bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Insulin Receptor/Insulin-Like Growth Factor Receptor Family as a Therapeutic Target in Oncology
Authors: Pollak Michael 
Published: January 2012

Abstract
Over the past decade, encouraging preclinical and early clinical data concerning the relevance of the insulin receptor/insulin-like growth factor (IGF) receptor family to neoplasia led to ambitious clinical trial programs of more than a dozen drug candidates that target these receptors. These candidates include antireceptor antibodies, antiligand antibodies, receptor-specific tyrosine kinase inhibitors, and agents such as picropodophyllin and metformin that have novel mechanisms of action. Several recently reported phase III clinical trials of anti–IGF-I receptor antibodies have been disappointing and are sufficient to disprove the hypothesis that the antibodies tested have large favorable impacts on unselected patients with cancer. However, many of these trials were designed prior to recent insights concerning pathophysiology and predictive biomarkers. Future studies are required, but it will be important to optimize their design rather than simply repeat the approaches taken to date. Clin Cancer Res; 18(1); 40–50. ©2012 AACR.
Hsp90 Molecular Chaperone Inhibitors: Are We There Yet?
Authors: Neckers Len , Workman Paul 
Published: January 2012

AbstractHeat shock protein (Hsp) 90 is an ATP-dependent molecular chaperone that is exploited by malignant cells to support activated oncoproteins, including many cancer-associated kinases and transcription factors, and it is essential for oncogenic transformation. Originally viewed with skepticism, Hsp90 inhibitors are now being actively pursued by the pharmaceutical industry, with 17 agents having entered clinical trials. Investigators established Hsp90′s druggability using the natural products geldanamycin and radicicol, which mimic the unusual ATP structure adopted in the chaperone's N-terminal nucleotide-binding pocket and cause potent and selective blockade of ATP binding/hydrolysis, inhibit chaperone function, deplete oncogenic clients, and show antitumor activity. Preclinical data obtained with these natural products have heightened interest in Hsp90 as a drug target, and 17-allylamino-17-demethoxygeldanamycin (17-AAG, tanespimycin) has shown clinical activity (as defined by Response Evaluation Criteria in Solid Tumors) in HER2+ breast cancer. Many optimized synthetic, small-molecule Hsp90 inhibitors from diverse chemotypes are now in clinical trials. Here, we review the discovery and development of Hsp90 inhibitors and assess their potential. There has been significant learning from studies of the basic biology of Hsp90, as well as translational drug development involving this chaperone, enhanced by the use of Hsp90 inhibitors as chemical probes. Success will likely lie in treating cancers that are addicted to particular driver oncogene products (e.g., HER2, ALK, EGFR, and BRAF) that are sensitive Hsp90 clients, as well as malignancies (especially multiple myeloma) in which buffering of proteotoxic stress is critical for survival. We discuss approaches for enhancing the effectiveness of Hsp90 inhibitors and highlight new chaperone and stress-response pathway targets, including HSF1 and Hsp70. Clin Cancer Res; 18(1); 64–76. ©2012 AACR.
Memory and Reconciliation in Japanese History
Authors: Inagaki Hisakazu 
Published: January 2012

