tbuckley/cabot-search huggingface dataset:
A common rejection module (CRM) for acute rejection across multiple organs identifies novel therapeutics for organ transplantation
Authors: Purvesh Khatri, Silke Roedder, Naoyuki Kimura, Katrien De Vusser, Alexander A. Morgan, Yongquan Gong, Michael P. Fischbein, Robert C. Robbins, Maarten Naesens, Atul J. Butte, Minnie M. Sarwal
Journal: The Journal of Experimental Medicine (2013)

Using meta-analysis of eight independent transplant datasets (236 graft biopsy samples) from four organs, we identified a common rejection module (CRM) consisting of 11 genes that were significantly overexpressed in acute rejection (AR) across all transplanted organs. The CRM genes could diagnose AR with high specificity and sensitivity in three additional independent cohorts (794 samples). In another two independent cohorts (151 renal transplant biopsies), the CRM genes correlated with the extent of graft injury and predicted future injury to a graft using protocol biopsies. Inferred drug mechanisms from the literature suggested that two FDA-approved drugs (atorvastatin and dasatinib), approved for nontransplant indications, could regulate specific CRM genes and reduce the number of graft-infiltrating cells during AR. We treated mice with HLA-mismatched mouse cardiac transplant with atorvastatin and dasatinib and showed reduction of the CRM genes, significant reduction of graft-infiltrating cells, and extended graft survival. We further validated the beneficial effect of atorvastatin on graft survival by retrospective analysis of electronic medical records of a single-center cohort of 2,515 renal transplant patients followed for up to 22 yr. In conclusion, we identified a CRM in transplantation that provides new opportunities for diagnosis, drug repositioning, and rational drug design.
A LIPOLYTIC ENZYME IN REACTIVE HISTIOCYTES OF GUINEA PIGS WITH EXPERIMENTAL ENCEPHALOMYELITIS
Authors: F. Stephen Vogel
Journal: The Journal of Experimental Medicine (1951)

A lipolytic enzyme has been demonstrated by means of a cytochemical technique and by direct chemical assay in granulomatous tissues of guinea pigs with encephalomyelitis and demyelinization resulting from the injection of an emulsion comprised of brain tissue and adjuvants, including Mycobacterium butyricum. Combined histologic and cytochemical studies showed that the lipolytic enzyme was present in the cytoplasm of a large proportion of the reactive histiocytes in the granulomatous tissue around the site of injection in the diseased animals, and that the enzyme-containing histiocytes were even more numerous in the inflamed regional lymph nodes. In control experiments, when emulsions lacking either brain tissue or M. butyricum were injected in previously normal guinea pigs, the experimental condition did not develop; under these circumstances the lipolytic enzyme was found in only a small proportion of the cells of the granulomatous tissue around the injection sites, and it was almost negligible in the regional lymph nodes of these animals. It was absent from the cells of the lymph nodes of normal animals, and from the cells of talcum and aluminum hydroxide granulomas produced experimentally in guinea pigs. The lipolytic enzyme may be a factor in the pathogenesis of the experimental encephalomyelitis and demyelinization.
The Evolutionary History of Human and Chimpanzee Y-Chromosome Gene Loss
Authors: G. H. Perry, R. Y. Tito, B. C. Verrelli
Journal: Molecular Biology and Evolution (2006)

Recent studies have suggested that gene gain and loss may contribute significantly to the divergence between humans and chimpanzees. Initial comparisons of the human and chimpanzee Y-chromosomes indicate that chimpanzees have a disproportionate loss of Y-chromosome genes, which may have implications for the adaptive evolution of sex-specific as well as reproductive traits, especially because one of the genes lost in chimpanzees is critically involved in spermatogenesis in humans. Here we have characterized Y-chromosome sequences in gorilla, bonobo, and several chimpanzee subspecies for 7 chimpanzee gene–disruptive mutations. Our analyses show that 6 of these gene-disruptive mutations predate chimpanzee–bonobo divergence at ∼1.8 MYA, which indicates significant Y-chromosome change in the chimpanzee lineage relatively early in the evolutionary divergence of humans and chimpanzees.
The early decline in renal function in patients with type 1 diabetes and proteinuria predicts the risk of end-stage renal disease
Authors: Jan Skupien, James H. Warram, Adam M. Smiles, Monika A. Niewczas, Tomohito Gohda, Marcus G. Pezzolesi, Diego Cantarovich, Robert Stanton, Andrzej S. Krolewski
Journal: Kidney International (2012)
The Challenge and Promise of the Genomic Era
Authors: George W. Sledge
Journal: Journal of Clinical Oncology (2011)

