tbuckley/cabot-search huggingface dataset:
Identification and targeting of internalizing breast tumor receptors for immunotherapy
Authors: Yu Zhou, Helen Huang, Lindsay McDonald, Hao Zou, James D. Marks
Journal: Cancer Research (2005)

567  Breast tumors can be histologically classified into basal, luminal, and mesenchymal cell types which vary in prognosis and response to different therapies. Expression array analysis reveals significant differences in the genes up and down regulated in these three tumor types. We hypothesized that these differences would result in a different pattern of cell surface receptor overexpression which could be exploited for antibody based molecular therapies. Such therapies could potentially target most members of a given tumor type. To test this hypothesis, we selected monovalent and multivalent non-immune single chain Fv(scFv) phage antibody libraries on a panel of luminal (SKBR3, MCF7, T47D, MDA-MB-453 and MDA-MB-361) and mesenchymal (MDA-MB-231 and BT549) breast tumor cell lines. We employed a strategy developed in the lab that selects phage antibodies that trigger receptor mediated endocytosis. The resulting antibodies can thus be employed therapeutically not only as naked antibodies but also to deliver targeted therapies including immunotoxins, immunoliposomes, antibody-drug conjugates and for the targeted delivery of genes or viral DNA into cells. After two rounds of selection on the target cell line, large panels of antibodies were isolated which could be classified into three groups: 1) non specific antibodies (bind all cell types tested, 50% of antibodies); 2) cell line specific (bind only the cell line used for selection, 5% of antibodies); and 3) cell type specific (bind most, or all, members of a given breast tumor cell type, 45% of antibodies. For example, after selection of phage libraries on MDA-MB-231 cells, at least 8 unique antibodies were generated which bound all mesenchymal cell lines analyzed (MDA-MB-231, MDA-MB-231-guise, BT549, Hs578T) but not luminal cell lines (SKBR3, MCF7, T47D, MDA-MB-453) These preliminary results suggest that a large panel of antibodies against native tumor surface proteins can be developed through direct selection of phage antibody libraries on breast tumor cell lines. The resulting antibodies appear largely cell type specific and may be a route to antibodies which can be used for intracellular drug delivery and to identify the antigens bound. It is likely that a subset of antibodies may also directly inhibit growth or induce apoptosis. Studies are ongoing to: 1) profile the antibodies on a larger panel of mesenchymal and luminal cell lines; 2) determine whether the antibodies are efficiently internalized; and 3) determine whether the antibodies have direct antiproliferative activity.
Valproic acid sensitizes human melanoma cells to karenitecin in vitro and in vivo
Authors: Jana L. Gump, Douglas C. Marchion, Elona Bicaku, Joel G. Turner, Frederick H. Hausheer, Adil I. Daud, Pamela N. Munster, Daniel M. Sullivan
Journal: Cancer Research (2006)

Proc Amer Assoc Cancer Res, Volume 47, 2006

1355 

Melanoma continues to be a difficult disease to treat and rarely achieves a stable clinical response. A Phase II clinical trial performed at our institution achieved stable disease in 34% of patients with advanced stage melanoma using the topoisomerase (topo) I inhibitor, karenitecin (KTN), a novel lipophilic camptothecin analog (Daud et al, Clin Cancer Res 11:(8), 2005). Another novel class of anti-tumor agents, the histone deacetylase inhibitors (HDACi), have shown promising results in the laboratory, by potentiating the anti-tumor effects of topo II inhibitors in breast cancer cells (Marchion et al, Cancer Res 65:(9), 2005). These experiments demonstrated that valproic acid (VPA) induced chromatin decondensation, which led to increased access of drug to the target DNA substrate in breast cancer cells. The focus of the current project was to determine if VPA would enhance the cytotoxic effects of KTN in melanoma cells. The sensitivity of four human melanoma cell lines to KTN-induced apoptosis, starting with the most sensitive cell line, is A375, A2058, SK-MEL-5 and SK-MEL-28. When pre-treated with VPA for 48 hours, all four cell lines were 2.5- to 6- fold more sensitive to KTN, compared to KTN treatment alone. Enhanced cell death was also seen in the A375 cells when VPA and KTN were given at the same time, but was lost if KTN was given prior to VPA. Pre-treatment of A375 cells with Suberoylanilide Hydroxamic Acid (SAHA), another HDACi, followed by KTN, resulted in similar synergistic apoptotic effects. However, this sensitization was lost when these two agents were administered concurrently. The results seen in human melanoma cell lines have been confirmed in a mouse model, where a statistically significant decrease in tumor volume was observed in the mouse A375 xenograft model when KTN treatment followed VPA administration. Early experiments to define the mechanism of sequence-dependent synergy of HDAC → topo I inhibitors suggests that HDAC inhibitor exposure augments KTN-induced DNA damage. Finally, a Phase I/II trial of VPA → KTN in patients with metastatic melanoma has enrolled 11 subjects, and minimal toxicity has been observed thus far. Supported in part by NIH grant CA82533.
Abstract 16160: Common Autosomal Variants are Associated With Bicuspid Aortic Valve in Turner Syndrome
Authors: Siddharth Prakash, Michael Silberbach, Federico Asch, Giuseppe Limongelli, Hector Michelena, Dongchuan Guo, Cheryl Maslen, Carolyn A Bondy, Dianna M Milewicz
Journal: Circulation (2014)

