tbuckley/cabot-search huggingface dataset:
Direct Evaluation of Myocardial Viability and Stem Cell Engraftment Demonstrates Salvage of the Injured Myocardium
Authors: Paul J. Kim, Morteza Mahmoudi, Xiaohu Ge, Yuka Matsuura, Ildiko Toma, Scott Metzler, Nigel G. Kooreman, John Ramunas, Colin Holbrook, Michael V. McConnell, Helen Blau, Phillip Harnish, Eric Rulifson, Phillip C. Yang
Journal: Circulation Research (2015)

Rationale: The mechanism of functional restoration by stem cell therapy remains poorly understood. Novel manganese-enhanced MRI and bioluminescence reporter gene imaging were applied to follow myocardial viability and cell engraftment, respectively. Human-placenta–derived amniotic mesenchymal stem cells (AMCs) demonstrate unique immunoregulatory and precardiac properties. In this study, the restorative effects of 3 AMC-derived subpopulations were examined in a murine myocardial injury model: (1) unselected AMCs, (2) ckit + AMCs, and (3) AMC-derived induced pluripotent stem cells (MiPSCs). Objective: To determine the differential restorative effects of the AMC-derived subpopulations in the murine myocardial injury model using multimodality imaging. Methods and Results: SCID (severe combined immunodeficiency) mice underwent left anterior descending artery ligation and were divided into 4 treatment arms: (1) normal saline control (n=14), (2) unselected AMCs (n=10), (3) ckit + AMCs (n=13), and (4) MiPSCs (n=11). Cardiac MRI assessed myocardial viability and left ventricular function, whereas bioluminescence imaging assessed stem cell engraftment during a 4-week period. Immunohistological labeling and reverse transcriptase polymerase chain reaction of the explanted myocardium were performed. The unselected AMC and ckit + AMC–treated mice demonstrated transient left ventricular functional improvement. However, the MiPSCs exhibited a significantly greater increase in left ventricular function compared with all the other groups during the entire 4-week period. Left ventricular functional improvement correlated with increased myocardial viability and sustained stem cell engraftment. The MiPSC-treated animals lacked any evidence of de novo cardiac differentiation. Conclusion: The functional restoration seen in MiPSCs was characterized by increased myocardial viability and sustained engraftment without de novo cardiac differentiation, indicating salvage of the injured myocardium.
HER-2 Overexpression in Breast Tumors Lacking Gene Amplification
Authors: Steven M. Sorscher
Journal: Journal of Clinical Oncology (2004)

thoughtful cost-effective analysis of trastuzumab therapy by examining the costs and benefits of alternative HER-2 testing strategies, including the use of immunohistochemical analysis (IHC) and fluorescence in situ hybridization (FISH). The authors define a false-positive IHC test as “the probability of a 3 HercepTest (DAKO, Carpinteria, CA) result conditional on a negative FISH result.” Several questions arise when using a test that detects “false-positive” protein overexpression (IHC) based on a test that detects gene amplification (FISH). The authors themselves cite several studies that suggest single-genecopy HER-2 overexpressors in 3% to 8% of breast tumors. 2-4 Their own data suggest that the false-positive rate is 1.7% (95% CI, 0.4% to 2.9%; Table 2 of their article). 1 In practical terms, therefore, if FISH is negative in a 3 HercepTest tumor, it is still about three times more likely that overexpression is occurring due to single-gene overexpression. The authors also point out that “the likelihood that single-gene overexpression will respond to trastuzumab is unknown.” With these results, why administer FISH testing in the 3 HercepTest group? The study of Elkin et al provides important new information regarding IHC and FISH. However, only a more definitive test for protein expression should be used to define false-positives, not an assay for gene amplification. Also, until the response of single-gene overexpressing tumors to trastuzumab is known, it would seem that a positive result from FISH testing in the 3 HercepTest group can only confirm a more likely response, but a negative result may lack therapeutic usefulness.
FACT: An Open-Label Randomized Phase III Study of Fulvestrant and Anastrozole in Combination Compared With Anastrozole Alone As First-Line Therapy for Patients With Receptor-Positive Postmenopausal Breast Cancer
Authors: Jonas Bergh, Per-Ebbe Jönsson, Elisabet Kerstin Lidbrink, Maureen Trudeau, Wolfgang Eiermann, Daniel Brattström, Justin P.O. Lindemann, Fredrik Wiklund, Roger Henriksson
Journal: Journal of Clinical Oncology (2012)

