bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluation of Fab and F(ab′)
2
Fragments and Isotype Variants of a Recombinant Human Monoclonal Antibody against Shiga Toxin 2
Authors: Akiyoshi Donna E. , Sheoran Abhineet S. , Rich Curtis M. , Richard L. , Chapman-Bonofiglio Susan , Tzipori Saul 
Published: January 2010

ABSTRACT

5C12 HuMAb is a human monoclonal antibody against the A subunit of Shiga toxin 2 (Stx2). We have previously shown that 5C12 HuMAb effectively neutralizes the cytotoxic effects of this toxin by redirecting its transport within the cell and also by neutralizing the toxin's ability to inhibit protein synthesis. The 5C12 HuMAb and its recombinant IgG1 version protect mice at a dose of 0.6 μg against a lethal challenge of Stx2. The contribution of the Fc region to this observed neutralization activity of the 5C12 antibody against Stx2 was investigated in this study. Using recombinant DNA technology, 5C12 isotype variants (IgG1, IgG2, IgG3, and IgG4) and antibody fragments [Fab, F(ab′)
2
] were expressed in Chinese hamster ovary cells and evaluated
in vitro
and
in vivo
. All four 5C12 isotype variants showed protection
in vitro
, with the IgG3 and IgG4 variants showing the highest protection
in vivo
. The Fab and F(ab′)
2
fragments also showed protection
in vitro
but no protection in the mouse toxicity model. Similar results were obtained for a second HuMAb (5H8) against the B subunit of Stx2. The data suggest the importance of the Fc region for neutralization activity, but it is not clear if this is related to the stability of the full-length antibody or if the Fc region is required for effective elimination of the toxin from the body.
Regulation of Ceramide Synthase–Mediated Crypt Epithelium Apoptosis by DNA Damage Repair Enzymes
Authors: Rotolo Jimmy A. , Mesicek Judith , Maj Jerzy , Truman Jean-Philip , Haimovitz-Friedman Adriana , Kolesnick Richard , Fuks Zvi 
Published: January 2010

Abstract
Acute endothelial cell apoptosis and microvascular compromise couple gastrointestinal tract irradiation to reproductive death of intestinal crypt stem cell clonogens (SCCs) following high-dose radiation. Genetic or pharmacologic inhibition of endothelial apoptosis prevents intestinal damage, but as the radiation dose is escalated, SCCs become directly susceptible to an alternate cell death mechanism, mediated via ceramide synthase (CS)–stimulated de novo synthesis of the proapoptotic sphingolipid ceramide, and p53-independent apoptosis of crypt SCCs. We previously reported that ataxia-telangiectasia mutated deficiency resets the primary radiation lethal pathway, allowing CS-mediated apoptosis at the low-dose range of radiation. The mechanism for this event, termed target reordering, remains unknown. Here, we show that inactivation of DNA damage repair pathways signals CS-mediated apoptosis in crypt SCCs, presumably via persistent unrepaired DNA double-strand breaks (DSBs). Genetic loss of function of sensors and transducers of DNA DSB repair confers the CS-mediated lethal pathway in intestines of sv129/B6Mre11ATLD1/ATLD1 and C57BL/6Prkdc/SCID (severe combined immunodeficient) mice exposed to low-dose radiation. In contrast, CS-mediated SCC lethality was mitigated in irradiated gain-of-function Rad50s/s mice, and epistasis studies order Rad50 upstream of Mre11. These studies suggest unrepaired DNA DSBs as causative in target reordering in intestinal SCCs. As such, we provide an in vivo model of DNA damage repair that is standardized, can be exploited to understand allele-specific regulation in intact tissue, and is pharmacologically tractable. Cancer Res; 70(3); 957– 67
Tumor Cell Death and ATP Release Prime Dendritic Cells and Efficient Anticancer Immunity
Authors: Aymeric Laetitia , Apetoh Lionel , Ghiringhelli François , Tesniere Antoine , Martins Isabelle , Kroemer Guido , Smyth Mark J. , Zitvogel Laurence 
Published: January 2010

