bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibitors Targeting Mitosis: Tales of How Great Drugs against a Promising Target Were Brought Down by a Flawed Rationale
Authors: Komlodi-Pasztor Edina , Sackett Dan L. , Fojo Antonio Tito 
Published: January 2012

Abstract
Although they have been advocated with an understandable enthusiasm, mitosis-specific agents such as inhibitors of mitotic kinases and kinesin spindle protein have not been successful clinically. These drugs were developed as agents that would build on the success of microtubule-targeting agents while avoiding the neurotoxicity that encumbers drugs such as taxanes and vinca alkaloids. The rationale for using mitosis-specific agents was based on the thesis that the clinical efficacy of microtubule-targeting agents could be ascribed to the induction of mitotic arrest. However, the latter concept, which has long been accepted as dogma, is likely important only in cell culture and rapidly growing preclinical models, and irrelevant in patient tumors, where interference with intracellular trafficking on microtubules is likely the principal mechanism of action. Here we review the preclinical and clinical data for a diverse group of inhibitors that target mitosis and identify the reasons why these highly specific, myelosuppressive compounds have failed to deliver on their promise. Clin Cancer Res; 18(1); 51–63. ©2012 AACR.
Drug Development: Portals of Discovery
Authors: Bates Susan E. , Amiri-Kordestani Laleh , Giaccone Giuseppe 
Published: January 2012

Abstract
A British humorist said, “There is much to be said for failure. It is much more interesting than success.” This CCR Focus section is aimed at identifying lessons to be learned from difficulties encountered in recent years during development of anticancer agents. Clearly, we have not found a silver bullet tyrosine kinase inhibitor against solid tumors comparable with imatinib in chronic myelogenous leukemia. Although vemurafenib for B-Raf–mutated melanoma and crizotinib for non–small cell lung cancers with echinoderm microtubule-associated protein-like 4 (EML4)–anaplastic lymphoma kinase (ALK) rearrangements were developed rapidly and offer hope for individualized targeted therapies, the development of agents targeting a number of other pathways has been slower and less successful. These agents include drugs for blocking the insulin-like growth factor I/insulin receptor pathways, mitotic kinase inhibitors, and Hsp90 antagonists. Several potentially useful, if not groundbreaking, agents have had setbacks in clinical development, including trastuzumab emtansine, gemtuzumab ozogamicin, and satraplatin. From experience, we have learned the following: (i) not every altered protein or pathway is a valid anticancer target; (ii) drugs must effectively engage the target; (iii) the biology of the systems we use must be very well understood; and (iv) clinical trials must be designed to assess whether the drug reached and impaired the target. It is also important that we improve the drug development enterprise to enhance enrollment, streamline clinical trials, reduce financial risk, and encourage the development of agents for niche indications. Such enormous challenges are offset by potentially tremendous gains in our understanding and treatment of cancer. Clin Cancer Res; 18(1); 23–32. ©2012 AACR.
Elusive Extranuclear Estrogen Receptors in Breast Cancer
Authors: Levin Ellis R. 
Published: January 2012

Abstract
Estrogen receptors at the plasma membrane and cytoplasm have been difficult to detect in breast cancer specimens. New imaging approaches are needed to determine the percentage of cancers expressing extranuclear estrogen receptors and their impact on cancer biology and treatment. Clin Cancer Res; 18(1); 6–8. ©2012 AACR.
Dose-dependent effect of early antiplatelet therapy in acute ischaemic stroke
Authors: Overbeck Ursula , Endres Heinz G. , Krogias Christos , Neubauer Horst , Meves Saskia H. 
Published: January 2012

