tbuckley/cabot-search huggingface dataset:
Randomized Comparison of Sirolimus-Eluting Stent Versus Standard Stent for Percutaneous Coronary Revascularization in Diabetic Patients
Authors: Manel Sabaté, Pilar Jiménez-Quevedo, Dominick J. Angiolillo, Joan Antoni Gómez-Hospital, Fernando Alfonso, Rosana Hernández-Antolín, Javier Goicolea, Camino Bañuelos, Javier Escaned, Raúl Moreno, Cristina Fernández, Francisco Fernández-Avilés, Carlos Macaya
Journal: Circulation (2005)

Outcomes after percutaneous coronary interventions in diabetic patients are shadowed by the increased rate of recurrence compared with nondiabetic patients.We conducted a multicenter, randomized trial to demonstrate the efficacy of sirolimus-eluting stents compared with standard stents to prevent restenosis in diabetic patients with de novo lesions in native coronary arteries. The primary end point of the trial was in-segment late lumen loss as assessed by quantitative coronary angiography at 9-month follow-up. The trial was stratified by diabetes treatment status. One hundred sixty patients were randomized to sirolimus-eluting stents (80 patients; 111 lesions) or standard stent implantation (80 patients; 110 lesions). On average, reference diameter was 2.34+/-0.6 mm, lesion length was 15.0+/-8 mm, and 13.1% of lesions were chronic total occlusions. In-segment late lumen loss was reduced from 0.47+/-0.5 mm for standard stents to 0.06+/-0.4 mm for sirolimus stents (P<0.001). Target-lesion revascularization and major adverse cardiac event rates were significantly lower in the sirolimus group (31.3% versus 7.3% and 36.3% versus 11.3%, respectively; both P<0.001). Non-insulin- and insulin-requiring patients demonstrated similar reductions in angiographic and clinical parameters of restenosis after sirolimus-eluting stent implantation. During the 9-month follow-up, stent thrombosis occurred in 2 patients after standard stent implantation. Conversely, this phenomenon was not seen in the sirolimus stent group.This randomized trial demonstrated that sirolimus stent implantation is safe and efficacious in reducing both angiographic and clinical parameters of restenosis compared with standard stents in diabetic patients with de novo coronary stenoses.
Barley landraces are characterized by geographically heterogeneous genomic origins
Authors: Ana M. Poets, Zhou Fang, Michael T. Clegg, Peter L. Morrell
Journal: Genome biology (2015)

The genetic provenance of domesticated plants and the routes along which they were disseminated in prehistory have been a long-standing source of debate. Much of this debate has focused on identifying centers of origins for individual crops. However, many important crops show clear genetic signatures of multiple domestications, inconsistent with geographically circumscribed centers of origin. To better understand the genetic contributions of wild populations to domesticated barley, we compare single nucleotide polymorphism frequencies from 803 barley landraces to 277 accessions from wild populations.We find that the genetic contribution of individual wild populations differs across the genome. Despite extensive human movement and admixture of barley landraces since domestication, individual landrace genomes indicate a pattern of shared ancestry with geographically proximate wild barley populations. This results in landraces with a mosaic of ancestry from multiple source populations rather than discrete centers of origin. We rule out recent introgression, suggesting that these contributions are ancient. The over-representation in landraces of genomic segments from local wild populations suggests that wild populations contributed locally adaptive variation to primitive varieties.This study increases our understanding of the evolutionary process associated with the transition from wild to domesticated barley. Our findings indicate that cultivated barley is comprised of multiple source populations with unequal contributions traceable across the genome. We detect putative adaptive variants and identify the wild progenitor conferring those variants.
Chemoresistance of glioblastoma cancer stem cells - much more complex than expected
Authors: Dagmar Beier, Joerg B Schulz, Christoph P Beier
Journal: Molecular Cancer (2011)

Glioblastomas (GBM) are a paradigm for the investigation of cancer stem cells (CSC) in solid malignancies. The susceptibility of GBM CSC to standard chemotherapeutic drugs is controversial as the existing literature presents conflicting experimental data. Here, we summarize the experimental evidence on the resistance of GBM CSC to alkylating chemotherapeutic agents, with a special focus on temozolomide (TMZ). The data suggests that CSC are neither resistant nor susceptible to chemotherapy per se. Detoxifying proteins such as O6-methylguanine-DNA-methyltransferase (MGMT) confer a strong intrinsic resistance to CSC in all studies. Extrinsic factors may also contribute to the resistance of CSC to TMZ. These may include TMZ concentrations in the brain parenchyma, TMZ dosing schemes, hypoxic microenvironments, niche factors, and the re-acquisition of stem cell properties by non-stem cells. Thus, the interaction of CSC and chemotherapy is more complex than may be expected and it is necessary to consider these factors in order to overcome chemoresistance in the patient.
Impact of intra-individual molecular heterogeneity in personalized treatment of hepatocellular carcinoma
Authors: Augusto Villanueva, Josep M. Llovet
Journal: Hepatology (2012)