Abstract
By destroying tumor cells, conventional anticancer therapies may stimulate the host immune system to eliminate residual disease. Anthracyclines, oxaliplatin, and ionizing irradiation activate a type of tumor cell death that elicits efficient anticancer immune responses depending on interferon γ (IFNγ) and the IFNγ receptor. Thus, dying tumor cells emit danger signals that are perceived by dendritic cells (DC), which link innate and cognate immune responses. Recently, we observed that ATP was released by tumor cells succumbing to chemotherapy. ATP activates purinergic P2RX7 receptors on DC, thus activating the NLRP3/ASC/caspase-1 inflammasome and driving the secretion of interleukin-1β (IL-1β). IL-1β then is required for the adequate polarization of IFNγ-producing CD8+ T cells. These results imply a novel danger signal, ATP, and a novel receptor, P2RX7, in the chemotherapy-elicited anticancer immune response. Cancer Res; 70(3); 855–8
Intracellular Activation of SGN-35, a Potent Anti-CD30 Antibody-Drug Conjugate
Authors: Okeley Nicole M. , Miyamoto Jamie B. , Zhang Xinqun , Sanderson Russell J. , Benjamin Dennis R. , Sievers Eric L. , Senter Peter D. , Alley Stephen C. 
Published: January 2010

AbstractPurpose: SGN-35 is an antibody-drug conjugate (ADC) containing the potent antimitotic drug, monomethylauristatin E (MMAE), linked to the anti-CD30 monoclonal antibody, cAC10. As previously shown, SGN-35 treatment regresses and cures established Hodgkin lymphoma and anaplastic large cell lymphoma xenografts. Recently, the ADC has been shown to possess pronounced activity in clinical trials. Here, we investigate the molecular basis for the activities of SGN-35 by determining the extent of targeted intracellular drug release and retention, and bystander activities.Experimental Design: SGN-35 was prepared with 14C-labeled MMAE. Intracellular ADC activation on CD30+ and negative cell lines was determined using a combination of radiometric and liquid chromatograhpy/mass spectrometry-based assays. The bystander activity of SGN-35 was determined using mixed tumor cell cultures consisting of CD30+ and CD30− lines.Results: SGN-35 treatment of CD30+ cells leads to efficient intracellular release of chemically unmodified MMAE, with intracellular concentrations of MMAE in the range of 500 nmol/L. This was due to specific ADC binding, uptake, MMAE retention, and receptor recycling or resynthesis. MMAE accounts for the total detectable released drug from CD30+ cells, and has a half-life of retention of 15 to 20 h. Cytotoxicity studies with mixtures of CD30+ and CD30− cell lines indicated that diffusible released MMAE from CD30+ cells was able to kill cocultivated CD30− cells.Conclusions: MMAE is efficiently released from SGN-35 within CD30+ cancer cells and, due to its membrane permeability, is able to exert cytotoxic activity on bystander cells. This provides mechanistic insight into the pronounced preclinical and clinical antitumor activities observed with SGN-35. Clin Cancer Res; 16(3); 888–97
Aggressive Chronic Lymphocytic Leukemia with Elevated Genomic Complexity Is Associated with Multiple Gene Defects in the Response to DNA Double-Strand Breaks
Authors: Ouillette Peter , Fossum Samuel , Parkin Brian , Ding Li , Bockenstedt Paula , Al-Zoubi Ammar , Shedden Kerby , Malek Sami N. 
Published: January 2010

Abstract
Purpose: Genomic complexity is present in approximately 15% to 30% of all chronic lymphocytic leukemia (CLL) and has emerged as a strong independent predictor of rapid disease progression and short remission duration in CLL. We conducted this study to advance our understanding of the causes of genomic complexity in CLL.
Experimental Design: We have obtained quantitative measurements of radiation-induced apoptosis and radiation-induced ATM autophosphorylation in purified CLL cells from 158 and 140 patients, respectively, and have used multivariate analysis to identify independent contributions of various biological variables on genomic complexity in CLL.
Results: Here, we identify a strong independent effect of radiation resistance on elevated genomic complexity in CLL and describe radiation resistance as a predictor for shortened CLL survival. Furthermore, using multivariate analysis, we identify del17p/p53 aberrations, del11q, del13q14 type II (invariably resulting in Rb loss), and CD38 expression as independent predictors of genomic complexity in CLL, with aberrant p53 as a predictor of ∼50% of genomic complexity in CLL. Focusing on del11q, we determined that normalized ATM activity was a modest predictor of genomic complexity but was not independent of del11q. Through single nucleotide polymorphism array–based fine mapping of del11q, we identified frequent monoallelic loss of Mre11 and H2AFX in addition to ATM, indicative of compound del11q–resident gene defects in the DNA double-strand break response.
Conclusions: Our quantitative analysis links multiple molecular defects, including for the first time del11q and large 13q14 deletions (type II), to elevated genomic complexity in CLL, thereby suggesting mechanisms for the observed clinical aggressiveness of CLL in patients with unstable genomes. Clin Cancer Res; 16(3); 835–47
Early MRI in optic neuritis: the risk for clinically definite multiple sclerosis
Authors: Swanton JK , Fernando KT , Dalton CM , Miszkiel KA , Altmann DR , Plant GT , Thompson AJ , Miller DH 
Published: January 2010