Purpose To compare the effect of therapy with anastrozole versus a combination of fulvestrant and anastrozole in women in first relapse of endocrine-responsive breast cancer. Patients and Methods Postmenopausal women, or premenopausal women receiving a gonadotropin-releasing hormone agonist, with estrogen receptor– and/or progesterone receptor–positive disease at first relapse after primary treatment of localized disease were open-label randomly assigned to a fulvestrant loading dose (LD) regimen followed by monthly injection plus 1 mg of anastrozole daily or to 1 mg of anastrozole daily alone. The primary end point was time to progression (TTP). Results In all, 514 women were randomly assigned to fulvestrant plus anastrozole (experimental arm; n = 258) or anastrozole (standard arm; n = 256). Approximately two thirds had received adjuvant antiestrogens, but only eight individuals had received an aromatase inhibitor. Median TTP was 10.8 and 10.2 months in the experimental versus standard arm, respectively (hazard ratio [HR] = 0.99; 95% CI, 0.81 to 1.20; P = .91); median overall survival was 37.8 and 38.2 months, respectively (HR = 1.0; 95% CI, 0.76 to 1.32; P = 1.00). Incidences of prespecified adverse events (AEs) were similar. Hot flashes were more common in the experimental arm: 63 patients (24.6%) versus 35 patients (13.8%) in the standard arm (P = .0023). Death owing to AEs was reported in 11 (4.3%) and five patients (2.0%) in the experimental versus standard arm, respectively. Conclusion Fulvestrant (250 mg + LD regimen) in combination with anastrozole offered no clinical efficacy advantage over anastrozole monotherapy in this population of individuals with a relatively high proportion of previous adjuvant antiestrogen exposure.
Pathological Complete Response in Triple Negative Poorly Differentiated Invasive Ductal Breast Carcinoma Detected During Pregnancy
Authors: Garima Agrawal, Jeon Hor Chen, Choong Hyun Baick, Antony Eugene Chen, Rita S. Mehta, Orhan Nalcioglu, Min-Ying Su
Journal: Journal of Clinical Oncology (2007)
The death of a microsatellite: a phylogenetic perspective on microsatellite interruptions
Authors: J. S. Taylor, J. M. Durkin, F. Breden
Journal: Molecular Biology and Evolution (1999)

mapping microsatellite sequences onto a phylogeny revealed the ''birth'' of two microsatellites (but see Gordon 1997).''Birth,'' as applied to microsatellite evolution by Messier, Li, and Stewart (1996), refers to a combination of two mutations.The first mutation produces repeats of sufficient length for slippedstrand mispairing.The second mutation is caused by slipped-strand mispairing and produces repeat length variation.In this paper, we characterize microsatellite ''death.''We hypothesize that ''death,'' as it relates to microsatellites, also refers to a combination of two mutations.The first mutation interrupts the repeat, preventing slipped-strand mispairing and stabilizing the repeat.The second involves the deletion of large sections of the repeat.We use the term ''death,'' because the ultimate result of these interruptions and deletions is an almost unrecognizable homologous DNA sequence that includes only a small portion of the original repeat region.The first component of microsatellite death, interruption-induced microsatellite stability, has been reported elsewhere (Weber 1990;Garza, Slatkin, and Freimer 1995;Bichara, Schumacher, and Fuchs 1995;Petes, Greenwell, and Dominska 1997).Interruptions may inhibit the formation of mutational intermediates (e.g., hairpin structures) or alter intermediates such that they are more easily recognized and repaired (Bichara, Schumacher, and Fuchs 1995).The second component of microsatellite death, a reduction in allele size, was observed by mapping sequences of a (TTA) n microsatellite locus from five Poecilia (Cyprinodontiformes: Poeciliidae) species onto a phylogeny.Poecilia reticulata, Poecilia picta, and Poecilia caucana are variable at the (TTA) n locus, with allele length ranging from 30 to 117 bp, whereas Poecilia parae and Poecilia bifurca are monomorphic and short, possessing 30-and 27-bp alleles, respectively (fig.1A).In P. picta and P. caucana,
A Phase I Biological and Pharmacologic Study of the Heparanase Inhibitor PI-88 in Patients with Advanced Solid Tumors
Authors: Michele Basche, Daniel L. Gustafson, Scott N. Holden, Cindy L. O'Bryant, Lia Gore, Samir Witta, Mary Kay Schultz, Mark Morrow, Adrah Levin, Brian R. Creese, Michael Kangas, Kaye Roberts, Thu Nguyen, Kat Davis, Russell S. Addison, Jane C. Moore, S. Gail Eckhardt
Journal: Clinical Cancer Research (2006)

