tbuckley/cabot-search huggingface dataset:
Custom Design of the Cardiac Microenvironment With Biomaterials
Authors: Michael E. Davis, Patrick C.H. Hsieh, Alan J. Grodzinsky, Richard T. Lee
Journal: Circulation Research (2005)

Many strategies for repairing injured myocardium are under active investigation, with some early encouraging results. These strategies include cell therapies, despite little evidence of long-term survival of exogenous cells, and gene or protein therapies, often with incomplete control of locally-delivered dose of the factor. We propose that, ultimately, successful repair and regeneration strategies will require quantitative control of the myocardial microenvironment. This precision control can be engineered through designed biomaterials that provide quantitative adhesion, growth, or migration signals. Quantitative timed release of factors can be regulated by chemical design to direct cellular differentiation pathways such as angiogenesis and vascular maturation. Smart biomaterials respond to the local environment, such as protease activity or mechanical forces, with controlled release or activation. Most of these new biomaterials provide much greater flexibility for regenerating tissues ex vivo, but emerging technologies like self-assembling nanofibers can now establish intramyocardial cellular microenvironments by injection. This may allow percutaneous cardiac regeneration and repair approaches, or injectable-tissue engineering. Finally, materials can be made to multifunction by providing sequential signals with custom design of differential release kinetics for individual factors. Thus, new rationally-designed biomaterials no longer simply coexist with tissues, but can provide precision bioactive control of the microenvironment that may be required for cardiac regeneration and repair.
Targeted Gene Silencing Using RGD-Labeled Chitosan Nanoparticles
Authors: Hee Dong Han, Lingegowda S. Mangala, Jeong Won Lee, Mian M.K. Shahzad, Hye Sun Kim, Deyu Shen, Eun Ji Nam, Edna M. Mora, Rebecca L. Stone, Chunhua Lu, Sun Joo Lee, Ju Won Roh, Alpa M. Nick, Gabriel Lopez-Berestein, Anil K. Sood
Journal: Clinical Cancer Research (2010)

Abstract Purpose: This study aimed to develop an Arg-Gly-Asp (RGD) peptide-labeled chitosan nanoparticle (RGD-CH-NP) as a novel tumor targeted delivery system for short interfering RNA (siRNA). Experimental Design: RGD peptide conjugated with chitosan by thiolation reaction was confirmed by proton-NMR (H-NMR). Binding of RGD-CH-NP with ανβ3 integrin was examined by flow cytometry and fluorescence microscopy. Antitumor efficacy was examined in orthotopic mouse models of ovarian carcinoma. Results: We show that RGD-CH-NP loaded with siRNA significantly increased selective intratumoral delivery in orthotopic animal models of ovarian cancer. In addition, we show targeted silencing of multiple growth-promoting genes (POSTN, FAK, and PLXDC1) along with therapeutic efficacy in the SKOV3ip1, HeyA8, and A2780 models using siRNA incorporated into RGD-CH-NP (siRNA/RGD-CH-NP). Furthermore, we show in vivo tumor vascular targeting using RGD-CH-NP by delivering PLXDC1-targeted siRNA into the ανβ3 integrin–positive tumor endothelial cells in the A2780 tumor-bearing mice. This approach resulted in significant inhibition of tumor growth compared with controls. Conclusions: This study shows that RGD-CH-NP is a novel and highly selective delivery system for siRNA with the potential for broad applications in human disease. Clin Cancer Res; 16(15); 3910–22. ©2010 AACR.
Antibody-Drug Conjugates of Calicheamicin Derivative: Gemtuzumab Ozogamicin and Inotuzumab Ozogamicin
Authors: Alejandro D. Ricart
Journal: Clinical Cancer Research (2011)