AbstractJapanese history is a part of the long history of Northeast Asia. Since Japan began to form a unified nation from the time of Shotoku-Taishi (AD. 574-622) in the early seventh century, it continued to cultivate a rather independent culture. In its long history, the most catastrophic era was the Asian-Pacific War in 1931-45, ending with the atomic bomb in Hiroshima and Nagasaki. The recovery from the aftereffects and trauma of the War Japan has initiated is the topic I would like to write here as a problem of memory and reconciliation with other countries involved in the War.In 2006, Prime Minister Jyun-ichiro Koizumi, when he worshiped at Yasukuni Shrine, spoke in the meeting of news reporters that “The freedom of the heart is protected by our Constitution, and cannot be violated by anyone.” It was completely unspeakable to me that Mr. Koizumi, in his official role as Prime Minister, made use of the Japanese Constitution for the purpose of defending his personal right to worship at Yasukuni Shrine. A half of the nation, however, accepted this way of speaking. As long as we Japanese insist on and are not liberated from Yasukuni Shrine, we cannot become reconciled and co-exist with other nations, because this shrine is seen as the symbol of the Japanese past militarism which was centered on the Emperor.But the situation around Yasukuni becomes more complex if we go probe beneath the political dimension, because memory is always deeply connected with the problem of identity regard-less of whether it is personal or collective. For some conservative groups, the formation of modern Japan starts from the Meiji Restoration in 1868, which seeks to center the identity of the modern state in the Emperor, rather than in the democracy starting from the end of the War on August 15, 1945. The difference in the memory of the starting points of modern Japan between conservatives and others shapes the different identities in present-day Japan, sometimes becoming a hindrance to form a civil society. I will call this situation “Yasukuni fundamentalism” in today’s Japan.The purpose of the present paper is to propose a way to overcome this Yasukuni fundamentalism by developing a public philosophy and by its application to today’s civil society.
The Idea of Trans-national Public Philosophy as a Comprehensive Trans-Discipline for the 21st Century
Authors: Yamawaki Naoshi 
Published: January 2012

AbstractIn my paper, I will try to renew the public philosophy. As a result of specialization and professionalization of academic disciplines since the late 19th centuries, a rather unsound academic situation prevails at many universities in the world; social sciences without any philosophical foundation on the one hand and an academic philosophy without any concern about social theory on the other hand. In order to break out of such deadlock, the public philosophy that has a long tradition since Aristotle to Smith and Hegel must be renewed as a comprehensive trans-discipline now. The public philosophy in this sense is an attempt in the “time of post-specialization of sciences.” What I mean by the time of post-specialization is the academic environment in which social sciences, humanities and natural sciences cooperate with one another to tackle serious problems of our time such as human rights, peace building, dialogue among religions and so on.
Japanese Feminism in East-Asian Networking
Authors: Kitagawa Sakiko 
Published: January 2012

AbstractJapanese feminist philosophy has in the last 15 years focused on the theme of‘ sexual slavery’, especially on the issue of ‘comfort women’. The issue of ‘comfort women’ was not only a highly charged social and political issue, but also the turning point in conceptualizing the category of ‘the other’ from the viewpoint of East Asian feminist philosophy. It enabled Asian women philosophers to rethink the feminine solidarity and also to create a new forum for a transnational feminist philosophy in East Asia. For this purpose of feminist philosophy in networking, a group of East Asian women philosopher is working together on the task of Asian philosophy of gender as well as on a new line in the philosophy of ‘the other’.In my paper, I would like to describe the conceptual framework of this feminist philosophy in networking and want to try to redefine the concept of gender from East Asian feminist philosophy.
From Philosophy of the Feminine to Clinical Philosophy
Authors: Kanai Yoshiko 
Published: January 2012

AbstractBy focusing on the concept of “clinical philosophy”, this paper develops a Narrative/Trauma approach to deal with the philosophical problematic of oppression and violence. It establishes a link to a “philosophy of the feminine” and brings it together with clinical wisdom to describe a “sphere of intimacy without violence”. The ideology of motherhood so deeply embedded in Japanese society makes unavoidable for feminist philosophy in Japan to question femininity from the standpoint of the double nature of female self as woman and mother. Confronting the motherhood that regulates core Japanese culture and mentality requires a critique of the practice of matri-archy in the intimate sphere. Historically, post-war Japanese family appears in continuity with the matriarchal nature of the imperial and military regime in pre-war Japan. To be fully effective, feminism should therefore transform itself from a gender category to a philosophy, and create a concept of feminine that would be the core notion of feminism as a philosophy.
Does the Word Exhaust Meaning?
Authors: Nakajima Takahiro 
Published: January 2012