Abstract Purpose: PI-88 is a mixture of highly sulfated oligosaccharides that inhibits heparanase, an extracellular matrix endoglycosidase, and the binding of angiogenic growth factors to heparan sulfate. This agent showed potent inhibition of placental blood vessel angiogenesis as well as growth inhibition in multiple xenograft models, thus forming the basis for this study. Experimental Design: This study evaluated the toxicity and pharmacokinetics of PI-88 (80-315 mg) when administered s.c. daily for 4 consecutive days bimonthly (part 1) or weekly (part 2). Results: Forty-two patients [median age, 53 years (range, 19-78 years); median performance status, 1] with a range of advanced solid tumors received a total of 232 courses. The maximum tolerated dose was 250 mg/d. Dose-limiting toxicity consisted of thrombocytopenia and pulmonary embolism. Other toxicity was generally mild and included prolongation of the activated partial thromboplastin time and injection site echymosis. The pharmacokinetics were linear with dose. Intrapatient variability was low and interpatient variability was moderate. Both AUC and Cmax correlated with the percent increase in activated partial thromboplastin time, showing that this pharmacodynamic end point can be used as a surrogate for drug exposure. No association between PI-88 administration and vascular endothelial growth factor or basic fibroblast growth factor levels was observed. One patient with melanoma had a partial response, which was maintained for &amp;gt;50 months, and 9 patients had stable disease for ≥6 months. Conclusion: The recommended dose of PI-88 administered for 4 consecutive days bimonthly or weekly is 250 mg/d. PI-88 was generally well tolerated. Evidence of efficacy in melanoma supports further evaluation of PI-88 in phase II trials.
Mechanisms of emphysema in α<sub>1</sub>-antitrypsin deficiency: molecular and cellular insights
Authors: B. Gooptu, U. I. Ekeowa, D. A. Lomas
Journal: European Respiratory Journal (2009)

The severe, early onset emphysema that occurs in patients with circulating deficiency of α 1 -antitrypsin (α 1 -AT) attests to the importance of this protease inhibitor in maintaining lung parenchymal integrity. It has led to the powerful concept of protease:antiprotease balance being crucial to alveolar homeostasis. Pathogenic mutations cause α 1 -AT to self-associate into polymer chains that accumulate intracellularly rather than proceeding along the secretory pathway. Polymerisation of α 1 -AT abolishes antiprotease activity and confers toxic gain-of-function effects. Since α 1 -AT is predominantly synthesised in the liver, where it does not play a major homeostatic role, the directly toxic effects of polymerisation are clearest here. However, data from molecular, cellular, animal and ex vivo studies indicate that intrapulmonary polymerisation of α 1 -AT and inflammatory positive feedback loops may augment the destructive effects of decreased antiprotease levels in the lung. This review integrates the findings from these different approaches and highlights how multiple pathways may converge to give the severe, panacinar emphysema phenotype seen in α 1 -AT deficiency.
Long-term prognosis of patients treated for erythema migrans in France
Authors: D. Lipsker, N. Antoni-Bach, Y. Hansmann, B. Jaulhac
Journal: British Journal of Dermatology (2002)

The long-term prognosis of patients treated for erythema migrans has only rarely been assessed.To evaluate the clinical characteristics and long-term prognosis of patients treated for erythema migrans in the region of Alsace, France.In a prospective study, 56 consecutive patients presenting with erythema migrans at the Strasbourg University Hospital between 1995 and 1999 were examined and a Borrelia burgdorferi enzyme immunoassay was performed. Patients were treated with tetracyclines or amoxycillin. Patients were re-examined 6 weeks later and a telephone interview was performed in summer 2000 to evaluate the long-term outcome.There were 25 women and 31 men of mean age 49 years presenting with single (n = 54) or multiple (n = 2) erythema migrans lesions. At the time of diagnosis, 30% of the patients had systemic signs, myalgias or arthralgias and only 36% of 50 patients were seroreactive against B. burgdorferi. None of the 51 patients evaluated at 6 weeks and none of the 37 patients interviewed after a median delay of 3 years had developed complications attributable to Lyme borreliosis.The prognosis of patients treated for Lyme borreliosis in this part of France is excellent. Therefore, a complete clinical examination is sufficient as an initial evaluation and long-term follow-up is not necessary.
Impaired cutaneous wound healing in granulocyte/ macrophage colony-stimulating factor knockout mice
Authors: Y. Fang, S-J. Gong, Y-H. Xu, B.D. Hambly, S. Bao
Journal: British Journal of Dermatology (2007)

