palotie, Ituro Inoue, Richard P Lifton, Murat Günel
Journal: Nature Genetics (2008)
Decreased SLIM1 Expression and Increased Gelsolin Expression in Failing Human Hearts Measured by High-Density Oligonucleotide Arrays
Authors: Jiacheng Yang, Christine S. Moravec, Mark A. Sussman, Nicholas R. DiPaola, Dechen Fu, Lesley Hawthorn, Christina A. Mitchell, James B. Young, Gary S. Francis, Patrick M. McCarthy, Meredith Bond
Journal: Circulation (2000)

Background —Failing human hearts are characterized by altered cytoskeletal and myofibrillar organization, impaired signal transduction, abnormal protein turnover, and impaired energy metabolism. Thus, expression of multiple classes of genes is likely to be altered in human heart failure. Methods and Results —We used high-density oligonucleotide arrays to explore changes in expression of ≈7000 genes in 2 nonfailing and 2 failing human hearts with diagnoses of end-stage ischemic and dilated cardiomyopathy, respectively. We report altered expression of (1) cytoskeletal and myofibrillar genes (striated muscle LIM protein-1 [SLIM1], myomesin, nonsarcomeric myosin regulatory light chain-2 [MLC 2 ], and β-actin); (2) genes responsible for degradation and disassembly of myocardial proteins (α 1 -antichymotrypsin, ubiquitin, and gelsolin); (3) genes involved in metabolism (ATP synthase α-subunit, succinate dehydrogenase flavoprotein [SDH Fp] subunit, aldose reductase, and TIM17 preprotein translocase); (4) genes responsible for protein synthesis (elongation factor-2 [EF-2], eukaryotic initiation factor-4AII, and transcription factor homologue-HBZ17); and (5) genes encoding stress proteins (αB-crystallin and μ-crystallin). In 5 additional failing hearts and 4 additional nonfailing controls, we then compared expression of proteins encoded by the differentially expressed genes, αB-crystallin, SLIM1, gelsolin, α 1 -antichymotrypsin, and ubiquitin. In each case, changes in protein expression were consistent with changes in transcript measured by microarray analysis. Gelsolin protein expression was also increased in cardiomyopathic hearts from tropomodulin-overexpressing (TOT) mice and rac1-expressing (racET) mice. Conclusions —Altered expression of the genes identified in this study may contribute to development of the heart failure phenotype and/or represent compensatory mechanisms to sustain cardiac function in failing human hearts.
MACOP-B regimen in the treatment of adult Langerhans cell histiocytosis: experience on seven patients
Authors: E. Derenzini, M.P. Fina, V. Stefoni, C. Pellegrini, F. Venturini, A. Broccoli, L. Gandolfi, S. Pileri, S. Fanti, E. Lopci, P. Castellucci, C. Agostinelli, M. Baccarani, P.L. Zinzani
Journal: Annals of Oncology (2009)
Genome-driven integrated classification of breast cancer validated in over 7,500 samples
Authors: H Raza Ali, Oscar M Rueda, Suet-Feung Chin, Christina Curtis, Mark J Dunning, Samuel Ajr Aparicio, Carlos Caldas
Journal: Genome biology (2014)

Abstract Background IntClust is a classification of breast cancer comprising 10 subtypes based on molecular drivers identified through the integration of genomic and transcriptomic data from 1,000 breast tumors and validated in a further 1,000. We present a reliable method for subtyping breast tumors into the IntClust subtypes based on gene expression and demonstrate the clinical and biological validity of the IntClust classification. Results We developed a gene expression-based approach for classifying breast tumors into the ten IntClust subtypes by using the ensemble profile of the index discovery dataset. We evaluate this approach in 983 independent samples for which the combined copy-number and gene expression IntClust classification was available. Only 24 samples are discordantly classified. Next, we compile a consolidated external dataset composed of a further 7,544 breast tumors. We use our approach to classify all samples into the IntClust subtypes. All ten subtypes are observable in most studies at comparable frequencies. The IntClust subtypes are significantly associated with relapse-free survival and recapitulate patterns of survival observed previously. In studies of neo-adjuvant chemotherapy, IntClust reveals distinct patterns of chemosensitivity. Finally, patterns of expression of genomic drivers reported by TCGA (The Cancer Genome Atlas) are better explained by IntClust as compared to the PAM50 classifier. Conclusions IntClust subtypes are reproducible in a large meta-analysis, show clinical validity and best capture variation in genomic drivers. IntClust is a driver-based breast cancer classification and is likely to become increasingly relevant as more targeted biological therapies become available.
Morphogenesis of the right ventricle requires myocardial expression of Gata4
Authors: Elisabeth M. Zeisberg, Qing Ma, Amy L. Juraszek, Kelvin Moses, Robert J. Schwartz, Seigo Izumo, William T. Pu
Journal: Journal of Clinical Investigation (2005)

