tbuckley/cabot-search huggingface dataset:
SMC3 knockdown triggers genomic instability and p53-dependent apoptosis in human and zebrafish cells.
Authors: Giancarlo Ghiselli
Journal: Molecular Cancer (2006)

The structural maintenance of chromosome 3 (SMC3) protein is a constituent of a number of nuclear multimeric protein complexes that are involved in DNA recombination and repair in addition to chromosomal segregation. Overexpression of SMC3 activates a tumorigenic cascade through which mammalian cells acquire a transformed phenotype. This has led us to examine in depth how SMC3 level affects cell growth and genomic stability. In this paper the effect of SMC3 knockdown has been investigated. Mammalian cells that are SMC3 deficient fail to expand in a clonal population. In order to shed light on the underlying mechanism, experiments were conducted in zebrafish embryos in which cell competence to undergo apoptosis is acquired at specific stages of development and affects tissue morphogenesis. Zebrafish Smc3 is 95% identical to the human protein, is maternally contributed, and is expressed ubiquitously at all developmental stages. Antisense-mediated loss of Smc3 function leads to increased apoptosis in Smc3 expressing cells of the developing tail and notocord causing morphological malformations. The apoptosis and the ensuing phenotype can be suppressed by injection of a p53-specific MO that blocks the generation of endogenous p53 protein. Results in human cells constitutively lacking p53 or BAX, confirmed that a p53-dependent pathway mediates apoptosis in SMC3-deficient cells. A population of aneuploid cells accumulated in zebrafish embryos following Smc3-knockdown whereas in human cells the transient downregulation of SMC3 level lead to the generation of cells with amplified centrosome number. Smc3 is required for normal embryonic development. Its deficiency affects the morphogenesis of tissues with high mitotic index by triggering an apoptotic cascade involving p53 and the downstream p53 target gene bax. Cells with low SMC3 level display centrosome abnormalities that can lead to or are the consequence of dysfunctional mitosis and/or aneuploidy. Collectively the data support the view that SMC3 deficiency affects chromosomal stability leading to the activation of p53-dependent mitotic checkpoint.
Transgenic Remodeling of the Contractile Apparatus in the Mammalian Heart
Authors: Joseph Palermo, James Gulick, Melissa Colbert, Jason Fewell, Jeffrey Robbins
Journal: Circulation Research (1996)

Abstract The structure-function relationships of the sarcomeric proteins in the mammalian cardiac compartment remain ill-defined because of the lack of a suitable model in which they can be readily manipulated or exchanged in vivo. To establish the validity of the transgenic paradigm for remodeling the mammalian heart, the murine α-cardiac myosin heavy chain gene promoter was used to express a ventricular myosin light chain-2 transgene ( MLC2v ) in both the atria and ventricles of the adult animal. Expression resulted in high levels of the transgene’s transcript in both compartments. In the ventricle, the transgene was expressed against the background expression of the normal isoform. In the atrium, the transgene’s expression would be ectopic, in that normally, MLC2v expression is restricted to the ventricle. Ectopic expression of the transgene in the atria resulted in a complete replacement of the atrial myosin light chain-2 protein isoform, although the endogenous isoform’s steady state transcript levels were unchanged. In contrast, ventricular expression of the transgene had no effect at the protein level, despite an eightfold increase in MLC2v transcript levels. The data show that sarcomeric protein stoichiometry is maintained rigorously via posttranscriptional regulation and that protein replacement can be achieved through a single transgenic manipulation.
Limited joint mobility (LJM) of the hand in patients with diabetes mellitus: relation to chronic complications.
Authors: H S Starkman, R E Gleason, L I Rand, D E Miller, J S Soeldner
Journal: Annals of the Rheumatic Diseases (1986)

Limited joint mobility (LJM) of the hand was studied by visual examination in 361 diabetic outpatients aged 11 to 83 years, and 45 non-diabetic controls, without evidence of arthritis. LJM was evident in 58% of diabetic subjects and 4% of controls (p less than 0.001). LJM was noted in 131 (55%) of the 238 patients with insulin-dependent diabetes mellitus (IDDM) as opposed to 31 of the 41 patients (76%) with non-insulin-dependent diabetes mellitus (NIDDM). LJM occurred in 60 of the 82 diabetic subjects (73%) receiving insulin therapy who developed diabetes after the age of 35 years. LJM was significantly related to duration of diabetes in the patients with IDDM less than 40 years of age but was not associated with duration in the patients with NIDDM. A significant association of LJM and neuropathy was noted in patients less than 40 years of age with less than 20 years of diabetes. A significant association of LJM and retinopathy was also noted in those less than 40 years of age with less than 30 years of diabetes. There was no association of LJM and nephropathy regardless of age or duration of diabetes.
S56 Flat Trachea Syndrome: an under-diagnosed and under-treated condition?
Authors: G. Niranjan, J. F. K. Marzouk
Journal: Thorax (2010)