Intratumor heterogeneity may foster tumor evolution and adaptation and hinder personalized-medicine strategies that depend on results from single tumor-biopsy samples. To examine intratumor heterogeneity, we performed exome sequencing, chromosome aberration analysis, and ploidy profiling on multiple spatially separated samples obtained from primary renal carcinomas and associated metastatic sites. We characterized the consequences of intratumor heterogeneity using immunohistochemical analysis, mutation functional analysis, and profiling of messenger RNA expression. Phylogenetic reconstruction revealed branched evolutionary tumor growth, with 63 to 69% of all somatic mutations not detectable across every tumor region. Intratumor heterogeneity was observed for a mutation within an autoinhibitory domain of the mammalian target of rapamycin (mTOR) kinase, correlating with S6 and 4EBP phosphorylation in vivo and constitutive activation of mTOR kinase activity in vitro. Mutational intratumor heterogeneity was seen for multiple tumor-suppressor genes converging on loss of function; SETD2, PTEN, and KDM5C underwent multiple distinct and spatially separated inactivating mutations within a single tumor, suggesting convergent phenotypic evolution. Gene-expression signatures of good and poor prognosis were detected in different regions of the same tumor. Allelic composition and ploidy profiling analysis revealed extensive intratumor heterogeneity, with 26 of 30 tumor samples from four tumors harboring divergent allelic-imbalance profiles and with ploidy heterogeneity in two of four tumors. Intratumor heterogeneity can lead to underestimation of the tumor genomics landscape portrayed from single tumor-biopsy samples and may present major challenges to personalized-medicine and biomarker development. Intratumor heterogeneity, associated with heterogeneous protein function, may foster tumor adaptation and therapeutic failure through Darwinian selection. (Funded by the Medical Research Council and others.)
Multiple mouse-protective antibodies directed against group B streptococci. Special reference to antibodies effective against protein antigens.
Authors: R C Lancefield, M McCarty, W N Everly
Journal: The Journal of Experimental Medicine (1975)

The data presented in this paper establish the finding that multiple specific protective antibodies exist in rabbits in response to immunization with Group B streptococci. The summary in Table I indicates the serological types into which Group B streptococci have been divided on the basis of their antigenic composition. This classification is dependent upon passive protection of mice with antibodies directed against the specific antigens, and types are defined in these terms. Heretofore, it was thought that type-specific polysaccharides accounted for all such protection in Group B streptococci. Certain exceptions of cross-protection between types due to minor polysaccharide determinants soon appeared; cross-protection reactions based on protein determinants in at least two types were also discovered. The present experiments show that specific antibodies directed to either polysaccharide or protein antigens of a single strain can be protective against infection with streptococci containing these antigens.
B-Raf Is Dispensable for K-Ras-Mediated Oncogenesis in Human Cancer Cells
Authors: Jung-Sik Kim, Carolyn Lee, Aaron Foxworth, Todd Waldman
Journal: Cancer Research (2004)

Abstract Oncogenic mutations in B-Raf and Kirsten-Ras (K-Ras) are mutually exclusive during human cancer pathogenesis. In an effort to study the biological basis of this epistasis, gene targeting was used to create isogenic sets of human cancer cells differing only in presence or absence of endogenous oncogenic K-Ras or wild-type B-Raf. Whereas cells lacking the K-Ras oncogene were unable to efficiently form xenograft tumors, isogenic cells retaining activated K-Ras but deleted for B-Raf remained highly tumorigenic. Deletion of oncogenic K-Ras failed to reduce the activation state of B-Raf or ERK1/2, despite the requirement of oncogenic K-Ras for tumorigenesis. Genechip analysis revealed numerous genes in which the regulation by oncogenic K-Ras did not require B-Raf. These studies suggest that despite the mutual exclusivity of K-Ras and B-Raf mutations in human cancer and the well-described role for Raf proteins as Ras effectors, B-Raf is dispensable for K-Ras-mediated oncogenesis in a human cancer cell line. Additional studies are required to demonstrate the generalizability of these unexpected findings.
Failure to detect the presence of Chlamydia pneumoniae in sarcoid pathology specimens
Authors: F Blasi, G Rizzato, M Gambacorta, R Cosentini, R Raccanelli, P Tarsia, C Arosio, E Savini, C Cantoni, L Fagetti, L Allegra
Journal: European Respiratory Journal (1997)