Welcome, colleagues, to the 47th annual meeting of the American Society of Clinical Oncology (ASCO). Thank you all for attending—and for the passion and intelligence you bring to our society. It has been my great honor to serve as your president this past year, a year of momentous change not only for ASCO but for health care and for cancer biology as well. It is a time of real progress in the science of cancer, and I would like to spend some time with you today sharing my thoughts on where the emerging science of cancer is taking us as a profession. I am dedicating this talk to my administrative assistant, Lisa Miller, who is here with us today. Lisa keeps me out of trouble; she is dedicated, cheerful, kind, and smart. She is a wife and the mother of two beautiful daughters. Lisa also harbors a BRCA1 mutation. Recently, she was diagnosed with triplenegative breast cancer and is currently receiving chemotherapy. She is one of more than a million and a half Americans who will be diagnosed with cancer this year. I know that you will share my best wishes for Lisa, who is here today, and thank her for her willingness to represent those fighting their own personal battles with this disease. My family, and in particular my wife, Carolyn, have had to put up with my many absences this past year. I am grateful for their forbearance and loving support. ASCO Presidents benefit greatly from the support of ASCO volunteers. This year, I drew on a hugely talented group of members who populate our many committees. I do not have time to name them all, but I will draw your attention to Kathy Miller and Chuck Blanke, Chairs of the Scientific Program and Education Committees. They have devoted their all to making this meeting a success, and I am grateful to them. ASCO also benefits from an incredibly talented staff. Their esprit de corps, their work ethic, and their intelligence are incredible. From our CEO Allen Lichter on down, I have never worked with such an impressive staff in any organization. They go out of their way every day in support of our mission. STATE OF THE AMERICAN SOCIETY OF CLINICAL ONCOLOGY
β-catenin represses expression of the tumour suppressor 15-prostaglandin dehydrogenase in the normal intestinal epithelium and colorectal tumour cells
Authors: Helena J M Smartt, Alexander Greenhough, Paloma Ordóñez-Morán, Elena Talero, Catherine A Cherry, Catherine A Wallam, Lee Parry, Manal Al Kharusi, Heather R Roberts, John M Mariadason, Alan R Clarke, Joerg Huelsken, Ann C Williams, Chris Paraskeva
Journal: Gut (2011)

Cyclooxygenase-2 (COX-2) overexpression in colorectal cancer increases levels of its pro-tumorigenic product prostaglandin E2 (PGE(2)). The recently identified colorectal tumour suppressor 15-prostaglandin dehydrogenase (15-PGDH) catalyses prostaglandin turnover and is downregulated at a very early stage in colorectal tumorigenesis; however, the mechanism responsible remains unclear. As Wnt/β-catenin signalling is also deregulated early in colorectal neoplasia, a study was undertaken to determine whether β-catenin represses 15-PGDH expression.The effect of modulating Wnt/β-catenin signalling (using β-catenin siRNA, mutant TCF4, Wnt3A or GSK3 inhibition) on 15-PGDH mRNA, protein expression and promoter activity was determined in colorectal cell lines by immunoblotting, qRT-PCR and reporter assays. The effect of β-catenin deletion in vivo was addressed by 15-PGDH immunostaining of β-catenin(-/lox)-villin-creERT2 mouse tissue. 15-PGDH promoter occupancy was determined using chromatin immunoprecipitation and PGE(2) levels by ELISA.The study shows for the first time that β-catenin knockdown upregulates 15-PGDH in colorectal adenoma and carcinoma cells without affecting COX-2 protein levels. A dominant negative mutant form of TCF4 (dnTCF4), unable to bind β-catenin, also upregulated 15-PGDH; conversely, increasing β-catenin activity using Wnt3A or GSK3 inhibition downregulated 15-PGDH. Importantly, inducible β-catenin deletion in vivo also upregulated intestinal epithelial 15-PGDH. 15-PGDH regulation occurred at the protein, mRNA and promoter activity levels and chromatin immunoprecipitation indicated β-catenin/TCF4 binding to the 15-PGDH promoter. β-catenin knockdown decreased PGE(2) levels, and this was significantly rescued by 15-PGDH siRNA.These data suggest a novel role for β-catenin in promoting colorectal tumorigenesis through very early 15-PGDH suppression leading to increased PGE(2) levels, possibly even before COX-2 upregulation.
Pharmacokinetics of alemtuzumab used for in vivo and in vitro T-cell depletion in allogeneic transplantations: relevance for early adoptive immunotherapy and infectious complications
Authors: Emma C. Morris, Peppy Rebello, Kirsty J. Thomson, Karl S. Peggs, Charalampia Kyriakou, Anthony H. Goldstone, Stephen Mackinnon, Geoff Hale
Journal: Blood (2003)
Cardiac Resynchronization Therapy Improves Heart Rate Variability in Patients with Symptomatic Heart Failure
Authors: Philip B. Adamson, Karen J. Kleckner, Warren L. VanHout, Sriram Srinivasan, William T. Abraham
Journal: Circulation (2003)