Journal Article Impaired cutaneous wound healing in granulocyte/ macrophage colony‐stimulating factor knockout mice Get access Y. Fang, Y. Fang Department of Plastic Surgery, The Third People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai 201900, China Search for other works by this author on: Oxford Academic Google Scholar S‐J. Gong, S‐J. Gong Department of Plastic Surgery, The Third People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai 201900, China Search for other works by this author on: Oxford Academic Google Scholar Y‐H. Xu, Y‐H. Xu Discipline of Pathology, School of Medical Science, The University of Sydney, Sydney, NSW 2006, Australia Search for other works by this author on: Oxford Academic Google Scholar B.D. Hambly, B.D. Hambly Discipline of Pathology, School of Medical Science, The University of Sydney, Sydney, NSW 2006, Australia Search for other works by this author on: Oxford Academic Google Scholar S. Bao S. Bao Department of Plastic Surgery, The Third People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai 201900, ChinaDiscipline of Pathology, School of Medical Science, The University of Sydney, Sydney, NSW 2006, Australia Correspondence: Shisan Bao. E‐mail: bobbao@pathology.usyd.edu.au Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 157, Issue 3, 1 September 2007, Pages 458–465, https://doi.org/10.1111/j.1365-2133.2007.07979.x Published: 01 September 2007
Confocal microscopy immunofluorescence localization of desmin and other intermediate filament proteins in fetal rat livers
Authors: Jany Vassy, Jean Paul Rigaut, Dominique Briane, Michel Kraemer
Journal: Hepatology (1993)

Immunolocalization of desmin in fetal rat livers shows that on day 12 of gestation a high number of liver cells express desmin. This number decreases from day 14 onward. On day 20 about the same density of desmin-containing cells is found in fetal rat livers as is found in adult rat livers. Desmin-containing cells show two types of labeling patterns, especially on days 12 and 13 of gestation: (a) a basketlike network of intermediate filaments throughout the whole cell, similar to the labeling pattern of cytokeratin in hepatocytes; and (b) more strongly labeled intermediate filaments developing long and slender processes between adjacent cells, close to the labeling pattern of Ito cells in adult rats. From day 14 of gestation, the first type becomes rare, and from day 18 only the second type remains. Double-labeling experiments show that coexpression of desmin and cytokeratin is found in cells of the first type on days 12, 13 and 14 of gestation. Cells containing desmin with the labeling pattern of the second type never express cytokeratin. Coexpression of vimentin and cytokeratin is never found in fetal hepatocytes, even on day 12 of gestation. Numerous nonhepatocyte cells coexpress desmin and vimentin, but some cells contain vimentin or desmin alone. In desmin-containing cells the labeling pattern is of the first type (basketlike network). These results suggest that in early stages of fetal liver development, desmin is found in two different types of liver cells.(ABSTRACT TRUNCATED AT 250 WORDS)
Wnt Antagonism in Multiple Myeloma: A Potential Cause of Uncoupled Bone Remodeling
Authors: Roger N. Pearse
Journal: Clinical Cancer Research (2006)

Abstract Bone disease in patients with multiple myeloma (MM) is characterized by uncoupled bone remodeling, evident as enhanced osteolytic resorption and decreased rather than increased bone formation. MM-triggered osteolysis follows deregulation of the receptor activator of nuclear factor κB ligand (RANKL)/osteoprotegerin cytokine axis. Inhibition of bone formation may result from the ability of MM to inhibit the function of Wnts, secreted glycoproteins critical to osteoblast development. Recent studies show how these processes may be linked.
Lung Dendritic Cells Elicited by Fms-like Tyrosin 3-Kinase Ligand Amplify the Lung Inflammatory Response to Lipopolysaccharide
Authors: Werner von Wulffen, Mirko Steinmueller, Susanne Herold, Leigh M. Marsh, Patrick Bulau, Werner Seeger, Tobias Welte, Jürgen Lohmeyer, Ulrich A. Maus
Journal: American Journal of Respiratory and Critical Care Medicine (2007)

