다중혈관 관상동맥 환자에서 y-문합을 이용하여 양쪽 내흉동맥만을 사용한 우회술의 조기 성적

抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Recent data have expanded the concept that inflammation is a critical component of tumour progression. Many cancers arise from sites of infection, chronic irritation and inflammation. It is now becoming clear that the tumour microenvironment, which is largely orchestrated by inflammatory cells, is an indispensable participant in the neoplastic process, fostering proliferation, survival and migration. In addition, tumour cells have co-opted some of the signalling molecules of the innate immune system, such as selectins, chemokines and their receptors for invasion, migration and metastasis. These insights are fostering new anti-inflammatory therapeutic approaches to cancer development.

Inflammation and cancer

Statistical method for testing the neutral mutation hypothesis by DNA polymorphism.

Integrins: versatility, modulation, and signaling in cell adhesion.

The ethics of egg manipulation

Some aspects of human cognition and behavior appear unusual or exaggerated relative to those of other intelligent, warm-blooded, long-lived social species––including certain mammals (cetaceans, elephants, and great apes) and birds (corvids and passerines). One collection of such related features is our remarkable ability for ignoring or denying reality in the face of clear facts, a high capacity for self-deception and false beliefs, overarching optimism bias, and irrational risk-taking behavior (herein collectively called “reality denial”). Such traits should be maladaptive for reproductive success when they first appear as consistent features in individuals of any species. Meanwhile, available data suggest that self-awareness (knowledge of one’s own personhood) and basic theory of mind (ToM, also termed mind-reading, intentionality etc.) have evolved independently several times, particularly in the same kinds of species mentioned above. Despite a long-standing opportunity spanning tens of millions of years, only humans appear to have gone on to evolve an extended ToM (multilevel intentionality), a trait required for optimal expression of many other unusual cognitive attributes of our species, such as advanced linguistic communication and cumulative cooperative culture. The conventional view is that extended ToM emerged gradually in human ancestors, via stepwise positive selection of multiple traits that were each beneficial. A counterintuitive alternate possibility is that establishment of extended ToM has been repeatedly obstructed in all other species with the potential to achieve it, due to a “psychological evolutionary barrier,” that would arise in isolated individuals of a given species that develop the genetic ability for extended ToM. Such individuals would observe deaths of conspecifics whose minds they fully understood, become aware of mortality, and translate that knowledge into mortality salience (understanding of personal mortality). The resulting conscious realization and exaggeration of an already existing intrinsic fear of death risk would have then reduced the reproductive fitness of such isolated individuals (by favoring personal survival over reproduction). This “psychological evolutionary barrier” would have thus persisted until hominin ancestors broke through, via a rare and unlikely combination of cognitive changes, in which two intrinsically maladaptive traits (reality denial and extended ToM) evolved in the minds of the same individuals, allowing a “mind over reality transition” (MORT) over the proposed barrier. Once some individuals broke through in this manner, conventional natural selection could take over, with further evolution of beneficial aspects of the initial changes. This theory also provides a unifying evolutionary explanation for other unusual features of humans, including our recent emergence as the dominant species on the planet, and replacement of all other closely related evolutionary cousins, with limited interbreeding and no remaining hybrid species. While not directly falsifiable by experiment, the MORT theory fits with numerous facts about humans and human origins, and no known fact appears to strongly militate against it. It is also consistent with most other currently viable theories on related subjects, including terror management theory. Importantly, it has major implications for the human condition, as well as for many serious current issues, ranging all the way from lack of personal health responsibility to ignoring anthropogenic global climate disruption, which now threatens the very existence of our species.

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Did Human Reality Denial Breach the Evolutionary Psychological Barrier of Mortality Salience? A Theory that Can Explain Unusual Features of the Origin and Fate of Our Species

Humans cannot synthesize the common mammalian sialic acid N-glycolylneuraminic acid (Neu5Gc) because of an inactivating deletion in the cytidine-5'-monophospho-(CMP)-N-acetylneuraminic acid hydroxylase (CMAH) gene responsible for its synthesis. Human Neu5Gc deficiency can lead to development of anti-Neu5Gc serum antibodies, the levels of which can be affected by Neu5Gc-containing diets and by disease. Metabolic incorporation of dietary Neu5Gc into human tissues in the face of circulating antibodies against Neu5Gc-bearing glycans is thought to exacerbate inflammation-driven diseases like cancer and atherosclerosis. Probing of sera with sialoglycan arrays indicated that patients with Duchenne muscular dystrophy (DMD) had a threefold increase in overall anti-Neu5Gc antibody titer compared with age-matched controls. These antibodies recognized a broad spectrum of Neu5Gc-containing glycans. Human-like inactivation of the Cmah gene in mice is known to modulate severity in a variety of mouse models of human disease, including the X chromosome-linked muscular dystrophy (mdx) model for DMD. Cmah-/-mdx mice can be induced to develop anti-Neu5Gc-glycan antibodies as humans do. The presence of anti-Neu5Gc antibodies, in concert with induced Neu5Gc expression, correlated with increased severity of disease pathology in Cmah-/-mdx mice, including increased muscle fibrosis, expression of inflammatory markers in the heart, and decreased survival. These studies suggest that patients with DMD who harbor anti-Neu5Gc serum antibodies might exacerbate disease severity when they ingest Neu5Gc-rich foods, like red meats.