Abstract Antibody-drug conjugates (ADC) are an attractive approach for the treatment of acute myeloid leukemia and non-Hodgkin lymphomas, which in most cases, are inherently sensitive to cytotoxic agents. CD33 and CD22 are specific markers of myeloid leukemias and B-cell malignancies, respectively. These endocytic receptors are ideal for an ADC strategy because they can effectively carry the cytotoxic payload into the cell. Gemtuzumab ozogamicin (GO, Mylotarg) and inotuzumab ozogamicin consist of a derivative of calicheamicin (a potent DNA-binding cytotoxic antibiotic) linked to a humanized monoclonal IgG4 antibody directed against CD33 or CD22, respectively. Both of these ADCs have a target-mediated pharmacokinetic disposition. GO was the first drug to prove the ADC concept in the clinic, specifically in phase II studies that included substantial proportions of older patients with relapsed acute myeloid leukemia. In contrast, in phase III studies, it has thus far failed to show clinical benefit in first-line treatment in combination with standard chemotherapy. Inotuzumab ozogamicin has shown remarkable clinical activity in relapsed/refractory B-cell non-Hodgkin lymphoma, and it has started phase III evaluation. The safety profile of these ADCs includes reversible myelosuppression (especially neutropenia and thrombocytopenia), elevated hepatic transaminases, and hyperbilirubinemia. There have been postmarketing reports of hepatotoxicity, especially veno-occlusive disease, associated with GO. The incidence is ∼2%, but patients who undergo hematopoietic stem cell transplantation have an increased risk. As we steadily move toward the goal of personalized medicine, these kinds of agents will provide a unique opportunity to treat selected patient subpopulations based on the expression of their specific tumor targets. Clin Cancer Res; 17(20); 6417–27. ©2011 AACR.
Recurrence of Autism Spectrum Disorders in Full- and Half-Siblings and Trends Over Time
Authors: Therese K. Grønborg, Diana E. Schendel, Erik T. Parner
Journal: JAMA Pediatrics (2013)

To date, this is the first population-based study to examine the recurrence risk for autism spectrum disorders (ASDs), including time trends, and the first study to consider the ASDs recurrence risk for full- and half-siblings.To estimate the relative recurrence risk for ASDs in a Danish population, including recurrence in full- and half-siblings, and to examine time trends in ASDs relative to the recurrence risk.Population-based cohort study in Denmark. All children (about 1.5 million) born in Denmark between January 1, 1980, and December 31, 2004, were identified and followed up to December 31, 2010. We identified a maternal sibling subcohort derived from mothers with at least 2 children and a paternal sibling subcohort derived from fathers with at least 2 children.Children having an older sibling with ASDs are compared with children not having an older sibling with ASDs.The adjusted hazard ratio for ASDs among children having an older sibling with ASDs compared with children not having an older sibling with ASDs. RESULTS The overall relative recurrence risk for ASDs was 6.9 (95% CI, 6.1-7.8), and it did not change significantly over time; similar risks were observed in maternal and paternal full-siblings. The relative recurrence risks were 2.4 (95% CI, 1.4-4.1) for maternal half-siblings and 1.5 (95% CI, 0.7-3.4) for paternal half-siblings.Our population-based recurrence risk estimate is lower than the recently reported estimates from clinical samples. Our results demonstrate no time trend in the ASDs recurrence risk as seen in the ASDs prevalence. The difference in the recurrence risk between full- and half-siblings supports the role of genetics in ASDs, while the significant recurrence risk in maternal half-siblings may support the role of factors associated with pregnancy and the maternal intrauterine environment in ASDs.
Insulin receptor down-regulation is linked to an insulin-induced postreceptor defect in the glucose transport system in rat adipocytes.
Authors: W T Garvey, J M Olefsky, S Marshall
Journal: Journal of Clinical Investigation (1985)