Mutations in developmental regulatory genes have been found to be responsible for some cases of congenital heart defects. One such regulatory gene is Gata4, a zinc finger transcription factor. In order to circumvent the early embryonic lethality of Gata4-null embryos and to investigate the role of myocardial Gata4 expression in cardiac development, we used Cre/loxP technology to conditionally delete Gata4 in the myocardium of mice at an early and a late time point in cardiac morphogenesis. Early deletion of Gata4 by Nkx2-5Cre resulted in hearts with striking myocardial thinning, absence of mesenchymal cells within the endocardial cushions, and selective hypoplasia of the RV. RV hypoplasia was associated with downregulation of Hand2, a transcription factor previously shown to regulate formation of the RV. Cardiomyocyte proliferation was reduced, with a greater degree of reduction in the RV than in the LV. Late deletion of Gata4 by Cre recombinase driven by the alpha myosin heavy chain promoter did not selectively affect RV development or generation of endocardial cushion mesenchyme but did result in marked myocardial thinning with decreased cardiomyocyte proliferation, as well as double-outlet RV. Our results demonstrate a general role of myocardial Gata4 in regulating cardiomyocyte proliferation and a specific, stage-dependent role in regulating the morphogenesis of the RV and the atrioventricular canal.
Phase 1 Study Evaluating Safety and Tolerability of Medi4736, an Anti-Programmed Cell Death Ligand-1 (Pd-L1) Antibody, in Combination with Dabrafenib and Trametinib or Trametinib Alone in Patients with Unresectable or Metastatic Melanoma
Authors: M.S. Gordon, J. Lutzky, D. Lawrence, M. Butler, P.A. Ascierto, B. Hug, A. Blake-Haskins, A. Di Pietro, X. Li, P.B. Robbins, A. Ribas
Journal: Annals of Oncology (2014)
Sharing of Ia antigens between species. I. Detection of Ia specificities shared by rats and mice.
Authors: D H Sachs, G W Humphrey, J K Lunney
Journal: The Journal of Experimental Medicine (1977)

A mouse anti-rat xenogeneic antiserum, B10.D2 anti-BN, has been found to react with a subpopulation of lymphoid cells of certain mouse strains. The corresponding alloantiserum, B10.D2 anti-B10.BR, reacted in analogous fashion with lymphoid cells of BN rats. In the case of the cross-reaction on mouse cells, mapping studies indicated that at least part of the reactivity was with the product of gene(s) determined by the I-A subregion of the H-2 complex. Chemical isolation studies with radiolabeled cell surface preparations indicated that the antigens detected in both mouse and rat had mol wt characteristic of Ia antigens (35,000 and 28,000 dalton molecules). Testing of fractionated spleen cell populations revealed that the cross-reactive antigens were expressed predominatly on B cells, but that a subpopulation of T cells were also reactive. Wider strain and species distribution studies are in progress to determine the extent of such Ia cross-reactions between species and to further assess the practical and theoretical importance of such cross-reactions.
Nodular Glomerulosclerosis with Deposition of Monoclonal Immunoglobulin Heavy Chains Lacking CH1
Authors: BRUNO MOULIN, SOPHIE DERET, XAVIER MARIETTE, OLIVIER KOURILSKY, HIROKAZU IMAI, LUC DUPOUET, LUC MARCELLIN, ISABELLE KOLB, PIERRE AUCOUTURIER, JEAN-CLAUDE BROUET, PIERRE M. RONCO, BÉATRICE MOUGENOT
Journal: Journal of the American Society of Nephrology (1999)

Abstract. The objective of this study was to further characterize the clinical and immunopathologic features of heavy chain deposition disease (HCDD), a recently described entity. Four patients were diagnosed as having HCDD on a kidney biopsy. All presented with nodular glomerulosclerosis with deposition of γ1 heavy chains lacking C H 1 epitopes, but without light chains. Two different patterns were observed in the serum. First, patients 1 and 2 had a circulating monoclonal IgGλ containing a short γ1 heavy chain lacking C H 1 epitopes, with an apparent molecular weight of 40 kD consistent with a complete C H 1 deletion. Biosynthetic experiments also showed that the deleted heavy chain was produced in excess compared with light chains, and was secreted in vitro together with half Ig molecules, although these abnormal components were not detected by Western blot analysis of whole serum. Second, patients 3 and 4 had a circulating monoclonal IgG1λ with an apparently normal, nondeleted heavy chain subunit, but serum fractionation followed by immunoblotting revealed an isolated monoclonal γ1 chain lacking C H 1 epitopes. These data strongly suggest that renal deposition of a C H 1-deleted heavy chain circulating in low amounts in the serum as a free unassembled subunit is a major feature of HCDD. The C H 1 deletion is most likely responsible for the premature secretion in blood of the heavy chain by a clone of plasma cells.