Serum Antibodies to N-Glycolylneuraminic Acid Are Elevated in Duchenne Muscular Dystrophy and Correlate with Increased Disease Pathology in Cmah-/-mdx Mice.

Compelling evidence for naturally occurring immunosurveillance against malignancies informs and justifies some current approaches towards cancer immunotherapy. However, some types of immune reactions have also been shown to facilitate tumor progression. For example, our previous studies showed that experimental tumor growth in mice can be enhanced by low levels of circulating antibodies directed against the non-human sialic acid N-glycolyl-neuraminic acid (Neu5Gc, which accumulates in human tumors from dietary sources). However, tumor growth could instead be inhibited by anti-Neu5Gc antibodies from a different source, in a different model. Thus, anti-Neu5Gc antibodies appeared to be showing differential effects on tumor growth. However it remains generally unclear whether the immune responses that mediate cancer immunosurveillance versus those responsible for inflammatory facilitation are qualitatively and/or quantitatively distinct. Here, we address this question using multiple murine tumor growth models in which polyclonal antibodies against tumor antigens such as Neu5Gc can alter tumor progression. We found that while growth was stimulated at low antibody doses it was inhibited by high doses, over a linear and remarkably narrow range, defining an immune response curve (IRC), i.e., inverse hormesis. Moreover, modulation of immune responses against the tumor by altering antibody avidity or by enhancing innate immunity shifted the IRC in the appropriate direction. Thus, the dualistic role of immunosurveillance versus inflammation in modulating tumor progression can be quantitatively distinguished in multiple model systems, and can occur over a remarkably narrow range. We also reproduced the biphasic IRC in a model using the monoclonal anti-CD20 antibody rituximab. Furthermore, depletion of macrophages abrogated the growth promotion at low antibody concentrations and depletion of NK cells reduced growth inhibition at high antibody concentrations. These findings may have implications for the etiology and prevention of cancer, and for immunotherapeutic approaches utilizing antibodies. Citation Format: Oliver M.T. Pearce, Heinz Laubli, Andrea Verhagen, Patrick Secrest, Jiquan Zhang, Paul R. Crocker, Nissi Varki, Jack Bui, Ajit Varki. Inverse hormesis of cancer growth mediated by narrow ranges of tumor-directed antibodies. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1063. doi:10.1158/1538-7445.AM2014-1063

Abstract 1063: Inverse hormesis of cancer growth mediated by narrow ranges of tumor-directed antibodies

This unit describes metabolic labeling techniques that provide specific information about the structure, sequence, and distribution of the sugar chains of glycoconjugates. In the Basic Protocol, cells in culture are grown through several population doublings in complete medium supplemented with radiolabeled glycoconjugate precursors to reach a steady-state level of incorporation. In the alternate protocols, cells are cultured for a short period of time in a deficient medium that contains a high concentration of radiolabeled precursor. A pulse or pulse-chase labeling procedure is provided to analyze precursor-product relationships. With the sequential pulse-labeling method described here, it is possible to obtain quantities of labeled glycoconjugates with the use of a minimum amount of labeled precursor by using the same batch of medium to pulse-label a series of cultures. A support protocol describes the preparation of multiply deficient medium (MDM) for use in making appropriate deficient media.

Ajit Varki

Papers

The ethics of egg manipulation

Did Human Reality Denial Breach the Evolutionary Psychological Barrier of Mortality Salience? A Theory that Can Explain Unusual Features of the Origin and Fate of Our Species

Serum Antibodies to N-Glycolylneuraminic Acid Are Elevated in Duchenne Muscular Dystrophy and Correlate with Increased Disease Pathology in Cmah-/-mdx Mice.

Abstract 1063: Inverse hormesis of cancer growth mediated by narrow ranges of tumor-directed antibodies

Metabolic radiolabeling of animal cell glycoconjugates.