The pathogenesis of sarcoidosis is not yet known. On the basis of seroepidemiological data, an association between Chlamydia pneumoniae infection and sarcoidosis has been suggested, but so far no study has addressed the direct detection of this agent in the affected tissues. The aim of the present study was to detect C. pneumoniae deoxyribonucleic acid (DNA) within sarcoid tissue specimens by means of a two-step polymerase chain reaction. Lung biopsy specimens of 33 patients with histologically confirmed pulmonary sarcoidosis and 21 control lung biopsies or pathology specimens of patients with pulmonary carcinoma or emphysema were retrospectively analysed. A nested polymerase chain reaction was applied using two sets of primers designed to detect a fragment of the 16 strand ribosomal ribonucleic acid (rRNA) gene of C. pneumoniae. The results of the study failed to demonstrate the presence of C. pneumoniae in biopsy specimens of sarcoid tissue and in the control lung biopsies or pathology specimens. Our results, therefore, tend to rule out the possibility of a direct involvement of Chlamydia pneumoniae in the pathogenesis of sarcoidosis.
Influence of CD80, Interleukin-2, and Interleukin-7 Expression in Human Renal Cell Carcinoma on the Expansion, Function, and Survival of Tumor-Specific CTLs
Authors: Bernhard Frankenberger, Heike Pohla, Elfriede Noessner, Gerald Willimsky, Britta Papier, Antonio Pezzutto, Joachim Kopp, Ralph Oberneder, Thomas Blankenstein, Dolores J. Schendel
Journal: Clinical Cancer Research (2005)

Abstract Purpose: A renal cell carcinoma (RCC) line, RCC-26, has been identified as a suitable candidate for development of an allogeneic tumor cell vaccine based on its expression of a variety of tumor-associated antigens (TAA). To improve immunogenicity, RCC-26 cells were genetically engineered to express CD80 alone or in combination with interleukin (IL)-2 or IL-7. The effect of these modifications on proliferation, function, and survival of autologous and allogeneic tumor-specific CTLs was assessed. Experimental Design: RCC-26 sublines expressing different transgenes were tested for their capacity to reactivate cytokine secretion and cytotoxicity in autologous tumor-infiltrating lymphocytes, to improve proliferation and survival of tumor-associated T cells present in autologous peripheral blood, and to induce tumor-associated responses in naive allogeneic lymphocytes. The expression of several common TAA was quantitated in the RCC-26 sublines using reverse transcription-PCR to identify surrogate markers for immune monitoring in clinical trials. Results: Gene-modified RCC-26 cells showed enhanced immunogenicity. CD80 expression was necessary to induce RCC-associated CTL in blood of healthy allogeneic donors. It also improved proliferation of autologous effector-memory T cells. Further enhancement was achieved with IL-2 through induction of the antiapoptosis protein Bcl-xL. The candidate vaccine lines overexpressed several common TAA that are suitable markers for immune monitoring. Conclusions: RCC-26 cells coexpressing CD80 and cytokine transgenes display improved immunogenic characteristics, supporting their use as allogeneic tumor cell vaccines for HLA-A2-matched patients with metastatic RCC.
Array-Based Comparative Genomic Hybridization Analysis Reveals Recurrent Chromosomal Alterations and Prognostic Parameters in Primary Cutaneous Large B-Cell Lymphoma
Authors: Remco Dijkman, Cornelis P. Tensen, Ekaterina S. Jordanova, Jeroen Knijnenburg, Juliette J. Hoefnagel, Aat A. Mulder, Carla Rosenberg, Anton K. Raap, Rein Willemze, Károly Szuhai, Maarten H. Vermeer
Journal: Journal of Clinical Oncology (2005)