<h3>Objectives</h3> Flat Trachea Syndrome (Tracheobronchomalacia) is a central airway disease characterised by weakness of the wall and dynamic decrease in the tracheal lumen and the large bronchi, particularly while exhaling. It causes chronic symptoms such as cough, dyspnoea, increase in recurrent infections, and poor secretion management, but it can also progress to chronic respiratory failure and death. It remains largely under-diagnosed unless clinicians are thoroughly acquainted with its peculiar symptomology being usually confused with other common diseases like chronic obstructive pulmonary disease (COPD) or asthma. Surgery with posterior tracheobronchial splinting (tracheobronchoplasty) using a polytetrafluoroethylene (PTFE) Teflon patch has been considered as a possible treatment option for this condition. <h3>Methods</h3> A retrospective series of 28 patients that underwent tracheobronchoplasty using a PTFE Teflon patch between July 1998 and July 2010 were evaluated for symptoms, lung capacity and exercise capacity. <h3>Results</h3> The age range of patients treated was from 24 to 82 (mean 66). 61% (17) of those treated were men, with all cases being diagnosed with obstructive airways disease on spirometry, with the FEV1 ranging from 34% to 65% pre-operatively. 25 patients (89%) presented with severe dyspnoea, 23 patients (82%) with uncontrollable cough, and 21 patients (75%) reported recurrent pulmonary infections. There was no in-hospital or 30-day mortality. After surgery symptomatic improvement in dyspnoea was reported in 24 of 28 patients (p&lt;0.001), with the cough disappearing in 19 of 21 patients (p&lt;0.001). At 3 months the FEV1 was &gt;80% in all 28 patients. The mean exercise capacity was improved in 17 (61%) patients. <h3>Conclusions</h3> The condition of tracheobronchomalacia is a misnomer and we propose the term "Flat Trachea syndrome" and/or "expiratory prolapse of the tracheobronchial posterior membrane". It is a rare but severely debilitating condition which can be diagnosed easily by an awake flexible bronchoscopy and dynamic biphasic inspiratory/expiratory CT. Surgical airway splinting with a PTFE (Teflon) patch considerably improves respiratory symptoms, quality of life and functional status in highly selected patients with this under-diagnosed and under-treated condition.
Prospective follow-up after curettage-cryosurgery for scalp and face skin cancers
Authors: B. Lindemalm-Lundstam, J. Dalenbäck
Journal: British Journal of Dermatology (2009)

Journal Article Prospective follow‐up after curettage–cryosurgery for scalp and face skin cancers Get access B. Lindemalm‐Lundstam, B. Lindemalm‐Lundstam Departments of Dermatology Correspondence: Barbro Lindemalm‐Lundstam. E‐mail: barbro.lindemalm‐lundstam@vgregion.se Search for other works by this author on: Oxford Academic Google Scholar J. Dalenbäck J. Dalenbäck Surgery, Frölunda Specialist Hospital, University of Gothenburg, S‐421 22 Västra Frölunda/Gothenburg, Sweden Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 161, Issue 3, 1 September 2009, Pages 568–576, https://doi.org/10.1111/j.1365-2133.2009.09310.x Published: 01 September 2009
Phase II Trial of OGX-011 in Combination with Docetaxel in Metastatic Breast Cancer
Authors: Stephen Chia, Susan Dent, Susan Ellard, Peter M. Ellis, Ted Vandenberg, Karen Gelmon, Jean Powers, Wendy Walsh, Lesley Seymour, Elizabeth A. Eisenhauer
Journal: Clinical Cancer Research (2009)