We have examined the relationship between insulin-induced receptor downregulation and the induction of a postreceptor defect in the insulin-stimulated glucose transport system in rat adipocytes, and found that downregulation was linked to the expression of the postreceptor defect. When recycling of insulin receptors was inhibited by 20 mM Tris, insulin pretreatment (100 ng/ml) for 4 h at 37 degrees C induced both net loss (65%) of cell-surface receptors and a 63% decrease in maximal insulin responsiveness. In contrast, when cells were treated with insulin alone for 4 h at 37 degrees C so that receptors could recycle, or treated at 16 degrees C with Tris plus insulin to inhibit receptor internalization, neither receptor downregulation nor a postreceptor defect was observed. Induction of the postreceptor defect was specific for insulin under conditions when downregulation would occur, since treatment of cells with Tris and the insulin mimicker spermine did not result in receptor loss or the postreceptor defect. Other experiments revealed that receptor downregulation occurred first without loss of insulin responsiveness, but, once the postreceptor defect appeared, its severity was correlated to the degree of further receptor loss, as a function of insulin dose and exposure time. Tris (20 mM) alone acutely decreased maximally stimulated glucose transport rates slightly (22%), but this effect was rapidly reversible after Tris removal and could not have been directly responsible for the lasting and profound postreceptor defect seen after pretreatment with insulin plus Tris. Taken together, these data suggest that insulin-induced receptor loss is linked to the induction of the postreceptor defect. The postreceptor defect was due to an inability to maximally increase the maximum velocity of glucose transport. Furthermore, the expression of the postreceptor defect depended upon the extent to which the glucose transport system was allowed to deactivate; maintaining the glucose transport system in an activated state prevented its expression. Thus, the mechanism could involve rapid inactivation or sequestration of glucose transporters during deactivation such that they become refractory to the subsequent stimulatory effects of insulin. In conclusion, (a) insulin does not acutely induce a postreceptor defect in the glucose transport system of adipocytes without loss of cell-surface insulin receptors; (b) the defect in stimulated glucose transport has been induced distal to the insulin receptor via a mechanism linked to receptor loss; and (c) the postreceptor lesion is due to decreased number of intrinsic activity of glucose transporters on the cell-surface in the presence of a maximally effective insulin concentration. These data suggest that insulin receptor downregulation and postreceptor defects in insulin action, which frequently co-exist both in vivo and in vitro, may be linked mechanistically.
Reproducibility of Gene Expression Signature–Based Predictions in Replicate Experiments
Authors: Keith Anderson, Kenneth R. Hess, Mini Kapoor, Stephen Tirrell, Jean Courtemanche, Bailiang Wang, Yun Wu, Yun Gong, Gabriel N. Hortobagyi, W. Fraser Symmans, Lajos Pusztai
Journal: Clinical Cancer Research (2006)

Abstract Purpose: The goals of this analysis were to (a) determine concordance of gene expression results from replicate experiments, (b) examine prediction agreement of multigene predictors on replicate data, and (c) assess the robustness of prediction results in the face of noise. Patients and Methods: Affymetrix U133A gene chips were used for gene expression profiling of 97 fine-needle aspiration biopsies from breast cancer. Thirty-five cases were profiled in replicates: 17 within the same laboratory, 11 in two different laboratories, and 15 to assess manual and robotic labeling. We used data from 62 cases to develop 111 distinct pharmacogenomic predictors of response to therapy. These were tested on cases profiled in duplicates to determine prediction agreement and accuracy. To evaluate the robustness of the pharmacogenomic predictors, we also introduced random noise into the informative genes in one half of the replicates. Results: The average concordance correlation coefficient was 0.978 (range, 0.96-0.99) for intralaboratory replicates, 0.962 (range, 0.94-0.98) for between-laboratory replicates, and 0.971 (range, 0.93-0.99) for manual versus robotic labeling. The mean % prediction agreement on replicate data was 97% (95% CI, 0.96-0.98; SD, 0.006), 92% (95% CI, 0.90-0.93; SD, 0.009), and 94% (95% CI, 0.92-0.95; SD, 0.008) for support vector machines, diagonal linear discriminant analysis, and k-nearest neighbor prediction methods, respectively. Mean accuracy in the test set was 77% (95% CI, 0.74-0.79; SD, 0.014), 66% (95% CI, 0.63-0.73; SD, 0.015), and 64% (95% CI, 0.60-0.67; SD, 0.016), respectively. Conclusion: Gene expression results obtained with Affymetrix U133A chips are highly reproducible within and across two high-volume laboratories. Pharmacogenomic predictions yielded &amp;gt;90% agreement in replicate data.
Absent neutrophil alkaline phosphatase in the eosinophilia myalgia syndrome associated with <scp>L</scp>‐tryptophan use
Authors: Jeffrry P. Jaffe, Elie Gertner, Wesley Miller
Journal: American Journal of Hematology (1991)

Abstract The clinical constellation of leukocytosis, thrombocytosis, and low or absent stainable neutrophil alkaline phosphatase (NAP) is considered characteristic of chronic myelogenous leukemia (CML) [1]. CML with eosinophilic differentiation (eosinophilic leukemia) is well described [2], and leukemia and other clonal hematologic malignancies are associated with the syndrome of eosinophilic fasciitis [3]. We describe leukocytosis, thrombocytosis, eosinophilia, mild basophilia, and absent stainable NAP, initially suggesting the diagnosis of CML in a patient with the eosinophilia myalgia syndrome associated with L‐tryptophan use, a condition resembling eosinophilic fasciitis. Cytogenetic and molecular genetic studies failed to demonstrate a clonal proliferation of eosinophils.
An Epstein-Barr virus-specific cytotoxic T cell epitope in EBV nuclear antigen 3 (EBNA 3).
Authors: S R Burrows, T B Sculley, I S Misko, C Schmidt, D J Moss
Journal: The Journal of Experimental Medicine (1990)