MRI brain lesions at presentation with optic neuritis (ON) increase the risk for developing clinically definite (CD) multiple sclerosis (MS). More detailed early MRI findings may improve prediction of conversion. The objectives of this study were to investigate the influence of number, location and activity of lesions at presentation, new lesions at early follow-up and non-lesion MRI measures on conversion from optic neuritis (ON) to CDMS. 142/143 ON patients, prospectively recruited into a serial MRI and clinical follow-up study, were followed-up at least once. Cox regression analysis determined independent early MRI predictors of time to CDMS from: (i) baseline lesion number, location and activity measures, (ii) three-month lesion activity measures and (iii) brain atrophy, magnetization transfer ratio and spectroscopy measures. 114/142 (80%) had abnormal baseline brain or cord MRI. 57 (40%) developed CDMS (median of 16 months from clinically isolated syndrome onset). Median follow-up of the non-converters was 62 months. Multivariate analysis of baseline parameters revealed gender, periventricular and gadolinium-enhancing lesions as independent predictors of CDMS. Considering both scans together, gender, baseline periventricular and new T2 lesions at follow-up remained significant (hazard ratios 2.1, 2.4 and 4.9, respectively). No non-conventional measure predicted CDMS. It was concluded that new T2 lesions on an early follow-up scan were the strongest independent predictor of CDMS.
Anucleate platelets generate progeny
Authors: Schwertz Hansjörg , Köster Sarah , Kahr Walter H. A. , Michetti Noemi , Kraemer Bjoern F. , Weitz David A. , Blaylock Robert C. , Kraiss Larry W. , Greinacher Andreas , Zimmerman Guy A. , Weyrich Andrew S. 
Published: January 2010

AbstractPlatelets are classified as terminally differentiated cells that are incapable of cellular division. However, we observe that anucleate human platelets, either maintained in suspension culture or captured in microdrops, give rise to new cell bodies packed with respiring mitochondria and α-granules. Platelet progeny formation also occurs in whole blood cultures. Newly formed platelets are structurally indistinguishable from normal platelets, are able to adhere and spread on extracellular matrix, and display normal signal-dependent expression of surface P-selectin and annexin V. Platelet progeny formation is accompanied by increases in biomass, cellular protein levels, and protein synthesis in expanding populations. Platelet numbers also increase during ex vivo storage. These observations indicate that platelets have a previously unrecognized capacity for producing functional progeny, which involves a form of cell division that does not require a nucleus. Because this new function of platelets occurs outside of the bone marrow milieu, it raises the possibility that thrombopoiesis continues in the bloodstream.
Endothelial cell–specific chemotaxis receptor (ecscr) promotes angioblast migration during vasculogenesis and enhances VEGF receptor sensitivity
Authors: Verma Anjali , Bhattacharya Resham , Remadevi Indu , Li Keguo , Pramanik Kallal , Samant Ganesh V. , Horswill Mark , Chun Chang Z. , Zhao Baofeng , Wang Enfeng , Miao Robert Qing , Mukhopadhyay Debabrata , Ramchandran Ramani , Wilkinson George A. 
Published: January 2010

AbstractEndothelial cell–specific chemotaxis receptor (ECSCR) is a cell surface protein expressed by blood endothelial cells with roles in endothelial cell migration and signal transduction. We investigated the function of ecscr in the development of the zebrafish vasculature. Zebrafish ecscr is expressed in angioblasts and in axial vessels during angioblast migration and vasculogenesis. Morpholino-directed ecscr knockdown resulted in defective angioblast migration in the posterior lateral plate mesoderm, a process known to depend on vascular endothelial-derived growth factor (VEGF). In cultured cells, transfected ECSCR localized to actin-rich membrane protrusions, colocalizing with kinase insert domain protein receptor (KDR)/VEGF receptor 2 in these regions. ECSCR-silenced cells show reduced VEGF-induced phosphorylation of KDR but not of FMS-like tyrosine kinase 1 (FLT1)/VEGF receptor 1. Finally, chemical inhibition of VEGF receptor activity in zebrafish resulted in angioblast deficiencies that partially overlap with those seen in ecscr morphants. We propose that ecscr promotes migration of zebrafish angioblasts by enhancing endothelial kdr sensitivity to VEGF.
Automatic symptom name normalization in clinical records of traditional Chinese medicine
Authors: Wang Yaqiang , Yu Zhonghua , Jiang Yongguang , Xu Kaikuo , Chen Xia 
Published: January 2010