Cardiac resynchronization therapy (CRT) using biventricular pacing improves symptoms and functional capacity in patients with moderate to severe heart failure. The present study examined whether an improvement in ventricular performance from resynchronization therapy changes the autonomic control of heart rate.Heart rate variability (HRV) was examined in 50 patients implanted with the InSync biventricular pacing system who were randomized to therapy-on (n=25) or therapy-off (n=25). HRV was computed as the standard deviation of the atrial cycle length sensed from the system over 2 months of continuous monitoring. HRV was compared between CRT-on and CRT-off groups. HRV was higher in patients randomized to CRT-on compared with CRT-off (148+/-47 ms for CRT-on versus 118+/-45 ms for CRT-off; P=0.02), despite the lack of difference in mean atrial cycle length (844+/-129 ms for CRT-on versus 851+/-110 ms for CRT-off; P=0.82). Changes in plasma catecholamines were not different between the CRT-on and CRT-off groups from baseline to the 3-month follow-up.Improvement in ventricular performance from CRT shifts cardiac autonomic balance toward a more favorable profile that is less dependent on sympathetic activation.
Viability of fresh aortic valve homografts: a quantitative assessment
Authors: N. Al-Janabi, L. Gonzalez-Lavin, R. Neirotti, D. N. Ross
Journal: Thorax (1972)

Accumulated evidence indicates that fresh aortic valve homografts function longer than preserved grafts. Thus it becomes important to assess the viability of fresh homografts on a quantitative basis. Recently, we have used autoradiography in addition to tissue culture to determine the viability of fresh aortic and pulmonary valve homografts. The uptake of thymidine was gradually reduced to 50% after 18 days of preservation in a balanced salt solution with antibiotics and the uptake was reduced to 21% in 63 days. We think that a nutrient medium is necessary if longer viability is to be obtained.
Helicobacter and gastric MALT lymphoma
Authors: M Stolte, E Bayerdorffer, A Morgner, B Alpen, T Wundisch, C Thiede, A Neubauer
Journal: Gut (2002)

<i>Helicobacter pylori</i> infection is a pre-MALT lymphoma condition. <i>H pylori</i> eradication leads to complete remission in 80% of low grade stage E1 lymphomas, with a yearly recurrence rate of approximately 5%. The possibility for complete remission in high grade lymphomas needs to be investigated in prospective studies. In addition, the significance of persistent B cell monoclonality (stable disease? danger of relapse? regression of monoclonality?) needs to be investigated in follow up studies.
Synovial sarcoma in children and adolescents: the European Pediatric Soft Tissue Sarcoma Study Group prospective trial (EpSSG NRSTS 2005)
Authors: A. Ferrari, G.L. De Salvo, B. Brennan, M.M. van Noesel, A. De Paoli, M. Casanova, N. Francotte, A. Kelsey, R. Alaggio, O. Oberlin, M. Carli, M. Ben-Arush, C. Bergeron, J.H.M. Merks, M. Jenney, M.C. Stevens, G. Bisogno, D. Orbach
Journal: Annals of Oncology (2014)
Effects of p27Kip1 on cell cycle status and viability in A549 lung adenocarcinoma cells
Authors: T. Ishii, M. Fujishiro, M. Masuda, Y. Goshima, H. Kitamura, S. Teramoto, T. Matsuse
Journal: European Respiratory Journal (2004)