Introduction: The prevalence of bicuspid aortic valves (BAV) is enriched thirty-fold in women with Turner Syndrome (TS) in comparison with the general population. Hypothesis: Common autosomal variants influence the development of BAV in TS women, who may be uniquely sensitized to these variants by the loss of one X chromosome. We sought to identify autosomal BAV susceptibility genes in a cohort of TS women (average age 30 years, 38% BAV, 18% coarctation). Methods: A total of 106 TS women of European ancestry with BAV and 173 TS women with tricuspid aortic valves were genotyped on Illumina Omni-Express arrays. Valve phenotypes were determined by independent review of echocardiograms from the enrolling sites. Tests of association were performed using logistic regression without adjustment for covariates and were summarized in a meta-analysis. Results: Xp dosage was inversely and quantitatively associated with BAV status (P=0.02). Large, recurrent copy number variants in 1p36.13, 3q29, 8p23.1 and 9p24.3 were significantly enriched in BAV cases. After exclusion of 26 outlier samples in multidimensional scaling analysis, there was no significant genomic inflation (lambda= 1.02). The strongest genome-wide association signals were observed in 1p36.23, 3q23, 12q21.2, 18q21 and 22q13.31, and did not overlap with previously reported loci for BAV. A total of 13 SNPs in 18q21 were positively associated with BAV (OR=2.5-4.3) with a minimum P value of 1x10-7. Replication of these regions in independent groups of cases is ongoing. Conclusion: Our results demonstrate that autosomal variants with large magnitudes of effect contribute to BAV in TS women, confirming our hypothesis, and provide evidence for gene-gene interactions in BAV formation.
癫痫定义及分类:历史、内涵、新观念
Authors: 王学峰
Journal: BMJ (2007)

疾病定义是对这种疾病特征的高度概括，定义仅作为医务人员认识这种疾病和与其他疾病进行鉴别的理论依据。而疾病的分类则是在疾病错综复杂的临床表现中操繁就简，提纲挈领地认识疾病的方法。国际抗癫痫联盟（ILAE）最重要的任务之一就是给癫痫这个古老的名词注入特殊内涵，制定能被全世界同行认同的癫痫定义，并按癫痫的特征进行分类以便同行交流。
Laboratory capability for molecular detection and confirmation of novel coronavirus in Europe, November 2012
Authors: D Palm, D Pereyaslov, J Vaz, E Broberg, H Zeller, D Gross, C S Brown, M  J Struelens, None on behalf of the Joint ECDC-WHO Reg
Journal: Eurosurveillance (2012)

A rapid survey by the European Centre for Disease Prevention and Control (ECDC) and the World Health Organization (WHO) Regional Office for Europe ascertained the availability of national reference laboratory testing for a recently detected novel coronavirus as of 28 November 2012. Screening by internal quality controlled upE-RT-PCR assay was available in 23/46 of responding countries in the WHO European Region, of which 19/30 in European Union (EU) and European Economic Area (EEA) countries. Confirmation of positive screened samples by either ORF1b - RT-PCR, or other target RT-PCR assays with sequence analysis or whole-genome sequence analysis was available in 22/46 responding countries of which 18/30 in EU/EEA countries.
The Role of Neutrophils in Measles Virus–mediated Oncolysis Differs Between B-cell Malignancies and Is Not Always Enhanced by GCSF
Authors: Aditi Dey, Yu Zhang, Anna Z Castleton, Katharine Bailey, Brendan Beaton, Bella Patel, Adele K Fielding
Journal: Molecular Therapy (2015)