AbstractIn order to control language Chinese philosophy discovered methods other than the ‘rectification of names’. On one hand there is the total annihilation of language, and on the other a greater clarification of language than the one performed by the ‘rectification of language’. To understand this situation better it is necessary to go backwards in the genealogy from the controversy over the theory that ‘language exhausts meaning’ and the one that maintains ‘language does not exhaust meaning’, which took place in the period of the six dynasties (second half of the third century of the Christian era). We shall look at the controversy between the argument of Ouyang Jian and that of Xun Can. Then we reach the theory of Wang Bi, who synthesizes the controversy and invents another idea about language. This idea is a ‘forgotten language’ that tries to annihilate completely the alterity of language. What is aimed at in the annihilation of language is a world of pure meaning which increases profit, which is governed magnificently: it is a world where everything is reduced to the One.
Association between genetic variant on chromosome 12p13 and stroke survival and recurrence: a one year prospective study in Taiwan
Authors: Hsieh Yi-Chen , Seshadri Sudha , Chung Wen-Ting , Hsieh Fang-I , Hsu Yi-Hsiang , Lin Huey-Juan , Tseng Hung-Pin , Lien Li-Ming , Bai Chyi-Huey , Hu Chaur-Jong , Jeng Jiann-Shing , Tang Sung-Chun , Chen Chin-I , Yu Chia-Chen , Chiou Hung-Yi ,   the Formosa Stroke Genetic Consortium (FSGC)
Published: January 2012

Abstract

Background
The association between ischemic stroke and 2 single nucleotide polymorphisms (SNPs) on chromosome 12p13, rs12425791 and rs11833579 appears inconsistent across different samples. These SNPs are close to the ninjurin2 gene which may alter the risk of stroke by affecting brain response to ischemic injury. The purpose of this study was to investigate the association between these two SNPs and ischemic stroke risk, as well as prognostic outcomes in a Taiwanese sample.

Methods
We examined the relations of these two SNPs to the odds of new-onset ischemic stroke, ischemic stroke subtypes, and to the one year risk of stroke-related death or recurrent stroke following initial stroke in a case-control study. A total of 765 consecutive patients who had first-ever ischemic stroke were compared to 977 stroke-free, age-matched controls. SNPs were genotyped by Taqman fluorescent allelic discrimination assay. The association between ischemic stroke and SNPs were analyzed by multivariate logistic regression. Cox proportional hazard model was used to assess the effect of individual SNPs on stroke-related mortality or recurrent stroke.

Results
There was no significant association between SNP rs12425791 and rs11833579 and ischemic stroke after multiple testing corrections. However, the marginal significant association was observed between SNP rs12425791 and large artery atherosclerosis under recessive model (OR, 2.30; 95%CI, 1.22-4.34; q-value = 0.062). Among the 765 ischemic stroke patients, 59 died or developed a recurrent stroke. After adjustment for age, sex, vascular risk factors and baseline stroke severity, Cox proportional hazard analysis indicated that the hazard ratios were 2.76 (95%CI, 1.34-5.68; q-value, 0.02) and 2.15 (95%CI, 1.15-4.02; q-value, 0.03) for individuals with homozygous variant allele of rs12425791 and rs11833579, respectively.

Conclusions
This is a precedent study that found genetic variants of rs12425791 and rs11833579 on chromosome 12p13 are independent predictors of stroke-related mortality or stroke recurrence in patients with incident ischemic stroke in Taiwan. Further study is needed to explore the details of the physiological function and the molecular mechanisms underlying the association of this genetic locus with ischemic stroke.
siRNA against presenilin 1 (PS1) down regulates amyloid β42 production in IMR-32 cells
Authors: Kandimalla Ramesh JL , Wani Willayat Yousuf , BK Binukumar , Gill Kiran Dip 
Published: January 2012

Abstract

Background
One of the pathological hallmarks of Alzheimer's disease (AD) is the deposition of the ~4 kDa amyloid β protein (Aβ) within lesions known as senile plaques. Aβ is also deposited in the walls of cerebral blood vessels in many cases of AD. A substantial proportion of the Aβ that accumulates in the AD brain is deposited as Amyloid, which is highly insoluble, proteinaceous material with a β-pleated-sheet conformation and deposited extracellularly in the form of 5-10 nm wide straight fibrils. As γ-secretase catalyzes the final cleavage that releases the Aβ42 or 40 from amyloid β -protein precursor (APP), therefore, it is a potential therapeutic target for the treatment of AD. γ-Secretase cleavage is performed by a high molecular weight protein complex containing presenilins (PSs), nicastrin, Aph-1 and Pen-2. Previous studies have demonstrated that the presenilins (PS1 and PS2) are critical components of a large enzyme complex that performs γ-secretase cleavage.

