There is, I think, something ethereal about i —the square root of minus one. I remember first hearing about it at school. It seemed an odd beast at that time—an intruder hovering on the edge of reality.

Usually familiarity dulls this sense of the bizarre, but in the case of i it was the reverse: over the years the sense of its surreal nature intensified. It seemed that it was impossible to write mathematics that described the real world in …

I and i

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

[신간의 별자리x] 우리/미술, 그리고 ‘슬픔의 박물관’

Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field.

https://biblio.ugent.be/publication/8555786/file/8555788.pdf

Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018.

In 2009, the Nomenclature Committee on Cell Death (NCCD) proposed a set of recommendations for the definition of distinct cell death morphologies and for the appropriate use of cell death-related terminology, including 'apoptosis', 'necrosis' and 'mitotic catastrophe'. In view of the substantial progress in the biochemical and genetic exploration of cell death, time has come to switch from morphological to molecular definitions of cell death modalities. Here we propose a functional classification of cell death subroutines that applies to both in vitro and in vivo settings and includes extrinsic apoptosis, caspase-dependent or -independent intrinsic apoptosis, regulated necrosis, autophagic cell death and mitotic catastrophe. Moreover, we discuss the utility of expressions indicating additional cell death modalities. On the basis of the new, revised NCCD classification, cell death subroutines are defined by a series of precise, measurable biochemical features.

/pdf/molecular-definitions-of-cell-death-subroutines-q5g428rlyi.pdf

Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012

Autophagy is a highly conserved intracellular degradation process and plays an important role in hepatocarcinogenesis. Available data show that autophagy is involved in anti-hepatocarcinoma (HCC) therapies. Autophagy regulation involves a novel target for overcoming therapeutic resistance and sensitizing HCC to currently therapeutic methods. This is a systematic review on the interface of autophagy and the development of HCC and outlining the role of autophagy in current anti-HCC approaches. Understanding the significance of autophagy in anti-HCC therapy may offer a novel therapeutic target for improving anti-cancer efficacy and prolong survival for HCC patients.

/pdf/autophagy-a-novel-therapeutic-target-for-hepatocarcinoma-2f9a2emhvo.pdf

Autophagy: A novel therapeutic target for hepatocarcinoma (Review)

Colorectal cancer (CRC) is one of the most common malignant tumors and its development involves multi‑gene driven processes that affect the digestive system. The objective of this study was to identify tumorigenesis‑associated gene signatures using microarray expression profiling data. The gene expression profiling of GSE39582, a dataset containing 566 colon cancer samples and 19 non‑tumoral colorectal mucosae was downloaded from Gene Expression Omnibus (GEO) database. A total of 439 differentially expressed genes (DEGs) were extracted by GEO2R. Many of these DEGs were cancer‑related, involved in the regulation of cell proliferation, extracellular matrix (ECM)‑receptor interaction and phosphatidylinositol 3‑kinase (PI3K)‑Akt signaling pathway according to the results of pathway enrichment analysis in Database for Annotation, Visualization and Integrated Discovery (DAVID). Then, 10 genes were predicted to play an important role in the development of CRC. Transient receptor potential cation channel, subfamily M, and member 6 (TRPM6), a member of 10 hub genes, was confirmed to be downregulated in 16 (80%) of 20 colon cancer tissues using quantitative polymerase chain reaction (qPCR) technology. Furthermore, high expression of TRPM6 was indicative of a prolonged overall survival (OS) in CRC patients through the analysis of GSE39582. Hsa‑let‑7g and hsa‑let‑7f‑1 were believed to be the regulatory miRNAs of TRPM6 by TCGA and miRanda database. In conclusion, this study may play a critical role in promoting the discovery of potential targets for diagnosis, treatment and prognosis of CRC.

/pdf/identification-of-key-tumorigenesis-related-genes-and-their-4mmd37mb4a.pdf

Identification of key tumorigenesis‑related genes and their microRNAs in colon cancer.

This study aimed to identify differentially expressed genes (DEGs) related to the colorectal normal mucosa-adenoma-carcinoma sequence using bioinformatics analysis. Raw data files were downloaded from Gene Expression Omnibus (GEO) and underwent quality assessment and preprocessing. DEGs were analyzed by the limma package in R software (R version 3.3.2). Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed with the DAVID online tool. In a comparison of colorectal adenoma (n = 20) and colorectal cancer (CRC) stage I (n = 31), II (n = 38), III (n = 45), and IV (n = 62) with normal colorectal mucosa (n = 19), we identified 336 common DEGs. Among them, seven DEGs were associated with patient prognosis. Five (HEPACAM2, ITLN1, LGALS2, MUC12, and NXPE1) of the seven genes presented a sequentially descending trend in expression with tumor progression. In contrast, TIMP1 showed a sequentially ascending trend. GCG was constantly downregulated compared with the gene expression level in normal mucosa. The significantly enriched GO terms included extracellular region, extracellular space, protein binding, and carbohydrate binding. The KEGG categories included HIF-1 signaling pathway, insulin secretion, and glucagon signaling pathway. We discovered seven DEGs in the normal colorectal mucosa-adenoma-carcinoma sequence that was associated with CRC patient prognosis. Monitoring changes in these gene expression levels may be a strategy to assess disease progression, evaluate treatment efficacy, and predict prognosis.

https://www.onlinelibrary.wiley.com/doi/pdf/10.1002/cam4.1484

Analysis of potential genes and pathways associated with the colorectal normal mucosa-adenoma-carcinoma sequence.

p53, the “cellular gatekeeper” and the “guardian of the cellular genome”, is the most commonly mutated tumor suppressor in human cancer. In response to diverse stresses (that is, DNA damage, nutrient deprivation, oncogenic activation, hypoxia, oxidative stress, hyperproliferative signals and other forms of stress), p53 can be activated and subsequently functions as a transcription factor to orchestrate various biological outputs such as transient cell cycle arrest, apoptosis, cellular senescence, differentiation, metabolism, as well as regulation of autophagy [1].