The mechanism by which oncolytic measles virus (MV) kills cancer cells remains obscure. We previously showed that neutrophils are involved in MV-mediated tumor regressions and become activated, upon MV infection. In the present study, we attempted to enhance the neutrophil response toward MV-infected tumor targets by generating an oncolytic MV-expressing human granulocyte colony-stimulating factor (MVhGCSF). Evaluating the effects in two different models of B-cell malignancy, we showed that depletion of neutrophils abrogated the MV therapeutic effect in an in vivo Raji'but not Nalm-6 tumor model. Next, we compared MVhGCSF with the unmodified backbone virus MVNSe. MVhGCSF enhanced the oncolytic capacity of MV in the Raji model in vivo, whereas in the Nalm-6 model, the opposite was unexpectedly the case. This finding was recapitulated by exogenously administered hGCSF. MVhGCSF replicated within an MV-infectable CD46 transgenic mouse model with detectable serum levels of hGCSF but no toxicity. Our data suggest that a "one-size-fits-all" model of immune response to viral oncolysis is not appropriate, and each tumor target will need full characterization for the potential of both direct and indirect, innate immune responses to generate benefit. The mechanism by which oncolytic measles virus (MV) kills cancer cells remains obscure. We previously showed that neutrophils are involved in MV-mediated tumor regressions and become activated, upon MV infection. In the present study, we attempted to enhance the neutrophil response toward MV-infected tumor targets by generating an oncolytic MV-expressing human granulocyte colony-stimulating factor (MVhGCSF). Evaluating the effects in two different models of B-cell malignancy, we showed that depletion of neutrophils abrogated the MV therapeutic effect in an in vivo Raji'but not Nalm-6 tumor model. Next, we compared MVhGCSF with the unmodified backbone virus MVNSe. MVhGCSF enhanced the oncolytic capacity of MV in the Raji model in vivo, whereas in the Nalm-6 model, the opposite was unexpectedly the case. This finding was recapitulated by exogenously administered hGCSF. MVhGCSF replicated within an MV-infectable CD46 transgenic mouse model with detectable serum levels of hGCSF but no toxicity. Our data suggest that a "one-size-fits-all" model of immune response to viral oncolysis is not appropriate, and each tumor target will need full characterization for the potential of both direct and indirect, innate immune responses to generate benefit.
Abstract 17229: Quantity and Quality Culture Restores Diabetic Endothelial Progenitor Cell Dysfunction for Wound Healing
Authors: Rica Tanaka, Haruchika Masuda, Kayo Arita, Rie Hirano, Dewi Sukmawati, Satoshi Fujimura, Hiroshi Mizuno, Takayuki Asahara
Journal: Circulation (2012)

Background: The quality and quantity of endothelial progenitor cells (EPC), i.e., CD34+ cells is known to be impaired in diabetic patients, thereby raising declined tissue repair in autologous EPC ...
Abstract 9703: Lowering LDL Cholesterol, but not Raising LDL Receptor Activity, by Ezetimibe
Authors: Hiroshi Hayashi, Mitsunobu Kawamura
Journal: Circulation (2012)