p27Kip1 is a cyclin-dependent kinase inhibitor, it negatively regulates G1 progression and is reported to modulate apoptosis. Phosphorylation of this protein is thought to regulate its intracellular localisation and affect its stability. The aim of this study was to regulate p27Kip1 expression levels, and to examine how this protein affects cell cycle status and modulates viability in A549 lung adenocarcinoma cells. In addition, the association between phosphorylation status of p27Kip1 and its intracellular localisation was investigated, using expression vectors with cDNA of p27Kip1 or mutants in which the phosphorylation sites had been mutated. Although overexpression of p27Kip1 reduced cell cycle progression, its removal did not change cell cycle status. Modest induction of p27Kip1 rescued adenovector-induced apoptosis and its removal with short interfering RNA increased spontaneous cell death. It was also observed that p27Kip1 localised mainly in the cytoplasm, and forced expression of p27Kip1 cDNA with the substitution of serine (S) 10, threonine (T) 157 and T198 to glutamate (phosphor-mimetic) induced its cytoplasmic localisation. In conclusion, p27Kip1, when expressed physiologically, exists mainly in the cytoplasm, has little effect on cell cycle status and contributes viability in A549 lung adenocarcinoma cells. It was also surmised that intracellular localisation of p27Kip1 dominates its function and that its localisation was partly determined by its phosphorylation.
A Novel Nuclear Factor-κB Gene Signature Is Differentially Expressed in Head and Neck Squamous Cell Carcinomas in Association with TP53 Status
Authors: Tin Lap Lee, Xin Ping Yang, Bin Yan, Jay Friedman, Praveen Duggal, Lorena Bagain, Gang Dong, Ning T. Yeh, Jie Wang, Jian Zhou, Abdel Elkahloun, Carter Van Waes, Zhong Chen
Journal: Clinical Cancer Research (2007)

Abstract Purpose: To determine if gene signatures differentially expressed in head and neck squamous cell carcinomas (HNSCC) are related to alterations in transcription factors nuclear factor-κB (NF-κB) and TP53 previously associated with decreased cell death, response to therapy, and worse prognosis. Experimental Design: Unique gene signatures expressed by HNSCC lines were identified by cDNA microarray, principal components, and cluster analyses and validated by quantitative reverse transcription-PCR (RT-PCR) and in situ hybridization. Bioinformatic analysis of the promoters and ontogeny of these clustered genes was done. Expression of proteins encoded by genes of a putative NF-κB signature, NF-κB p65, and TP53 were examined in HNSCC tissue specimens by immunostaining. Predicted promoter binding and modulation of expression of candidate NF-κB genes and cell survival were evaluated by p65 chromatin immunoprecipitation (ChIP) and small interfering RNA (siRNA) knockdown. Results: Two groups of HNSCC exhibiting distinct gene signatures were identified: cluster A enriched for histone genes, with a higher prevalence of TP53 promoter binding motifs; and cluster B enriched for injury response genes with NF-κB regulatory motifs. Coexpression of cluster B proteins was observed with strong NF-κB phospho-p65 and weak TP53 staining, and NF-κB phospho-p65 was inversely associated with TP53 (P = 0.02). Promoter binding of the NF-κB signature genes was confirmed by p65 ChIP, and down-modulation of their expression and cell death were induced by p65 siRNA. Conclusion: NF-κB promotes expression of a novel NF-κB–related gene signature and cell survival in HNSCC that weakly express TP53, a subset previously associated with inactivated wild-type TP53, greater resistance to chemoradiotherapy, and worse prognosis.
Portsmouth Medical Union
Authors: T. F. Pearse
Journal: BMJ (1895)

<h3>Objectives</h3> To evaluate (1) the state of the art in sustainability research and (2) the outcomes of professionals’ adherence to guideline recommendations in medical practice. <h3>Design</h3> Systematic review. <h3>Data sources</h3> Searches were conducted until August 2015 in MEDLINE, CINAHL, EMBASE, Cochrane Central Register of Controlled Trials <i>(</i>CENTRAL) and the Guidelines International Network (GIN) library. A snowball strategy, in which reference sections of other reviews and of included papers were searched, was used to identify additional papers. <h3>Eligibility criteria</h3> Studies needed to be focused on sustainability and on professionals’ adherence to clinical practice guidelines in medical care. Studies had to include at least 2 measurements: 1 before (PRE) or immediately after implementation (EARLY POST) and 1 measurement longer than 1 year after active implementation (LATE POST). <h3>Results</h3> The search retrieved 4219 items, of which 14 studies met the inclusion criteria, involving 18 sustainability evaluations. The mean timeframe between the end of active implementation and the sustainability evaluation was 2.6 years (minimum 1.5–maximum 7.0). The studies were heterogeneous with respect to their methodology. Sustainability was considered to be successful if performance in terms of professionals’ adherence was fully maintained in the late postimplementation phase. Long-term sustainability of professionals’ adherence was reported in 7 out of 18 evaluations, adherence was not sustained in 6 evaluations, 4 evaluations showed mixed sustainability results and in 1 evaluation it was unclear whether the professional adherence was sustained. <h3>Conclusions</h3> (2) Professionals’ adherence to a clinical practice guideline in medical care decreased after more than 1 year after implementation in about half of the cases. (1) Owing to the limited number of studies, the absence of a uniform definition, the high risk of bias, and the mixed results of studies, no firm conclusion about the sustainability of professionals’ adherence to guidelines in medical practice can be drawn.
Constitutive and Induced CD44 Shedding by ADAM-Like Proteases and Membrane-Type 1 Matrix Metalloproteinase
Authors: Hiroyuki Nakamura, Naoko Suenaga, Kaori Taniwaki, Hirokazu Matsuki, Kayoko Yonezawa, Masato Fujii, Yasunori Okada, Motoharu Seiki
Journal: Cancer Research (2004)