SummaryAntiplatelet agents are essential in treating patients with acute ischaemic stroke (AIS) to prevent recurrent ischaemic events. The aim of this study was to evaluate the effectiveness of early antiplatelet therapy with different aspirin (ASA) dosages in patients with AIS. This observational study included 454 patients with AIS in whom antiplatelet treatment was initiated. The antiplatelet effect was determined by whole blood aggregometry within 48 hours after antplatelet therapy was initiated. An impedance change exceeding 0 Ω after stimulation with arachidonic acid was defined as ASA low response (ALR) and ≥5 Ω in ADP-stimulated specimen as clopidogrel LR. Of the study group 53.5% patients were treated with 200 mg ASA orally, 27.5% with 500 mg ASA intravenously, 8.6% with 100 mg ASA orally, and 7.7% with 75 mg clopidogrel. A dose-dependent antiplatelet effect of ASA treatment was found: 18.4% of patients with 500 mg ASA intravenously were ALR, in contrast to 32.5% on 200 mg and 35.9% on 100 mg ASA orally. Clopidogrel treatment without a loading dose resulted in a high proportion of LR (45.7%). Using the propensity score method revealed a three times higher risk for ALR for patients treated with ASA 200 mg [odds ratio 2.99 (1.55–5.79)] compared to treatment with ASA 500 mg. In conclusion, initiating antiplatelet therapy in patients with AIS resulted in a dose-dependent insufficient platelet inhibitory effect. Our findings suggest using a loading dose of 500 mg ASA intravenously as this seems to be favourable when a sufficient early platelet inhibitory effect is wanted.ClinicalTrials.gov Identifier: NCT01273935
The ‘promise’ of three methods of word association analysis to L2 lexical research
Authors: Zareva Alla , Wolter Brent 
Published: January 2012

The present study is an attempt to empirically test and compare the results of three methods of word association (WA) analysis. Two of the methods – namely, associative commonality and nativelikeness, and lexico-syntactic patterns of associative organization – have been traditionally used in both first language (L1) and second language (L2) associative research and the third one – collocational aspect of associative responses – is a more recent perspective on associative connections. The central assumption behind the study is that each method captures a different aspect of language users’ lexical organization and, in that, their findings may paint a different picture of how the L1 and L2 lexicons compare as proficiency increases. At the same time, the sensitivity of each method to reflect differences related to proficiency may also point to their potential as a research and assessment tool. Three equal size groups of participants ( N = 180) at different proficiency levels – native speakers (NSs), second language (L2) advanced and intermediate learners of English – completed a familiarity and a WA test in writing. The tests contained 36 items equated for lexical class (nouns, verbs, and adjectives) and frequency of occurrence (high, mid, and low). The participants’ WAs generated to familiar vocabulary were analysed in three different ways, following the methods of analysis practiced by each of the three traditions under investigation. In the main, the results showed that examining the lexico-syntactic patterns of associative organization as well as the collocational aspect of associative links are two more ‘promising’ ways of looking at WAs than examining them with respect to their nativelike associative commonality.
“Mind” in ancient Japanese: The primitive perception of its existence
Authors: Sasaki Ken-ichi 
Published: January 2012

AbstractWhat I am planning to write for Diogenes is an essay of elucidating the original meaning of “kokoro” in ancient Japanese.“Kokoro” is regarded as corresponding to mind in English; for example, we call philosophy of mind “philosophy of kokoro”. We can compare English with French in order to notice the problem concerning this notion. While we say in English “mind-body problem”, in French we call the problem (or rather “l’union”) of “l’âme et du corps”. But there are many cases where “mind” is translated with “l’esprit”. We can already ask the question from where comes this ambiguity. Much the more in Japanese.I should explain how the philosophical terms are constructed in Japanese. When we say philosophy tout court in Japan, that means the Western philosophy or philosophy in the Western style. Most of its technical terms were made as translation from the Western languages, and when we dare to translate the Western words, the most usual way is to use Chinese characters that are ideograms. In ordinary Japanese, terms originating from Chinese are mixed into its vocabulary. We feel certain “difference” in such words, especially in technical terms borrowed from the Western languages: such is the case of philosophical terms. But “kokoro” is not such a translated word, but an original Japanese word. So personally I feel that this word sounds slightly strange as a philosophical term.That is the motive of this paper of mine: I wish to conceive the original meaning of “kokoro” in its originating stage. I consult mainly Manyô-shû, ancient anthology of poem established about the mid 8th Century.
From Complex System to Integrative Science
Authors: Ikeda Yoshiaki 
Published: January 2012