Epstein-Barr virus (EBV)-specific CTL clones were isolated that recognized A-type EBV transformants but not B-type transformants. These A-type-specific CTL clones (HLA B8 restricted) were used to screen peptides derived from the EBV nuclear antigens (EBNAs) 2, 3, 4, and 6 as potential CTL epitopes. Of the 76 peptides screened, one sequence from EBNA 3 (residues 329-353) was recognized by A-type-specific CTL clones after absorption onto target cells (either autologous B-type transformants or PHA blasts). This report is the first description of an EBV target epitope recognized by specific CTL clones.
An examination of the frequency and severity of injuries and incidents at three levels of professional football
Authors: R D Hawkins, C W Fuller
Journal: British Journal of Sports Medicine (1998)

OBJECTIVE: To assess the risk of injury to professional footballers during European international and English Premier and First Division league matches. METHODS: Videotaped recordings of 29, 49, and 93 matches from the 1996 European Championship, 1996/1997 English Premier season and 1994 to 1997 English First Division seasons respectively were analysed. During each match, several relevant variables, including the number of fouls, injuries, time of incident, player identity, and injury mechanism, were recorded. RESULTS: Significantly more free kicks were awarded during international matches than during league matches; however, there were no significant differences between the numbers of free kicks awarded over the three First Division seasons assessed. Between 1.7 and 3.0% of fouls resulted in a player requiring treatment for injury, but only 15-28% of all injuries resulted from foul play. In all "non-foul" situations, in which injury resulted, at least 60% still involved player to player contact. No significant differences in injury frequency were observed between playing positions or match halves. CONCLUSIONS: The results equate to a total of 808 players per season from the estimated 2600 players in the four English professional football leagues sustaining a match injury that caused them to miss at least one game. The large number of underlying "non-injury" incidents is identified as the reason for this level of injury rather than a higher ratio of "injury" to "non-injury" incidents in professional football compared with other occupations.
Secular Trends in Cardiovascular Disease and Its Risk Factors in Japanese
Authors: Jun Hata, Toshiharu Ninomiya, Yoichiro Hirakawa, Masaharu Nagata, Naoko Mukai, Seiji Gotoh, Masayo Fukuhara, Fumie Ikeda, Kentaro Shikata, Daigo Yoshida, Koji Yonemoto, Masahiro Kamouchi, Takanari Kitazono, Yutaka Kiyohara
Journal: Circulation (2013)

Background— Changes in lifestyle and advances in medical technology during the past half century are likely to have affected the incidence and mortality of cardiovascular disease and the prevalence of its risk factors in Japan. Methods and Results— We established 5 cohorts consisting of residents aged ≥40 years in a Japanese community, in 1961 (n=1618), 1974 (n=2038), 1983 (n=2459), 1993 (n=1983), and 2002 (n=3108), and followed up each cohort for 7 years. The age-adjusted incidence of stroke decreased greatly, by 51% in men and by 43% in women, from the 1960s to the 1970s, but this decreasing trend slowed from the 1970s to the 2000s. Among the stroke subtypes, ischemic stroke in both sexes and intracerebral hemorrhage in men showed a similar pattern. Stroke mortality decreased as a result of the decline in incidence and a significant improvement in survival rate. Although the incidence of acute myocardial infarction did not change in either sex, disease mortality declined slightly in women. From the 1960s to the 2000s, blood pressure control among hypertensive individuals improved significantly and the smoking rate decreased, but the prevalence of glucose intolerance, hypercholesterolemia, and obesity increased steeply. Conclusions— Our findings suggest that in Japanese, the decreasing trends in the incidence of ischemic stroke have recently slowed down, and there has been no clear change in the incidence of acute myocardial infarction, probably because the benefits of hypertension control and smoking cessation have been negated by increasing metabolic risk factors.
T-cell regulation of human peripheral blood B-cells responsiveness.
Authors: A J Strelkauskas, B S Wilson, R T Callery, L Chess, S F Schlossman
Journal: The Journal of Experimental Medicine (1977)