Abstract CD44 is a receptor for hyaluronan and mediates signaling that regulates complex cell behavior including cancer cell migration and invasion. Shedding of the extracellular portion of CD44 is the last step in the regulation of the molecule-releasing interaction between the ligand and cell. However, highly glycosylated forms of CD44 have hampered the identification of the exact cleavage sites for shedding and the responsible proteases. In this study, we found that expression of membrane-type 1 matrix metalloproteinase (MT1-MMP) increased shedding of the 65–70 kDa CD44H (standard form) fragments and generated two additional smaller fragments. We purified the shed fragments and identified the cleaved sites by mass spectrometry. Specific antibodies that recognize the newly exposed COOH terminus by cleavage were prepared and used to analyze shedding at each site. Shedding of the 65–70 kDa fragments was inhibited by tissue inhibitor of metalloproteinase 3 (TIMP-3) but not by TIMP-1 and TIMP-2, suggesting involvement of a disintegrin and metalloproteinase (ADAM)-like proteases, although shedding is affected by MT1-MMP. Conversely, shedding of the two smaller fragments was inhibited by TIMP-2 and TIMP-3 but not TIMP-1, suggesting involvement of MT1-MMP itself. Shed fragments cleaved at these sites were also detected in human tumor tissues. Increased shedding at one of the MT1-MMP-sensitive sites was observed in the tumor compared with the surrounding normal tissue. However, no significant difference was observed with shedding by ADAM-like proteases. Thus, the cleavage sites for the shedding of CD44H were identified for the first time, and the results provide a basis for exploring the unknown biologic roles of shedding at different sites.
Induction of Fas Ligand Expression by HIV Involves the Interaction of Nef with the T Cell Receptor ζ Chain
Authors: Xiao-Ning Xu, Bernd Laffert, Gavin R. Screaton, Michael Kraft, Dietlinde Wolf, Waldemar Kolanus, Juthathip Mongkolsapay, Andrew J. McMichael, Andreas S. Baur
Journal: The Journal of Experimental Medicine (1999)

During HIV/SIV infection, there is widespread programmed cell death in infected and, perhaps more importantly, uninfected cells. Much of this apoptosis is mediated by Fas-Fas ligand (FasL) interactions. Previously we demonstrated in macaques that induction of FasL expression and apoptotic cell death of both CD4(+) and CD8(+) T cells by SIV is dependent on a functional nef gene. However, the molecular mechanism whereby HIV-1 induces the expression of FasL remained poorly understood. Here we report a direct association of HIV-1 Nef with the zeta chain of the T cell receptor (TCR) complex and the requirement of both proteins for HIV-mediated upregulation of FasL. Expression of FasL through Nef depended upon the integrity of the immunoreceptor tyrosine-based activation motifs (ITAMs) of the TCR zeta chain. Conformation for the importance of zeta for Nef-mediated signaling in T cells came from an independent finding. A single ITAM motif of zeta but not CD3epsilon was both required and sufficient to promote activation and binding of the Nef-associated kinase (NAK/p62). Our data imply that Nef can form a signaling complex with the TCR, which bypasses the requirement of antigen to initiate T cell activation and subsequently upregulation of FasL expression. Thus, our study may provide critical insights into the molecular mechanism whereby the HIV-1 accessory protein Nef contributes to the pathogenesis of HIV.
HYPERTROPHIED PAPILLAE OF MORGAGNI CAUSING RECTAL SYMPTOMS
Authors: A. C. Magarey
Journal: BMJ (1911)

CONCLUSIONS.1. Elicitation of the aortic reflexes aid the diagnosis of aortic aneurysm.2. Elic-itation of the aortic reflex of contraction results in the symptomatic cure of aortic aneurysms, and the results are so astonishiingly rapid that one is warranted in concluding that the method is practically a specific.given in these investigations.-
Microglial Cx3cr1 knockout prevents neuron loss in a mouse model of Alzheimer's disease
Authors: Martin Fuhrmann, Tobias Bittner, Christian K E Jung, Steffen Burgold, Richard M Page, Gerda Mitteregger, Christian Haass, Frank M LaFerla, Hans Kretzschmar, Jochen Herms
Journal: Nature Neuroscience (2010)