Rationale: Strategically located beneath the alveolar epithelial barrier, dendritic cells (DCs) of the lung are centrally involved in the sampling and processing of inhaled antigens. However, the contribution of DCs to acute lung inflammation induced by inhaled bacterial toxins is largely unknown.Objectives: To determine the effect of increased lung DC numbers elicited by Fms-like tyrosine kinase-3 ligand (Flt3L) on the acute lung inflammatory response to Escherichia coli lipopolysaccharide (LPS) and Klebsiella pneumoniae infection.Methods: Mice were pretreated with Flt3L either in the absence or presence of anti-CD11a antibodies to block the Flt3L-elicited lung DC accumulation or were made transiently neutropenic and then challenged with E. coli LPS or K. pneumoniae.Measurements and Main Results: Flt3L-pretreated mice challenged with LPS responded with drastically increased numbers of both lung parenchymal and alveolar DCs together with an aggravated neutrophilic alveolitis, elevated tumor necrosis factor-α and IL-12 levels, and a strongly increased lung permeability compared with LPS- or Flt3L-only–treated mice. Anti–CD11a-mediated blockade of lung DC accumulation significantly attenuated the lung permeability developing in response to LPS, whereas transient neutropenia did not affect lung permeability changes. Finally, Flt3L-pretreated mice responded with increased lung permeability and decreased survival upon infection with K. pneumoniae.Conclusions: Lung DCs actively participate in the early inflammatory response to both inhaled bacterial toxins and live bacteria and play a yet unrecognized role in regulating lung barrier integrity.
An Unexpected Life in Nutrition
Authors: Malden C. Nesheim
Journal: Annual Review of Nutrition (2012)

In this biographical article, I describe the evolution of my career in nutrition from an early period as an animal nutritionist interested in amino acid metabolism and genetic variation in nutrient requirements to an involvement in human nutrition and international public health. The career changes were in some respects a mirror of the evolution of nutritional science in my lifetime. I spent my entire career at Cornell University in what I think of as three distinct phases. As a researcher and teacher in the Poultry Science Department, I was able to do research in animal nutrition and witness the rapid industrialization of the production of poultry meat and eggs, helped by the findings of the era of nutrient discovery in nutritional science. Later I had the opportunity to lead the reorganization of human nutrition at Cornell during a period when research in nutritional science turned away from identifying new nutrients and became increasingly concerned with the roles of diet and chronic disease. During this period my research focus evolved as I became interested in aspects of international nutrition problems, particularly the influence of parasitic infections on child health and nutrition. I also became involved nationally in nutrition issues through participation in organizations such as the National Nutrition Consortium, the Food and Nutrition Board, and National Institutes of Health study sections at a time of great ferment in nutrition about the relationship of dietary patterns to health. Finally, I became provost of Cornell University and involved in the administration of a major research university. I describe my career in the context of my origins and early education springing from life on a sustainable family farm in rural Illinois.
Downregulation of cyclin-dependent kinase 2 activity and cyclin A promoter activity in vascular smooth muscle cells by p27(KIP1), an inhibitor of neointima formation in the rat carotid artery.
Authors: D Chen, K Krasinski, A Sylvester, J Chen, P D Nisen, V Andrés
Journal: Journal of Clinical Investigation (1997)

Abnormal proliferation of vascular smooth muscle cells (VSMCs) contributes to intimal hyperplasia during atherosclerosis and restenosis, but the endogenous cell cycle regulatory factors underlying VSMC growth in response to arterial injury are not well understood. In the present study, we report that downregulation of cyclin-dependent kinase 2 (cdk2) activity in serum-deprived VSMCs was associated with the formation of complexes between cdk2 and its inhibitory protein p27(KIP1) (p27). Ectopic overexpression of p27 in serum-stimulated VSMCs resulted in the inhibition of cdk2 activity and repression of cyclin A promoter activity. Collectively, these findings indicate that p27 may contribute to VSMC growth arrest in vitro. Using the rat carotid model of balloon angioplasty, a marked upregulation of p27 was observed in injured arteries. High levels of p27 expression in the media and neointima correlated with downregulation of cdk2 activity at 2 wk after angioplasty, and adenovirus-mediated overexpression of p27 in balloon-injured arteries attenuated neointimal lesion formation. Thus, the inhibition of cdk2 function and repression of cyclin A gene transcription through the induction of the endogenous p27 protein provides a mechanism for the inhibition of VSMC growth at late time points after angioplasty.