We have investigated the influence of human T cells on the synthesis and secretion of immunoglobulin by peripheral blood B cells. The plaque-forming assay used, which identified the number of B cells secreting Ig, is a short-term assay which requires no exogenous stimulation. We have shown that the B-cell population alone contains fewer secreting cells than the total lymphocyte population, and that T cells are required to achieve maximal plaque-forming cell levels. Cycloheximide treatment of cells at concentrations known to inhibit protein synthesis does not affect the cooperative potential of these cells. Additionally, this cooperation effect is markedly better among autologous mixtures of Ig- and Ig+ cells, than among mixtures obtained from randomly selected individuals.
P518 HEPATIC VENOUS PRESSURE GRADIENT, ASA CLASS AND TYPE OF SURGERY ARE PROGNOSTIC FACTORS OF EXTRA-HEPATIC SURGERY IN PATIENTS WITH CIRRHOSIS: A MULTI-CENTER PROSPECTIVE OBSERVATIONAL STUDY
Authors: E. Reverter, I. Cirera, A. Albillos, W. Debernardi-Venon, J.G. Abraldes, E. Llop, A. Flores, G. Martínez-Palli, A. Blasi, J. Martinez, F. Turon, A. Berzigotti, V. Hernández-Gea, J. Bosch, J.C. García-Pagaín
Journal: Journal of Hepatology (2014)
The biogenesis of platelets from megakaryocyte proplatelets
Authors: Sunita R Patel, John H Hartwig, Joseph E Italiano
Journal: Journal of Clinical Investigation (2005)

Platelets are formed and released into the bloodstream by precursor cells called megakaryocytes that reside within the bone marrow. The production of platelets by megakaryocytes requires an intricate series of remodeling events that result in the release of thousands of platelets from a single megakaryocyte. Abnormalities in this process can result in clinically significant disorders. Thrombocytopenia (platelet counts less than 150,000/μl) can lead to inadequate clot formation and increased risk of bleeding, while thrombocythemia (platelet counts greater than 600,000/μl) can heighten the risk for thrombotic events, including stroke, peripheral ischemia, and myocardial infarction. This Review will describe the process of platelet assembly in detail and discuss several disorders that affect platelet production.
<i>PXK</i>locus in systemic lupus erythematosus: fine mapping and functional analysis reveals novel susceptibility gene<i>ABHD6</i>
Authors: Nina Y Oparina, Angelica M Delgado-Vega, Manuel Martinez-Bueno, César Magro-Checa, Concepción Fernández, Rafaela Ortega Castro, Bernardo A Pons-Estel, Sandra D'Alfonso, Gian Domenico Sebastiani, Torsten Witte, Bernard R Lauwerys, Emoke Endreffy, László Kovács, Alejandro Escudero, Chary López-Pedrera, Carlos Vasconcelos, Berta Martins da Silva, Johan Frostegård, Lennart Truedsson, Javier Martin, Enrique Raya, Norberto Ortego-Centeno, Maria de los Angeles Aguirre, Enrique de Ramón Garrido, María-Jesús Castillo Palma, Marta E Alarcon-Riquelme, Sergey V Kozyrev
Journal: Annals of the Rheumatic Diseases (2014)

To perform fine mapping of the PXK locus associated with systemic lupus erythematosus (SLE) and study functional effects that lead to susceptibility to the disease.Linkage disequilibrium (LD) mapping was conducted by using 1251 SNPs (single nucleotide polymorphism) covering a 862 kb genomic region on 3p14.3 comprising the PXK locus in 1467 SLE patients and 2377 controls of European origin. Tag SNPs and genotypes imputed with IMPUTE2 were tested for association by using SNPTEST and PLINK. The expression QTLs data included three independent datasets for lymphoblastoid cells of European donors: HapMap3, MuTHER and the cross-platform eQTL catalogue. Correlation analysis of eQTLs was performed using Vassarstats. Alternative splicing for the PXK gene was analysed on mRNA from PBMCs.Fine mapping revealed long-range LD (>200 kb) extended over the ABHD6, RPP14, PXK, and PDHB genes on 3p14.3. The highly correlated variants tagged an SLE-associated haplotype that was less frequent in the patients compared with the controls (OR=0.89, p=0.00684). A robust correlation between the association with SLE and enhanced expression of ABHD6 gene was revealed, while neither expression, nor splicing alterations associated with SLE susceptibility were detected for PXK. The SNP allele frequencies as well as eQTL pattern analysed in the CEU and CHB HapMap3 populations indicate that the SLE association and the effect on ABHD6 expression are specific to Europeans.These results confirm the genetic association of the locus 3p14.3 with SLE in Europeans and point to the ABHD6 and not PXK, as the major susceptibility gene in the region. We suggest a pathogenic mechanism mediated by the upregulation of ABHD6 in individuals carrying the SLE-risk variants.