Methods
In this study we used RNA interference (RNAi) technology to examine the effects of small-interfering RNA (siRNA) against PS1 on expression levels of PS1 and Aβ42 in IMR-32 Cells using RTPCR, western blotting and immunofluorescence techniques.

Results
The results of the present study showed down regulation of PS1 and Aβ42 in IMR32 cells transfected with siRNA against PS1.

Conclusion
Our results substantiate the concept that PS1 is involved in γ-secretase activity and provides the rationale for therapeutic strategies aimed at influencing Aβ42 production.
GuiTope: an application for mapping random-sequence peptides to protein sequences
Authors: Halperin Rebecca F , Stafford Phillip , Emery Jack S , Navalkar Krupa Arun , Johnston Stephen Albert 
Published: January 2012

Abstract

Background
Random-sequence peptide libraries are a commonly used tool to identify novel ligands for binding antibodies, other proteins, and small molecules. It is often of interest to compare the selected peptide sequences to the natural protein binding partners to infer the exact binding site or the importance of particular residues. The ability to search a set of sequences for similarity to a set of peptides may sometimes enable the prediction of an antibody epitope or a novel binding partner. We have developed a software application designed specifically for this task.

Results
GuiTope provides a graphical user interface for aligning peptide sequences to protein sequences. All alignment parameters are accessible to the user including the ability to specify the amino acid frequency in the peptide library; these frequencies often differ significantly from those assumed by popular alignment programs. It also includes a novel feature to align di-peptide inversions, which we have found improves the accuracy of antibody epitope prediction from peptide microarray data and shows utility in analyzing phage display datasets. Finally, GuiTope can randomly select peptides from a given library to estimate a null distribution of scores and calculate statistical significance.

Conclusions
GuiTope provides a convenient method for comparing selected peptide sequences to protein sequences, including flexible alignment parameters, novel alignment features, ability to search a database, and statistical significance of results. The software is available as an executable (for PC) at http://www.immunosignature.com/software and ongoing updates and source code will be available at sourceforge.net.
Yeast-based assay identifies novel Shh/Gli target genes in vertebrate development
Authors: Milla Luis A , Cortés Claudio R , Hodar Q Christian , Oñate Maritza G , Cambiazo Veronica , Burgess Shawn M , Palma Verónica 
Published: January 2012

Abstract

Background
The increasing number of developmental events and molecular mechanisms associated with the Hedgehog (Hh) pathway from Drosophila to vertebrates, suggest that gene regulation is crucial for diverse cellular responses, including target genes not yet described. Although several high-throughput, genome-wide approaches have yielded information at the genomic, transcriptional and proteomic levels, the specificity of Gli binding sites related to direct target gene activation still remain elusive. This study aims to identify novel putative targets of Gli transcription factors through a protein-DNA binding assay using yeast, and validating a subset of targets both in-vitro and in-vivo. Testing in different Hh/Gli gain- and loss-of-function scenarios we here identified known (e.g., ptc1) and novel Hh-regulated genes in zebrafish embryos.

Results
The combined yeast-based screening and MEME/MAST analysis were able to predict Gli transcription factor binding sites, and position mapping of these sequences upstream or in the first intron of promoters served to identify new putative target genes of Gli regulation. These candidates were validated by qPCR in combination with either the pharmacological Hh/Gli antagonist cyc or the agonist pur in Hh-responsive C3H10T1/2 cells. We also used small-hairpin RNAs against Gli proteins to evaluate targets and confirm specific Gli regulation their expression. Taking advantage of mutants that have been identified affecting different components of the Hh/Gli signaling system in the zebrafish model, we further analyzed specific novel candidates. Studying Hh function with pharmacological inhibition or activation complemented these genetic loss-of-function approaches. We provide evidence that in zebrafish embryos, Hh signaling regulates sfrp2, neo1, and c-myc expression in-vivo.