Abstract Purpose: Clusterin is an antiapoptotic protein activated in response to cellular stress. OGX-011 is a second-generation antisense oligonucleotide that inhibits clusterin expression. The primary objective of this phase II trial was to assess the safety and efficacy of the combination of OGX-011 and docetaxel for metastatic breast cancer. Experimental Design: Women with measurable metastatic breast cancer and ≤1 chemotherapy regimen were eligible. Three loading doses of OGX-011 640 mg i.v. followed by weekly OGX-011 and docetaxel 75 mg/m2 (every 3 weeks) were given. A two-stage design was used with a hypothesis of H0 ≤35% and Ha ≥55%. Objective response in ≥6 of the first 14 patients was required for the trial to continue to the second stage. Results: Fifteen patients were enrolled. A median of six cycles were delivered (range, 2-10). Five partial responses were confirmed for a 33% response rate (95% confidence interval, 11.8-61.6%) with a further 9 (60%) patients showing stable disease. The median duration of stable disease was 9.3 months. The median time to progression was 8 months (95% confidence interval, 5.62-9.43 months). Toxic effects were similar to those with single agent docetaxel. Although serum clusterin decreased on treatment, there was no relationship observed between the magnitude of decrease and response. Conclusion: The combination of OGX-011 and docetaxel at 75 mg/m2 is well tolerated and clinical activity was seen in these patients with metastatic breast cancer, but there was an insufficient number of responses to meet the criteria for proceeding to the second stage of accrual.
Intrapericardial Aortico-Pulmonary Artery Shunt
Authors: S. FRANK REDO, ROGER R. ECKER
Journal: Circulation (1963)

An operative procedure for the creation of an aorticopulmonary artery anastomosis with use of a Teflon prosthesis was developed. After laboratory trial in animals, the operation was performed in six patients varying in age from 2 months to 14 years. In all but one instance the shunt remained patent. The longest observation in dogs is 1½ years. In this animal the shunt has remained open and there has been no evidence of pulmonary or cardiac embarrassment. One child, 5 years of age, has lived 10 months after the operation. He has had marked improvement in his cyanosis and clubbing, his hematocrit value remains less than 50 per cent, and he is generally well. The operation should carry no more risk than a Blalock-Taussig or Potts procedure and is thought to be another, perhaps better, method for increasing pulmonary blood flow in cyanotic infants and children.
Impact of Gene Polymorphisms on Clinical Outcome for Stage IV Melanoma Patients Treated with Biochemotherapy: An Exploratory Study
Authors: Dongxin Liu, Steven J. O'Day, Dongyun Yang, Peter Boasberg, Robert Milford, Tim Kristedja, Susan Groshen, Jeffrey Weber
Journal: Clinical Cancer Research (2005)

Biochemotherapy can achieve high response rates in advanced melanoma, but the factors that influence regression and survival remain unknown. The present exploratory study tested the hypothesis that cytokine gene polymorphisms predict clinical outcome in stage IV melanoma patients treated with biochemotherapy.Ninety patients with stage IV melanoma were treated with biochemotherapy, including cisplatin, vinblastine, and dacarbazine combined with interleukin (IL)-2 and IFN-alpha either with or without tamoxifen. Cytokine gene polymorphisms for IFN-gamma (+874A-->T) and IL-10 (-1082G-->A) were assessed. X-ray repair cross-complementing gene 1 (XRCC1; Arg399Gln), xeroderma pigmentosum complementary group D (XPD; Lys751Gln), and excision repair cross-complementing gene 1 (ERCC1; codon 118) DNA repair polymorphisms were also determined.IFN-gamma (+874A-->T) gene polymorphism was statistically significantly associated with response (P = 0.001), progression-free survival (P = 0.0012), and overall survival (P < 0.001), whereas the IL-10 polymorphism was marginally associated with response (P = 0.03) and overall survival (P = 0.065). Multivariate analysis revealed that IFN-gamma (+874A-->T) independently predicted overall survival (P = 0.003). The ERCC1 polymorphism was weakly associated with overall survival (P = 0.045). Combining polymorphisms for IFN-gamma, IL-10, and ERCC1 stratified patients into four distinct groups with significantly different clinical outcome (P < 0.001), so that patients with more "favorable" polymorphisms had a better outcome.Cytokine gene polymorphisms predicted clinical outcome for advanced melanoma patients who received biochemotherapy. The combined effects of multiple genetic polymorphisms may provide more accurate prognostic information. Additional independent studies are needed to confirm these pilot findings.
Influence of size and gene dosage on the survival of skin allografts on rats rendered tolerant at birth.
Authors: W K Silvers, N H Collins, M Naji
Journal: The Journal of Experimental Medicine (1983)

The attributes of the test grafts with which putatively tolerant rats are challenged influence their immune response. Lewis (Lew) rats inoculated at birth with Lew/BN F1 hybrid bone marrow cells accept large skin allografts more readily than small allografts, and F1 hybrid skin grafts survive better than BN transplants. The results indicate that the survivals of these major histocompatibility complex-incompatible grafts are determined by the same factors that operate when only weak histoincompatibilities prevail.
Genome-wide co-localization of Polycomb orthologs and their effects on gene expression in human fibroblasts
Authors: Helen Pemberton, Emma Anderton, Harshil Patel, Sharon Brookes, Hollie Chandler, Richard Palermo, Julie Stock, Marc Rodriguez-Niedenführ, Tomas Racek, Lucas de Breed, Aengus Stewart, Nik Matthews, Gordon Peters
Journal: Genome biology (2014)