Introduction: Ezetimibe, an inhibitor of intestinal cholesterol absorption, is effective in lowering serum low-density lipoprotein (LDL) cholesterol with or without co-administration of statin. Ezetimibe-plus-statin therapy enhances LDL receptor activity, but it is still unclear whether ezetimibe alone enhances LDL receptor activity resulting in LDL cholesterol decrease. Hypothesis: We assessed the hypothesis that ezetimibe lowers serum LDL cholesterol by raising LDL receptor activity in humans. Methods: Hypercholesterolemic patients (n = 28; age 61.3 ± 12.7 (mean ± SD); 57% male) were treated with ezetimibe (10 mg/day) for 4 months. Before and after the treatment, serum LDL cholesterol, high-density lipoprotein (HDL) cholesterol, and triglyceride were measured. Serum apolipoprotein A-I (apo A-I), B (apo B), and C-II (apo C-II) were also measured and the estimated LDL receptor activities were calculated by our previously reported methods as follows: LDL receptor activity (expressed as a percentage of normocholesterolemic subjects) = 63.6 + apo C-II (mg/dl) x 13.5 - apo B (mg/dl) x 0.37. Results: By the treatment of ezetimibe, LDL cholesterol (178.5 ± 26.2 vs. 141.1 ± 26.2 mg/dl, p &lt; 0.01) was lowered 21% significantly and HDL cholesterol (56.1 ± 12.3 vs. 59.5 ± 16.2 mg/dl, p &lt; 0.01) was increased 6% significantly. Triglyceride (184.4 ± 85.6 vs.174.8 ± 85.2 mg/dl, p = 0.60) was not changed. Serum apo B (136.2 ± 24.5 vs. 113.0 ± 23.8 mg/dl, p &lt; 0.01) was lowered 17% significantly and apo A-I (143.5 ± 28.5 vs. 150.3 ± 31.9 mg/dl, p &lt; 0.01) was increased 5% significantly. Apo C-II (5.9 ± 2.2 vs. 5.5 ± 2.2 mg/dl, p = 0.11) was not changed. The estimated LDL receptor activities before and after the ezetimibe treatment were 93.5 ± 25.1% and 96.9 ± 24.4%, respectively with no significant difference between them (p = 0.14). Conclusions: Ezetimibe lowered LDL cholesterol 21% significantly in hypercholesterolemic patients without raising LDL receptor activity. In conclusion, the enhancement of LDL receptor activity is suggested to be less involved in the pharmacological action of ezetimibe.
Abstract 4554: Drug-eluting vs. Bare-metal Stents for the Treatment of ST-elevation Myocardial Infarction: Three-year Clinical Outcome of the MISSION! Intervention Study
Authors: Jael Z Atary, Bas L van der Hoeven, Su San Liem, J W Jukema, Hein Putter, Douwe E Atsma, Marianne Bootsma, Katja Zeppenfeld, Ernst E van der Wall, Martin J Schalij
Journal: Circulation (2009)

Objective: To compare the long-term efficacy and safety of sirolimus-eluting stents (SES) to bare-metal stents (BMS) for the treatment of acute ST-segment myocardial infarction (STEMI). Method: All...
Optimizing aerosolization of a high-dose L-arginine powder for pulmonary delivery
Authors: Satu Lakio, David A.V. Morton, Anna P. Ralph, Pete Lambert
Journal: Asian Journal of Pharmaceutical Sciences (2015)

In this study a carrier-free dry powder inhalation (DPI) containing L-arginine (ARG) was developed. As such, it is proposed that ARG could be used for adjunctive treatment of cystic fibrosis and/or tuberculosis. Various processing methods were used to manufacture high-dose formulation batches consisting various amounts of ARG and excipients. The formulations were evaluated using several analytical methods to assess suitability for further investigation. Several batches had enhanced in vitro aerolization properties. Significant future challenges include the highly hygroscopic nature of unformulated ARG powder and identifying the scale of dose of ARG required to achieve the response in lungs.
Inhibition of Aggregation of Mutant Huntingtin by Nucleic Acid Aptamers In Vitro and in a Yeast Model of Huntington's Disease
Authors: Rajeev K Chaudhary, Kinjal A Patel, Milan K Patel, Radha H Joshi, Ipsita Roy
Journal: Molecular Therapy (2015)