To evaluate the clinical relevance of genomic aberrations in primary cutaneous large B-cell lymphoma (PCLBCL).Skin biopsy samples of 31 patients with a PCLBCL classified as either primary cutaneous follicle center lymphoma (PCFCL; n = 19) or PCLBCL, leg type (n = 12), according to the WHO-European Organisation for Research and Treatment of Cancer (EORTC) classification, were investigated using array-based comparative genomic hybridization, fluorescence in situ hybridization (FISH), and examination of promoter hypermethylation.The most recurrent alterations in PCFCL were high-level DNA amplifications at 2p16.1 (63%) and deletion of chromosome 14q32.33 (68%). FISH analysis confirmed c-REL amplification in patients with gains at 2p16.1. In PCLBCL, leg type, most prominent aberrations were a high-level DNA amplification of 18q21.31-q21.33 (67%), including the BCL-2 and MALT1 genes as confirmed by FISH, and deletions of a small region within 9p21.3 containing the CDKN2A, CDKN2B, and NSG-x genes. Homozygous deletion of 9p21.3 was detected in five of 12 patients with PCLBCL, leg type, but in zero of 19 patients with PCFCL. Complete methylation of the promoter region of the CDKN2A gene was demonstrated in one PCLBCL, leg type, patient with hemizygous deletion, in one patient without deletion, but in zero of 19 patients with PCFCL. Seven of seven PCLBCL, leg type, patients with deletion of 9p21.3 and/or complete methylation of CDKN2A died as a result of their lymphoma.Our results demonstrate prominent differences in chromosomal alterations between PCFCL and PCLBCL, leg type, that support their classification as separate entities within the WHO-EORTC scheme. Inactivation of CDKN2A by either deletion or methylation of its promoter could be an important prognostic parameter for the group of PCLBCL, leg type.
Intratumoral Epidermal Growth Factor Receptor Antisense DNA Therapy in Head and Neck Cancer: First Human Application and Potential Antitumor Mechanisms
Authors: Stephen Y. Lai, Priya Koppikar, Sufi M. Thomas, Erin E. Childs, Ann Marie Egloff, Raja R. Seethala, Barton F. Branstetter, William E. Gooding, Ashok Muthukrishnan, James M. Mountz, Vivian W.Y. Lui, Dong M. Shin, Sanjiv S. Agarwala, Rita Johnson, Larry A. Couture, Eugene N. Myers, Jonas T. Johnson, Gordon Mills, Athanassios Argiris, Jennifer R. Grandis
Journal: Journal of Clinical Oncology (2009)

Squamous cell carcinoma of the head and neck (SCCHN) is characterized by upregulation of the epidermal growth factor receptor (EGFR). We developed a novel strategy to target EGFR by using a therapeutic gene that consisted of an EGFR antisense (AS) gene sequence under U6 promoter control. A phase I clinical trial was conducted to evaluate the safety and biologic effects of EGFR AS.Patients with advanced SCCHN who were refractory to standard therapies and who had at least one assessable and accessible lesion were enrolled. The EGFR AS dose was escalated in successive cohorts (six dose levels; 60 to 1,920 microg/injection). Patients received four weekly intratumoral EGFR AS injections. Tumor biopsies were performed before and after completion of therapy. Treatment response was assessed by tumor volume measurements (positron emission tomography/computed tomography), and levels of target proteins were assessed by immunohistochemistry.Seventeen assessable patients were treated. No grades 3 to 4 or dose-limiting toxicities were noted, and a maximum-tolerated dose was not reached. Five patients (29%) achieved a clinical response, which included two complete responses (CRs) and three partial responses (PRs); two additional patients had stable disease (SD) as the best response. Patients with disease control (CR + PR + SD) had tumors with higher EGFR and lower STAT3 expression at baseline compared with patients who had progressive disease (P = .0312 and P = .095, respectively).Intratumoral EGFR AS was safe and resulted in antitumor activity in patients with advanced SCCHN. Baseline levels of high EGFR and low STAT3 may be associated with antitumor effects.
The Clinical Effectiveness and Cost-effectiveness of Screening for Anal Squamous Intraepithelial Lesions in Homosexual and Bisexual HIV-Positive Men
Authors: Sue J. Goldie
Journal: JAMA (1999)