Polycomb group proteins form multicomponent complexes that are important for establishing lineage-specific patterns of gene expression. Mammalian cells encode multiple permutations of the prototypic Polycomb repressive complex 1 (PRC1) with little evidence for functional specialization. An aim of this study is to determine whether the multiple orthologs that are co-expressed in human fibroblasts act on different target genes and whether their genomic location changes during cellular senescence.Deep sequencing of chromatin immunoprecipitated with antibodies against CBX6, CBX7, CBX8, RING1 and RING2 reveals that the orthologs co-localize at multiple sites. PCR-based validation at representative loci suggests that a further six PRC1 proteins have similar binding patterns. Importantly, sequential chromatin immunoprecipitation with antibodies against different orthologs implies that multiple variants of PRC1 associate with the same DNA. At many loci, the binding profiles have a distinctive architecture that is preserved in two different types of fibroblast. Conversely, there are several hundred loci at which PRC1 binding is cell type-specific and, contrary to expectations, the presence of PRC1 does not necessarily equate with transcriptional silencing. Interestingly, the PRC1 binding profiles are preserved in senescent cells despite changes in gene expression.The multiple permutations of PRC1 in human fibroblasts congregate at common rather than specific sites in the genome and with overlapping but distinctive binding profiles in different fibroblasts. The data imply that the effects of PRC1 complexes on gene expression are more subtle than simply repressing the loci at which they bind.
Optimizing Cell-Based Therapy for Cardiac Regeneration
Authors: Dominic P. Del Re, Junichi Sadoshima
Journal: Circulation (2009)

L ong thought to be a terminally differentiated organ, recent findings suggest that the adult mammalian heart is a slowly regenerating organ 1 and home to a resident population of cardiac progenitor cells (CPCs) that renew cardiomyocytes and have the potential to differentiate into multiple cell types within the myocardium. 2 In spite of this, the regenerative capacity of the mammalian heart is inadequate compared with the resulting damage caused by ischemic episodes.In light of the challenges faced by resident progenitor cells, many studies have focused on delivery of exogenously prepared stem or progenitor cell types to the damaged heart.CPCs are an ideal candidate for cardiac cell-based therapy because they are programmed to differentiate into cardiomyocytes, endothelial cells, and smooth muscle cells, thus providing not only contractile benefit but also increased vascularization.However, the ischemic myocardium is a hostile microenvironment, and multiple factors contribute to prevent cardiac regeneration, including ischemia, inflammation, and fibrosis.Therefore, it is critical to provide a complementary approach that promotes CPC survival, proliferation, and differentiation. Article see p 876In the study by Padin-Iruegas et al 3 in this issue of Circulation, insulin-like growth factor 1 (IGF-1), an endogenous peptide that is activated in response to cardiac injury, 4 is delivered to the heart using nanofiber tethering (NF-IGF-1) both alone and in combination with CPCs.In vivo administration of CPCs plus NF-IGF-1 led to significantly more CPC-derived cardiomyocytes that were larger, more differentiated, and incorporated electrically and mechanically into the host myocardium.This combination treatment also increased endogenous CPC proliferation and differentiation to cardiomyocytes, endothelial cells, and smooth muscle cells.Combination therapy led to significant improvement in both ventricular performance and morphological parameters compared with CPC or NF-IGF-1 treatment alone, emphasizing the therapeutic benefit of prolonged exposure of CPCs to IGF-1.
Somatic mutations in the<i>PTCH</i>,<i>SMOH</i>,<i>SUFUH</i>and<i>TP53</i>genes in sporadic basal cell carcinomas
Authors: J. Reifenberger, M. Wolter, C. B. Knobbe, B. Köhler, A. Schönicke, C. Scharwächter, K. Kumar, B. Blaschke, T. Ruzicka, G. Reifenberger
Journal: British Journal of Dermatology (2005)