Abstract

Background
In recent years, Data Mining technology has been applied more than ever before in the field of traditional Chinese medicine (TCM) to discover regularities from the experience accumulated in the past thousands of years in China. Electronic medical records (or clinical records) of TCM, containing larger amount of information than well-structured data of prescriptions extracted manually from TCM literature such as information related to medical treatment process, could be an important source for discovering valuable regularities of TCM. However, they are collected by TCM doctors on a day to day basis without the support of authoritative editorial board, and owing to different experience and background of TCM doctors, the same concept might be described in several different terms. Therefore, clinical records of TCM cannot be used directly to Data Mining and Knowledge Discovery. This paper focuses its attention on the phenomena of "one symptom with different names" and investigates a series of metrics for automatically normalizing symptom names in clinical records of TCM.

Results
A series of extensive experiments were performed to validate the metrics proposed, and they have shown that the hybrid similarity metrics integrating literal similarity and remedy-based similarity are more accurate than the others which are based on literal similarity or remedy-based similarity alone, and the highest F-Measure (65.62%) of all the metrics is achieved by hybrid similarity metric VSM+TFIDF+SWD.

Conclusions
Automatic symptom name normalization is an essential task for discovering knowledge from clinical data of TCM. The problem is introduced for the first time by this paper. The results have verified that the investigated metrics are reasonable and accurate, and the hybrid similarity metrics are much better than the metrics based on literal similarity or remedy-based similarity alone.
Genome-wide detection of predicted non-coding RNAs in Rhizobium etli expressed during free-living and host-associated growth using a high-resolution tiling array
Authors: Vercruysse Maarten , Fauvart Maarten , Cloots Lore , Engelen Kristof , Thijs Inge M , Marchal Kathleen , Michiels Jan 
Published: January 2010

Abstract

Background
Non-coding RNAs (ncRNAs) play a crucial role in the intricate regulation of bacterial gene expression, allowing bacteria to quickly adapt to changing environments. In the past few years, a growing number of regulatory RNA elements have been predicted by computational methods, mostly in well-studied γ-proteobacteria but lately in several α-proteobacteria as well. Here, we have compared an extensive compilation of these non-coding RNA predictions to intergenic expression data of a whole-genome high-resolution tiling array in the soil-dwelling α-proteobacterium Rhizobium etli.

Results
Expression of 89 candidate ncRNAs was detected, both on the chromosome and on the six megaplasmids encompassing the R. etli genome. Of these, 11 correspond to functionally well characterized ncRNAs, 12 were previously identified in other α-proteobacteria but are as yet uncharacterized and 66 were computationally predicted earlier but had not been experimentally identified and were therefore classified as novel ncRNAs. The latter comprise 17 putative sRNAs and 49 putative cis-regulatory ncRNAs. A selection of these candidate ncRNAs was validated by RT-qPCR, Northern blotting and 5' RACE, confirming the existence of 4 ncRNAs. Interestingly, individual transcript levels of numerous ncRNAs varied during free-living growth and during interaction with the eukaryotic host plant, pointing to possible ncRNA-dependent regulation of these specialized processes.

Conclusions
Our data support the practical value of previous ncRNA prediction algorithms and significantly expand the list of candidate ncRNAs encoded in the intergenic regions of R. etli and, by extension, of α-proteobacteria. Moreover, we show high-resolution tiling arrays to be suitable tools for studying intergenic ncRNA transcription profiles across the genome. The differential expression levels of some of these ncRNAs may indicate a role in adaptation to changing environmental conditions.
Lactobacillus acidophilus induces a slow but more sustained chemokine and cytokine response in naïve foetal enterocytes compared to commensal Escherichia coli
Authors: Zeuthen Louise H , Fink Lisbeth N , Metzdorff Stine B , Kristensen Matilde B , Licht Tine R , Nellemann Christine , Frøkiær Hanne 
Published: January 2010