ContextHomosexual and bisexual men infected with human immunodeficiency virus (HIV) are at increased risk for human papillomavirus–related anal neoplasia and anal squamous cell carcinoma (SCC).ObjectiveTo estimate the clinical benefits and cost-effectiveness of screening HIV-positive homosexual and bisexual men for anal squamous intraepithelial lesions (ASIL) and anal SCC.DesignCost-effectiveness analysis performed from a societal perspective that used reference case recommendations from the Panel on Cost-Effectiveness in Health and Medicine. A state-transition Markov model was developed to calculate lifetime costs, life expectancy, and quality-adjusted life expectancy for no screening vs several screening strategies for ASIL and anal SCC using anal Papanicolaou (Pap) testing at different intervals. Values for incidence, progression, and regression of anal neoplasia; efficacy of screening and treatment; natural history of HIV; health-related quality of life; and costs were obtained from the literature.Setting and ParticipantsHypothetical cohort of homosexual and bisexual HIV-positive men living in the United States.Main Outcome MeasuresLife expectancy, quality-adjusted life expectancy, quality-adjusted years of life saved, lifetime costs, and incremental cost-effectiveness ratio.ResultsScreening for ASIL increased quality-adjusted life expectancy at all stages of HIV disease. Screening with anal Pap tests every 2 years, beginning in early HIV disease (CD4 cell count >0.50×109/L), resulted in a 2.7-month gain in quality-adjusted life expectancy for an incremental cost-effectiveness ratio of $13,000 per quality-adjusted life year saved. Screening with anal Pap tests yearly provided additional benefit at an incremental cost of $16,600 per quality-adjusted life year saved. If screening was not initiated until later in the course of HIV disease (CD4 cell count <0.50×109/L), then yearly Pap test screening was preferred due to the greater amount of prevalent anal disease (cost-effectiveness ratio of less than $25,000 per quality-adjusted life year saved compared with no screening). Screening every 6 months provided little additional benefit over that of yearly screening. Results were most sensitive to the rate of progression of ASIL to anal SCC and the effectiveness of treatment of precancerous lesions.ConclusionsScreening HIV-positive homosexual and bisexual men for ASIL and anal SCC with anal Pap tests offers quality-adjusted life expectancy benefits at a cost comparable with other accepted clinical preventive interventions.
Notch Ligand Delta-Like 1 Is Essential for Postnatal Arteriogenesis
Authors: Anne Limbourg, Merlin Ploom, Diana Elligsen, Inga Sörensen, Tibor Ziegelhoeffer, Achim Gossler, Helmut Drexler, Florian P. Limbourg
Journal: Circulation Research (2007)

Growth of functional arteries is essential for the restoration of blood flow to ischemic organs. Notch signaling regulates arterial differentiation upstream of ephrin-B2 during embryonic development, but its role during postnatal arteriogenesis is unknown. Here, we identify the Notch ligand Delta-like 1 (Dll1) as an essential regulator of postnatal arteriogenesis. Dll1 expression was specifically detected in arterial endothelial cells, but not in venous endothelial cells or capillaries. During ischemia-induced arteriogenesis endothelial Dll1 expression was strongly induced, Notch signaling activated and ephrin-B2 upregulated, whereas perivascular cells expressed proangiogenic vascular endothelial growth factor, and the ephrin-B2 activator EphB4. In heterozygous Dll1 mutant mice endothelial Notch activation and ephrin-B2 induction after hindlimb ischemia were absent, arterial collateral growth was abrogated and recovery of blood flow was severely impaired, but perivascular vascular endothelial growth factor and EphB4 expression was unaltered. In vitro, angiogenic growth factors synergistically activated Notch signaling by induction of Dll1, which was necessary and sufficient to regulate ephrin-B2 expression and to induce ephrin-B2 and EphB4-dependent branching morphogenesis in human arterial EC. Thus, Dll1-mediated Notch activation regulates ephrin-B2 expression and postnatal arteriogenesis.
Antihypertensive Therapy With Ca2+: Antagonist Verapamil and/or ACE Inhibitor Enalapril in NIDDM Patients
Authors: Claudia Ferrier, Paolo Ferrari, Peter Weidmann, Ulrich Keller, Carlo Beretta-Piccoli, Walter F Riesen
Journal: Diabetes Care (1991)

Objective To assess the efficacy and tolerance of a diuretic-free antihypertensive therapy with a Ca2+ antagonist and an angiotensin-converting enzyme (ACE) inhibitor in patients with non-insulin-dependent diabetes mellitus (NIDDM). Research Design and Methods After a 2-wk washout and a 4-wk placebo phase, 47 hypertensive patients with NIDDM randomly received verapamil or enalapril alone and, if blood pressure remained elevated, both agents combined over 30 wk. Results Verapamil or enalapril alone normalized blood pressure to &amp;lt; 90 mmHg diastolic in 30 patients; verapamil decreased mean ± SE blood pressure from 159/98 ± 3/1 to 146/87 ± 3/2 mmHg (n = 18, P &amp;lt; 0.001) and enalapril from 166/99 ± 5/2 to 146/86 ± 3/1 mmHg (n = 12, P &amp;lt; 0.001). In 17 patients who were still hypertensive after 10 wk of monotherapy, combination of both drugs decreased blood pressure from 170/104 ± 4/2 to 152/90 ± 4/2 mmHg (P &amp;lt; 0.001). Fasting plasma glucose, glycosylated hemoglobin, serum fructosamine, total lipids, high-density and low-density lipoprotein cholesterol, apolipoproteins A-I and B, creatinine, and urinary albumin-creatinine ratio were not significantly modified. Conclusions In hypertensive patients with NIDDM, a diuretic-free therapy based on the Ca2+ antagonist verapamil and/or the ACE inhibitor enalapril can effectively decrease blood pressure without adversely affecting carbohydrate and lipid metabolism.