AbstractThis paper aims to introduce my thought as an “anti”-Logocentrism. To begin with, I would like to point out two aspects of this theme. First, even if philosophical thinking is essentially based on logical form, it is sometimes exposed to illogicality. But this illogicality is meaningful. Second, it has to do with differences between Western and my thought. The former respects rational thinking and follows strictly formal logic. It is true that we cannot think without rationality, but when, for example, we deal with complex systems, we cannot follow the law of excluded middle because of the contradictory effects that coexist in interfaces which emerge in complex systems.In terms of complex systems, it is not acceptable to choose only one possibility and to deny the other. It is not uncommon to see such ambiguous situations, but we often overlook them. These situations are, however, not as disordered as we think, and they can be accepted as they actually are. I refer to such thinking as “passive thinking”. In this way, there are two types of philosophical thinking. One is rational thinking, and the other is passive thinking. The latter stays often in contradiction without following logical form, which occurs in interfaces in complex systems. In such cases, we cannot think rationally, because contradictory effects coexist there. Furthermore, we find there something whole new, namely, “emergent property”; that is just what passive thinking deals with. Since early times, Japanese have attached more importance to passive thinking.
Philosophy of Nothingness and Process Theology
Authors: Tanaka Yutaka 
Published: January 2012

AbstractThis paper discusses the two representative philosophers of the Kyoto School, Kitaro Nishida and Hajime Tanabe from the perspective of process theology and the Buddhist-Christian dialogue in Japan.The first chapter explicates Nishida’s concept of “pure experience” in comparison with William James’ radical empiricism and with Kant’s dualism of sense and reason. Pure experience in Nishida’s sense is neither a passive reception of objective sense-data given before subjective mental operations, nor the raw material of experience which must be given “form” by experiencing subject. It is nothing but metaphysically ultimate activity from which both the experiencing subject and the whole range of the experienced objects from sense-perception to intellectual intuition emerge as its self-unfolding.The second and third chapters discuss the two key concepts of process theology, “concrescence” and “the extensive continuum” with a special reference to the Mahayana Buddhist concept of “emptiness (sunyata)” and “dependent arising (pratityasamutpada)”. Nishida’s tripartite concept of topos, i.e. a topos of relative being, a topos of relative nothingness, and the topos of absolute nothingness will be applied to process theology in order to explicate the relation of two ultimates in Whitehead’s metaphysics, i.e. the relation of God as the religious ultimate to creativity as the metaphysical ultimate.The fourth and fifth chapters discuss Hajime Tanabe as a critical successor of Nishida’s philosophy of Nothingness. Tanabe is more akin to Whitehead than to Nishida in that Tanabe reformulates Nishida’s concept of Nothingness from the temporal perspective of a finite human existence related essentially to “species” or “society” in the historical world. Tanabe transforms the unity of contradictories in the logic of topos into the contrasted opposites in the historical process of becoming, which involves novelty and discontinuous leaps at points of historical crisis. For him history has become “the overall Koan” in which the metaphysical topology of static being is to be superseded by the innovative principle of nothingness in the historical world.
Acting-Intuition and Pathos in Nishida and Miki: For the Invisible of the Post-Hiroshima Age, or Irradiated Bodies and Power
Authors: Kazashi Nobuo 
Published: January 2012

AbstractOne of the hallmarks of Kitaro Nishida (1870-1945) and the Kyoto School formed around him is their emphatic endeavor to reconsider perennial philosophical questions from what they called the “stand of the acting-self.” In this paper we begin by bringing into relief the contemporary significance of Nishida’s pioneering notions – such as “logic of place,” “acting-intuition,” and “historical body” – by relating them to some kindred meditations by James, Merleau-Ponty, and Heidegger. Along the way, we call into question some shortcomings that we consider inherent in these philosophical perspectives – with special attention to their expression in the thought of Nishida’s disciple, Kiyoshi Miki, who sought to advance his master’s thought critically under the headings of “dialectics of logos and pathos” and “formative imagination.” Then, we discuss some issues regarding inhuman weapons – particularly the so-called DU (depleted uranium) weapons, which we regard as the “nuclear shadow” – in order to illustrate the aspects of human reality to which Nishida and Miki failed to give adequate consideration. In particular, we examine the destructive capabilities of our “technological bodies” and the reality of the often invisible “pathos of others” – especially in times of war – which ultimately is ours as well.
The Birth of Ehiyehlogy: Beyond Buddhist Thought and Ontotheology
Authors: Miyamoto Hisao 
Published: January 2012