Autophagy is a dynamic catabolic process by which cytoplasmic components are targeted to a double-membrane vesicle called autophagosomes and subsequently delivered to the lysosome for terminal degradation and recycling [2]. When the cells are subjected to stressful stimuli such as starvation, autophagy is rapidly upregulated to restore their metabolic homeostasis and sustain energy requirements, thus facilitating their survival under stressful conditions. However, excessive or persistent autophagy is also shown to promote cell death. A series of stress signals can induce autophagy, including p53, nutrient deprivation, hypoxia, endoplasmic reticulum stress and so on. The direct evidence from Scherz-Shouval et al. suggests that p53-dependent regulation of autophagy supports cell survival in the face of chronic starvation [3]. The central checkpoints that regulate autophagy are AMPresponsive protein kinase (AMPK) and mammalian target of rapamycin (mTOR) [2].

Cellular senescence is a stress response that accompanies with the irreversible arrest and senescent morphology. Senescence may be initiated by various insults and has an important role in limiting cell proliferation, however, the mechanisms controlling cellular senescence are still debated [4]. Increasing evidence indicate that p53 and AMPK/mTOR pathway are critical mediators of the senescence response [5, 6]. Thus, p53 can induce cell cycle arrest and then active mTOR converts this arrest into senescence (geroconversion). Seemingly paradoxically, p53 can also function as a suppressor of cellular senescence by blocking the mTOR pathway [6]. Both p53 and mTOR are also involved in regulation of autophagy. mTOR inhibits autophagy. However, it remains to be determined whether p53- induced autophagy is associated with suppression of senescence (gerosuppression).

We have recently shown that p53 facilitated cell survival by inducing autophagy under the deprivation of serum [7]. Under serum starvation, an increased autophagic flux was observed in the HCT116 p53+/+ cells but not in the HCT116 p53−/− cells, suggesting that p53 promoted autophagy under serum-starved conditions. we showed p53-dependent autophagy protected cancer cells from starvation-induced death and inhibition of autophagy by the treatment with 3-MA resulted in a large number of cell death. Thus, p53-induced autophagy functions as a survival signal in response to serum starvation.

To determine the impact of p53-induced autophagy on cellular senescence, we assessed cell cycle and staining with β-gal. We found that p53 induces cell cycle arrest and cell quiescence (not senescence) in response to serum starvation. However, β-gal activity was significantly enhanced in the serum-starved HCT116 p53−/− cells, as compared with the serum-starved HCT116 p53+/+ cells. These results indicate that p53 may act as a suppressor of cellular senescence in response to serum starvation since β-gal is a well-known marker presented in senescent cells.

Next, we investigated whether inhibition of p53- dependent autophagy may promote cellular senescence. As mentioned above, increased autophagic flux and lack of the senescent phenotype were found in the serum-starved HCT116 p53+/+ cells. After the treatment with autophagic inhibitor 3-MA, the autophagy was attenuated and β-gal activity was markedly enhanced in the starved HCT116 p53+/+ cells, but hardly changed in the starved p53−/− cells. These data indicate that inhibition of p53-dependent autophagy promotes cellular senescence. In addition, it was demonstrated that suppression of senescence through p53-dependent autophagy may occur partly through the inhibition of the mTOR pathway.

Our results demonstrate that, in the absence of serum, p53 may activate autophagic flux and subsequent autophagy functions as a survival signal to inhibit cellular senescence partly through suppression of the mTOR pathway. This study delineates a potential association between autophagy and senescence and explains why p53 may suppress cellular senescence in response to starvation. Future experiments will further illuminate the molecular mechanisms responsible for the inhibitory effects of p53-indeced autophagy on cellular senescence. A better understanding of the role of p53 in autophagy and cellular senescence will hopefully provide new strategy for cancer therapy.

/pdf/p53-induced-autophagy-and-senescence-1x4cuzmmt7.pdf

p53-induced autophagy and senescence

Right-sided colon cancer (RCC) and left-sided colon cancer (LCC) differ in their clinical and molecular features. An investigation of differentially expressed genes (DEGs) between RCC and LCC could contribute to targeted therapy for colon cancer, especially RCC, which has a poor prognosis. Here, we identified HOXB13, which was significantly less expressed in RCC than in LCC and associated with prognosis in RCC, by using 5 datasets from the Gene Expression Omnibus (GEO). Tissue sample analysis showed that HOXB13 was differentially expressed between normal and only RCC tumor tissues. HOXB13 inhibited colon cancer cell proliferation and induced apoptosis both in vitro and in vivo. Furthermore, we found that HOXB13 might be regulated by DNMT3B and suppress C-myc expression to exert antitumor effects via β-catenin/TCF4 signals in RCC. In conclusion, the current study is the first to demonstrate that HOXB13 has a tumor-suppressive effect in RCC. High expression levels of HOXB13 are associated with prolonged overall survival in patients with RCC. The DNMT3B-HOXB13-C-myc signaling axis might be a molecular target for the treatment of RCC.

/pdf/tumor-suppressive-function-and-mechanism-of-hoxb13-in-right-110syn3op3.pdf

Weidong Han

Papers

Autophagy: A novel therapeutic target for hepatocarcinoma (Review)

Identification of key tumorigenesis‑related genes and their microRNAs in colon cancer.

Analysis of potential genes and pathways associated with the colorectal normal mucosa-adenoma-carcinoma sequence.

p53-induced autophagy and senescence

Tumor-suppressive function and mechanism of HOXB13 in right-sided colon cancer.