Elongated polyglutamine stretch in mutant huntingtin (mhtt) correlates well with the pathology of Huntington's disease (HD). Inhibition of aggregation of mhtt is a promising strategy to arrest disease progression. In this work, specific, high-affinity RNA aptamers were selected against monomeric mhtt (51Q-htt). Some of them inhibited its aggregation in vitro by stabilizing the monomer. They also recognized 103Q-htt but not 20Q-htt (nonpathogenic length). Inhibition of aggregation corresponded with reduced leakage of a fluorescent probe from liposomes and diminished oxidative stress in RBCs. The presence of aptamers was able to rescue the sequestration of the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) by aggregated mhtt. Some of the aptamers were able to enhance the partitioning of mhtt in the soluble fraction in a yeast model of HD. They were also able to rescue endocytotic defect due to aggregation of mhtt. The beneficial effect of a combination of aptamers was enhanced with improvement in cell survival. Since HD is a monogenic autosomal dominant disorder, aptamers may be developed as a viable strategy to slow down the progress of the disease. Since they are nonimmunogenic and nontoxic, aptamers may emerge as strong candidates to reduce protein–protein interaction and hence protein aggregation in protein misfolding disorders in general. Elongated polyglutamine stretch in mutant huntingtin (mhtt) correlates well with the pathology of Huntington's disease (HD). Inhibition of aggregation of mhtt is a promising strategy to arrest disease progression. In this work, specific, high-affinity RNA aptamers were selected against monomeric mhtt (51Q-htt). Some of them inhibited its aggregation in vitro by stabilizing the monomer. They also recognized 103Q-htt but not 20Q-htt (nonpathogenic length). Inhibition of aggregation corresponded with reduced leakage of a fluorescent probe from liposomes and diminished oxidative stress in RBCs. The presence of aptamers was able to rescue the sequestration of the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) by aggregated mhtt. Some of the aptamers were able to enhance the partitioning of mhtt in the soluble fraction in a yeast model of HD. They were also able to rescue endocytotic defect due to aggregation of mhtt. The beneficial effect of a combination of aptamers was enhanced with improvement in cell survival. Since HD is a monogenic autosomal dominant disorder, aptamers may be developed as a viable strategy to slow down the progress of the disease. Since they are nonimmunogenic and nontoxic, aptamers may emerge as strong candidates to reduce protein–protein interaction and hence protein aggregation in protein misfolding disorders in general.
Abstract 18: Coxsackievirus B3 Escapes Infected Cardiac Stem Cells via Ejected Autophagosomes
Authors: Jon Sin, Vrushali Mangale, Laura McIntyre, Ralph Feuer, Roberta A Gottlieb
Journal: Circulation Research (2014)

Many viruses have been shown to upregulate host autophagic processes during the course of infection. Originally this process was thought to be a response mechanism of the host cell in order to engulf viral particles and destroy them to prevent viral spread and host cell death. However, certain viruses have been shown to strategically hijack the autophagic pathway to evade host immunity and increase viral replication. Coxsackievirus B (CVB) is a non-enveloped picornavirus that most commonly causes a self-limited febrile illness in young children, but in rare severe cases can progress to myocarditis, pancreatitis, or meningo-encephalitis. It has also been associated with late-onset idiopathic dilated cardiomyopathy. CVB type 3 (CVB3) has previously been documented to upregulate host autophagic machinery upon infection, and we report here that the virus can infect cardiac stem cells and other muscle progenitors and allow itself to be engulfed in autophagosomes which later get shed from the surface of the host cell. This is a novel method of viral dissemination especially for a “naked” virus which would typically escape the infected host by triggering cytolysis. However, cytolytic viruses subsequently become exposed to neutralizing antibodies. The fact that CVB3 can hide itself in host membranes presents several fascinating possibilities. Not only could the ejected autophagosome mask the virus from adaptive immunity, but it may also bypass receptor-mediated endocytosis and infect cell-types that might lack CVB3 receptors. This mode of viral escape represents a unique evolutionary adaptation which obscures the line dividing enveloped and non-enveloped viruses.
Abstract 18810: Intralipid as Novel Antidote for Verapamil Poisoning
Authors: Dmytro Kryshtal, Sheila Dawling, Donna Seger, Bjorn C Knollmann
Journal: Circulation (2010)

Background:  Intralipid, a component of parenteral nutrition, consists of a fat emulsion of soy bean oil, egg phospholipids and glycerin. Case reports suggest that Intralipid may reverse the hypotension caused by acute overdoses of lipophilic drugs such as verapamil, but the mechanism of Intralipid action is not known.   Methods and Results:  We investigated the effect of Intralipid in vitro using isolated ventricular myocytes and in one patient with an acute verapamil overdose. Application of 0.5 vol% Intralipid significantly improved myocyte shortening and Ca 2+  transients (CaT) in the presence of 10 µM verapamil (mean increase in CaT 61±9 %, n=12, p 2+  currents (ICa, see Figure). The effect was concentration-dependent, with significant ICa recovery achieved at Intralipid concentrations as low as 0.03 vol% (ICa 15±4.7 % recovery, n=7, p   Conclusions:  Intralipid emulsion efficiently decreases free verapamil concentrations and reverses verapamil-induced Ca 2+  channel block. Rapid intravenous administration of Intralipid may be an effective antidote for hypotension caused by acute verapamil poisoning.