AbstractIn this article it is proposed to go beyond ontotheology, which has been seen as the start of totalitarian thought and totalitarianism. In order to do this and find the key to interpretation the author refers to narratology and Hayatology or Ehiyehlogy (a variety of Hebrew ontology). From the nar-ratological viewpoint he analyses and interpretes the following Old Testament texts: Abraham’s story and the narrative of the Exodus under the guidance of Moses.By means of this narratological analysis the author identifies in these Old Testament texts Hebrew ontological thought, that is, Ehiyehlogy. He therefore sets out some features of the Hebrew being (hayâh and ehyeh) in the following respects:i.it is an ecstatic becoming and differentiates;ii.this ecstasy has an intentionality focused on the other;iii.this intentionality tends towards creation of a community;iv.intervention by such a being (hayâh or ehyeh) articulates time, the historical kairos;v.this articulation takes the concrete form of an alliance;vi.the Hebrew being acts through being incarnate in people (prophets, sages, writers who wrote for Abraham, Moses or others, etc.).Taken together, these features of the being make up an ontology which has an open identity and is made manifest in the narrative identity that is not monopolistic but polyphonic, that is, in little stories or anonymous, marginal characters, or else people resisting totalitarianism.This Ehiyehlogy is supported not only by studying the Hebrew text but also by Buddhist inspiration, which emphasizes the relativity aspect rather than the substantial one. Hence, by building up Ehiyehlogy the author looks onto overcoming the totalitarian nature of contemporary civilization and look for the possibility of coexistence.
Endothelial-monocyte activating polypeptide II disrupts alveolar epithelial type II to type I cell transdifferentiation
Authors: Chen Yao , Legan Susan K , Mahan Anne , Thornton Janet , Xu Haiming , Schwarz Margaret A 
Published: January 2012

Abstract

Background
Distal alveolar morphogenesis is marked by differentiation of alveolar type (AT)-II to AT-I cells that give rise to the primary site of gas exchange, the alveolar/vascular interface. Endothelial-Monocyte Activating Polypeptide (EMAP) II, an endogenous protein with anti-angiogenic properties, profoundly disrupts distal lung neovascularization and alveolar formation during lung morphogenesis, and is robustly expressed in the dysplastic alveolar regions of infants with Bronchopulmonary dysplasia. Determination as to whether EMAP II has a direct or indirect affect on ATII→ATI trans-differentiation has not been explored.

Method
In a controlled nonvascular environment, an in vitro model of ATII→ATI cell trans-differentiation was utilized to demonstrate the contribution that one vascular mediator has on distal epithelial cell differentiation.

Results
Here, we show that EMAP II significantly blocked ATII→ATI cell transdifferentiation by increasing cellular apoptosis and inhibiting expression of ATI markers. Moreover, EMAP II-treated ATII cells displayed myofibroblast characteristics, including elevated cellular proliferation, increased actin cytoskeleton stress fibers and Rho-GTPase activity, and increased nuclear:cytoplasmic volume. However, EMAP II-treated cells did not express the myofibroblast markers desmin or αSMA.

Conclusion
Our findings demonstrate that EMAP II interferes with ATII → ATI transdifferentiation resulting in a proliferating non-myofibroblast cell. These data identify the transdifferentiating alveolar cell as a possible target for EMAP II's induction of alveolar dysplasia.
RAD tag sequencing as a source of SNP markers in Cynara cardunculus L
Authors: Scaglione Davide , Acquadro Alberto , Portis Ezio , Tirone Matteo , Knapp Steven J , Lanteri Sergio 
Published: January 2012

Abstract

Background
The globe artichoke (Cynara cardunculus L. var. scolymus) genome is relatively poorly explored, especially compared to those of the other major Asteraceae crops sunflower and lettuce. No SNP markers are in the public domain. We have combined the recently developed restriction-site associated DNA (RAD) approach with the Illumina DNA sequencing platform to effect the rapid and mass discovery of SNP markers for C. cardunculus.