Conclusion
A recently described yeast-based screening allowed us to identify new Hh/Gli target genes, functionally important in different contexts of vertebrate embryonic development.
Analysis of human immune responses in quasi-experimental settings: tutorial in biostatistics
Authors: Sarkar Rajiv , Ajjampur Sitara S , Ward Honorine D , Kang Gagandeep , Naumova Elena N 
Published: January 2012

Abstract

Background
Human immunology is a growing field of research in which experimental, clinical, and analytical methods of many life science disciplines are utilized. Classic epidemiological study designs, including observational longitudinal birth cohort studies, offer strong potential for gaining new knowledge and insights into immune response to pathogens in humans. However, rigorous discussion of methodological issues related to designs and statistical analysis that are appropriate for longitudinal studies is lacking.

Methods
In this communication we address key questions of quality and validity of traditional and recently developed statistical tools applied to measures of immune responses. For this purpose we use data on humoral immune response (IR) associated with the first cryptosporidial diarrhea in a birth cohort of children residing in an urban slum in south India. The main objective is to detect the difference and derive inferences for a change in IR measured at two time points, before (pre) and after (post) an event of interest. We illustrate the use and interpretation of analytical and data visualization techniques including generalized linear and additive models, data-driven smoothing, and combinations of box-, scatter-, and needle-plots.

Results
We provide step-by-step instructions for conducting a thorough and relatively simple analytical investigation, describe the challenges and pitfalls, and offer practical solutions for comprehensive examination of data. We illustrate how the assumption of time irrelevance can be handled in a study with a pre-post design. We demonstrate how one can study the dynamics of IR in humans by considering the timing of response following an event of interest and seasonal fluctuation of exposure by proper alignment of time of measurements. This alignment of calendar time of measurements and a child's age at the event of interest allows us to explore interactions between IR, seasonal exposures and age at first infection.

Conclusions
The use of traditional statistical techniques to analyze immunological data derived from observational human studies can result in loss of important information. Detailed analysis using well-tailored techniques allows the depiction of new features of immune response to a pathogen in longitudinal studies in humans. The proposed staged approach has prominent implications for future study designs and analyses.
Association of polymorphisms in survivin gene with the risk of hepatocellular carcinoma in Chinese han population: a case control study
Authors: Li Yuhua , Wang Jiaofeng , Jiang Feng , Lin Wenyao , Meng Wei 
Published: January 2012

Abstract

Background
Survivin, one of the strongest apoptosis inhibitors, plays a critical role in the development and progression of hepatocellular carcinoma (HCC). By comparison, relatively little is known about the effect of survivin gene polymorphisms on HCC susceptibility. Our study aimed to investigate the association of survivin gene polymorphisms with the risk of HCC in Chinese han population.

Methods
A case-control study was conducted in Chinese han population consisting of 178 HCC cases and 196 cancer-free controls. Information on demographic data and related risk factors was collected for all subjects. Polymorphisms of the survivin gene, including three loci of rs8073069, rs9904341 and rs1042489, were selected and genotyped by a polymerase chain reaction- restriction fragment length polymorphism (PCR-RFLP) technique. Association analysis of genotypes/alleles and haplotypes from these loci with the risk of HCC was conducted under different genetic models.

Results
Using univariate analysis of rs8073069, rs9904341 and rs1042489 under different genetic models, no statistically significant difference was found in genotype or allele distribution of HCC cases relative to the controls (P > 0.05). Linkage disequilibrium (LD) analysis showed that these loci were in LD. Multivariate logistic regression indicated that with no G-C-T haplotype as reference, the haplotype of G-C-T from these loci was associated with a lower risk for HCC under the recessive model (OR = 0.46, 95% confidence interval (CI): 0.24~0.90, P = 0.023). Both HBsAg+ and the medical history of viral hepatitis type B were risk factors for HCC. However, no statistically significant haplotype-environment interaction existed.

Conclusions
No association between rs8073069, rs9904341 or rs1042489 in survivin gene and the risk of HCC is found in Chinese han population, but rs8073069G-rs9904341C- rs1042489T is perhaps a protective haplotype for HCC.