Journal Article Somatic mutations in the PTCH, SMOH, SUFUH and TP53 genes in sporadic basal cell carcinomas Get access J. Reifenberger, J. Reifenberger Departments of Dermatology and Neuropathology, Heinrich‐Heine‐University, Moorenstraße 5, D‐40225 Düsseldorf, Germany Julia Reifenberger. E‐mail: reifenbergerj@med.uni‐duesseldorf.de Search for other works by this author on: Oxford Academic Google Scholar M. Wolter, M. Wolter Departments of Dermatology and Neuropathology, Heinrich‐Heine‐University, Moorenstraße 5, D‐40225 Düsseldorf, Germany Search for other works by this author on: Oxford Academic Google Scholar C. B. Knobbe, C. B. Knobbe Departments of Dermatology and Neuropathology, Heinrich‐Heine‐University, Moorenstraße 5, D‐40225 Düsseldorf, Germany Search for other works by this author on: Oxford Academic Google Scholar B. Köhler, B. Köhler Departments of Dermatology and Neuropathology, Heinrich‐Heine‐University, Moorenstraße 5, D‐40225 Düsseldorf, Germany Search for other works by this author on: Oxford Academic Google Scholar A. Schönicke, A. Schönicke Departments of Dermatology and Neuropathology, Heinrich‐Heine‐University, Moorenstraße 5, D‐40225 Düsseldorf, Germany Search for other works by this author on: Oxford Academic Google Scholar C. Scharwächter, C. Scharwächter Departments of Dermatology and Neuropathology, Heinrich‐Heine‐University, Moorenstraße 5, D‐40225 Düsseldorf, Germany Search for other works by this author on: Oxford Academic Google Scholar K. Kumar, K. Kumar Departments of Dermatology and Neuropathology, Heinrich‐Heine‐University, Moorenstraße 5, D‐40225 Düsseldorf, Germany Search for other works by this author on: Oxford Academic Google Scholar B. Blaschke, B. Blaschke Departments of Dermatology and Neuropathology, Heinrich‐Heine‐University, Moorenstraße 5, D‐40225 Düsseldorf, Germany Search for other works by this author on: Oxford Academic Google Scholar T. Ruzicka, T. Ruzicka Departments of Dermatology and Neuropathology, Heinrich‐Heine‐University, Moorenstraße 5, D‐40225 Düsseldorf, Germany Search for other works by this author on: Oxford Academic Google Scholar G. Reifenberger G. Reifenberger Departments of Dermatology and Neuropathology, Heinrich‐Heine‐University, Moorenstraße 5, D‐40225 Düsseldorf, Germany Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 152, Issue 1, 1 January 2005, Pages 43–51, https://doi.org/10.1111/j.1365-2133.2005.06353.x Published: 01 January 2005 Article history Accepted: 09 July 2004 Published: 01 January 2005
Low-dose flutamide-metformin therapy for hyperinsulinemic hyperandrogenism in non-obese adolescents and women
Authors: Lourdes Ibáñez, Francis de Zegher
Journal: Human Reproduction Update (2006)

Polycystic ovary syndrome (PCOS) is a variable disorder that is characterized in adolescents and young women by a broad spectrum of anomalies, including hyperandrogenemia, insulin resistance, dyslipidemia, body adiposity and low-grade inflammation. At present, there is no approved therapy for PCOS. Recent studies indicate that a low-dose combination of flutamide (Flu; a generic androgen-receptor blocker) and metformin (Met; a generic insulin-sensitizer) normalizes the adolescent PCOS spectrum more than an oral contraceptive (OC); in young women, the PCOS spectrum was found to be more normalized by OC plus Flu-Met than by OC alone. Within the pathophysiological cascade of PCOS, Flu-Met seems to counter upstream anomalies like hyperinsulinemia or hyperandrogenism, thereby preventing or reversing downstream effects. In contrast, an OC essentially masks downstream symptoms like hirsutism, acne or irregular menses, whereas the upstream aberrations remain unaltered or may even be worsened. The available experience with Flu-Met is limited but promising. We emphasize that Flu-Met may (as part of its efficacy) induce ovulation but is contra-indicated post-conception because of potential embryotoxicity; therefore, it seems wise to combine Flu-Met with an oral or a transdermal oestro-progestagen or with a non-endocrine method of contraception. May this update prompt further research into Flu-Met's therapeutic potential in patients with PCOS. Until the abovementioned effects have been broadly confirmed, Flu-Met should not be regarded as a standard therapy for widespread clinical practice.
Patient Profile and Tolerability of Raltitrexed in Monotherapy and in Combination with Oxaliplatin as Advanced Colorrectal Teatment. Ralto Study
Authors: Manuel Constenla, Jorge Aparicio, Maria Auxiliadora Gómez, Cristina Grávalos, Luis Jesús López Gómez, Jose Luis Manzano, Maria Dolores Pineda, Isabel Sevilla, Jose Maria Vieitez De Prado, Antonio Viudez, Miriam López-Gómez, Juan Carlos Cámara, Guillermo López-Vivanco, Fuensanta Aranda, Ana Barbón, Paloma Isabel Palomo-Jimenez, Jaime Feliu
Journal: Annals of Oncology (2013)