AbstractBackgroundThe first exposure to microorganisms at mucosal surfaces is critical for immune maturation and gut health. Facultative anaerobic bacteria are the first to colonise the infant gut, and the impact of these bacteria on intestinal epithelial cells (IEC) may be determinant for how the immune system subsequently tolerates gut bacteria.ResultsTo mirror the influence of the very first bacterial stimuli on infant IEC, we isolated IEC from mouse foetuses at gestational day 19 and from germfree neonates. IEC were stimulated with gut-derived bacteria, Gram-negativeEscherichia coliNissle and Gram-positiveLactobacillus acidophilusNCFM, and expression of genes important for immune regulation was measured together with cytokine production.E. coliNissle andL. acidophilusNCFM strongly induced chemokines and cytokines, but with different kinetics, and onlyE. coliNissle induced down-regulation of Toll-like receptor 4 and up-regulation of Toll-like receptor 2. The sensitivity to stimulation was similar before and after birth in germ-free IEC, although Toll-like receptor 2 expression was higher before birth than immediately after.ConclusionsIn conclusion, IEC isolated before gut colonisation occurs at birth, are highly responsive to stimulation with gut commensals, withL. acidophilusNCFM inducing a slower, but more sustained response thanE. coliNissle.E. colimay induce intestinal tolerance through very rapid up-regulation of chemokine and cytokine genes and down-regulation of Toll-like receptor 4, while regulating also responsiveness to Gram-positive bacteria.
Potent anti-tumor effects of a dual specific oncolytic adenovirus expressing apoptin in vitro and in vivo
Authors: Xiao Li , Yan Liu , Zhongmei Wen , Chang Li , Huijun Lu , Mingyao Tian , Kuoshi Jin , Lili Sun , Pegn Gao , Encheng Yang , Xiaohong Xu , Shifu Kan , Zhuoyue Wang , Yuhang Wang , Ningyi Jin 
Published: January 2010

Abstract

Background
Oncolytic virotherapy is an attractive drug platform of cancer gene therapy, but efficacy and specificity are important prerequisites for success of such strategies. Previous studies determined that Apoptin is a p53 independent, bcl-2 insensitive apoptotic protein with the ability to specifically induce apoptosis in tumor cells. Here, we generated a conditional replication-competent adenovirus (CRCA), designated Ad-hTERT-E1a-Apoptin, and investigated the effectiveness of the CRCA a gene therapy agent for further clinical trials.

Results
The observation that infection with Ad-hTERT-E1a-Apoptin significantly inhibited growth of the melanoma cells, protecting normal human epidermal melanocytes from growth inhibition confirmed cancer cell selective adenoviral replication, growth inhibition, and apoptosis induction of this therapeutic approach. The in vivo assays performed by using C57BL/6 mice containing established primary or metastatic tumors expanded the in vitro studies. When treated with Ad-hTERT-E1a-Apoptin, the subcutaneous primary tumor volume reduction was not only observed in intratumoral injection group but in systemic delivery mice. In the lung metastasis model, Ad-hTERT-E1a-Apoptin effectively suppressed pulmonary metastatic lesions. Furthermore, treatment of primary and metastatic models with Ad-hTERT-E1a-Apoptin increased mice survival.

Conclusions
These data further reinforce the previously research showing that an adenovirus expressing Apoptin is more effective and advocate the potential applications of Ad-hTERT-E1a-Apoptin in the treatment of neoplastic diseases in future clinical trials.
Can we use biomarkers in combination with self-reports to strengthen the analysis of nutritional epidemiologic studies?
Authors: Freedman Laurence S , Kipnis Victor , Schatzkin Arthur , Tasevska Nataša , Potischman Nancy 
Published: January 2010

AbstractIdentifying diet-disease relationships in nutritional cohort studies is plagued by the measurement error in self-reported intakes.The authors propose using biomarkers known to be correlated with dietary intake, so as to strengthen analyses of diet-disease hypotheses. The authors consider combining self-reported intakes and biomarker levels using principal components, Howe's method, or a joint statistical test of effects in a bivariate model. They compared the statistical power of these methods with that of conventional univariate analyses of self-reported intake or of biomarker level. They used computer simulation of different disease risk models, with input parameters based on data from the literature on the relationship between lutein intake and age-related macular degeneration.The results showed that if the dietary effect on disease was fully mediated through the biomarker level, then the univariate analysis of the biomarker was the most powerful approach. However, combination methods, particularly principal components and Howe's method, were not greatly inferior in this situation, and were as good as, or better than, univariate biomarker analysis if mediation was only partial or non-existent. In some circumstances sample size requirements were reduced to 20-50% of those required for conventional analyses of self-reported intake.The authors conclude that (i) including biomarker data in addition to the usual dietary data in a cohort could greatly strengthen the investigation of diet-disease relationships, and (ii) when the extent of mediation through the biomarker is unknown, use of principal components or Howe's method appears a good strategy.