Results
RAD tags were sequenced from the genomic DNA of three C. cardunculus mapping population parents, generating 9.7 million reads, corresponding to ~1 Gbp of sequence. An assembly based on paired ends produced ~6.0 Mbp of genomic sequence, separated into ~19,000 contigs (mean length 312 bp), of which ~21% were fragments of putative coding sequence. The shared sequences allowed for the discovery of ~34,000 SNPs and nearly 800 indels, equivalent to a SNP frequency of 5.6 per 1,000 nt, and an indel frequency of 0.2 per 1,000 nt. A sample of heterozygous SNP loci was mapped by CAPS assays and this exercise provided validation of our mining criteria. The repetitive fraction of the genome had a high representation of retrotransposon sequence, followed by simple repeats, AT-low complexity regions and mobile DNA elements. The genomic k-mers distribution and CpG rate of C. cardunculus, compared with data derived from three whole genome-sequenced dicots species, provided a further evidence of the random representation of the C. cardunculus genome generated by RAD sampling.

Conclusion
The RAD tag sequencing approach is a cost-effective and rapid method to develop SNP markers in a highly heterozygous species. Our approach permitted to generate a large and robust SNP datasets by the adoption of optimized filtering criteria.
Risk groups defined by Recursive Partitioning Analysis of patients with colorectal adenocarcinoma treated with colorectal resection
Authors: Chang Yun-Jau , Chen Li-Ju , Chang Yao-Jen , Chung Kuo-Piao , Lai Mei-Shu 
Published: January 2012

Abstract

Background
To define different prognostic groups of surgical colorectal adenocarcinoma patients derived from recursive partitioning analysis (RPA).

Methods
Ten thousand four hundred ninety four patients with colorectal adenocarcinoma underwent colorectal resection from Taiwan Cancer Database during 2003 to 2005 were included in this study. Exclusion criteria included those patients with stage IV disease or without number information of lymph nodes. For the definition of risk groups, the method of classification and regression tree was performed. Main primary outcome was 5-year cancer-specific survival.

Results
We identified six prognostic factors for cancer-specific survival, resulting in seven terminal nodes. Four risk groups were defined as following: Group 1 (mild risk, 1,698 patients), Group 2 (moderate risk, 3,129 patients), Group 3 (high risk, 4,605 patients) and Group 4 (very high risk, 1,062 patients). The 5-year cancer-specific survival for Group 1, 2, 3, and 4 was 86.6%, 62.7%, 55.9%, and 36.6%, respectively (p < 0.001). Hazard ratio of death was 2.13, 5.52 and 10.56 (95% confidence interval 1.74-2.60, 4.58-6.66 and 8.66-12.9, respectively) times for Group 2, 3, and 4 as compared to Group 1. The predictive capability of these grouping was also similar in terms of overall and progression-free survival.

Conclusion
The use of RPA offered an alternative grouping method that could predict the survival of patients who underwent surgery for colorectal adenocarcinoma.
High content live cell imaging for the discovery of new antimalarial marine natural products
Authors: Cervantes Serena , Stout Paige E , Prudhomme Jacques , Engel Sebastian , Bruton Matthew , Cervantes Michael , Carter David , Tae-Chang Young , Hay Mark E , Aalbersberg William , Kubanek Julia , Le Roch Karine G 
Published: January 2012

Abstract

Background
The human malaria parasite remains a burden in developing nations. It is responsible for up to one million deaths a year, a number that could rise due to increasing multi-drug resistance to all antimalarial drugs currently available. Therefore, there is an urgent need for the discovery of new drug therapies. Recently, our laboratory developed a simple one-step fluorescence-based live cell-imaging assay to integrate the complex biology of the human malaria parasite into drug discovery. Here we used our newly developed live cell-imaging platform to discover novel marine natural products and their cellular phenotypic effects against the most lethal malaria parasite, Plasmodium falciparum.

Methods
A high content live cell imaging platform was used to screen marine extracts effects on malaria. Parasites were grown in vitro in the presence of extracts, stained with RNA sensitive dye, and imaged at timed intervals with the BD Pathway HT automated confocal microscope.

Results
Image analysis validated our new methodology at a larger scale level and revealed potential antimalarial activity of selected extracts with a minimal cytotoxic effect on host red blood cells. To further validate our assay, we investigated parasite's phenotypes when incubated with the purified bioactive natural product bromophycolide A. We show that bromophycolide A has a strong and specific morphological effect on parasites, similar to the ones observed from the initial extracts.

Conclusion
Collectively, our results show that high-content live cell-imaging (HCLCI) can be used to screen chemical libraries and identify parasite specific inhibitors with limited host cytotoxic effects. All together we provide new leads for the discovery of novel antimalarials.