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

https://njc.rockefeller.edu/pdf4/Class2-LeeAmbros1993.pdf

The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14

The cBio Cancer Genomics Portal (http://cbioportal.org) is an open-access resource for interactive exploration of multidimensional cancer genomics data sets, currently providing access to data from more than 5,000 tumor samples from 20 cancer studies. The cBio Cancer Genomics Portal significantly lowers the barriers between complex genomic data and cancer researchers who want rapid, intuitive, and high-quality access to molecular profiles and clinical attributes from large-scale cancer genomics projects and empowers researchers to translate these rich data sets into biologic insights and clinical applications.

/pdf/the-cbio-cancer-genomics-portal-an-open-platform-for-4kclcxogdw.pdf

The cBio Cancer Genomics Portal: An Open Platform for Exploring Multidimensional Cancer Genomics Data

http://www.klinikaikozpont.u-szeged.hu/pedia/images/pdf/CME_TEL/Full-Text/25.pdf

The Hallmarks of Aging

We analysed primary breast cancers by genomic DNA copy number arrays, DNA methylation, exome sequencing, messenger RNA arrays, microRNA sequencing and reverse-phase protein arrays. Our ability to integrate information across platforms provided key insights into previously defined gene expression subtypes and demonstrated the existence of four main breast cancer classes when combining data from five platforms, each of which shows significant molecular heterogeneity. Somatic mutations in only three genes (TP53, PIK3CA and GATA3) occurred at >10% incidence across all breast cancers; however, there were numerous subtype-associated and novel gene mutations including the enrichment of specific mutations in GATA3, PIK3CA and MAP3K1 with the luminal A subtype. We identified two novel protein-expression-defined subgroups, possibly produced by stromal/microenvironmental elements, and integrated analyses identified specific signalling pathways dominant in each molecular subtype including a HER2/phosphorylated HER2/EGFR/phosphorylated EGFR signature within the HER2-enriched expression subtype. Comparison of basal-like breast tumours with high-grade serous ovarian tumours showed many molecular commonalities, indicating a related aetiology and similar therapeutic opportunities. The biological finding of the four main breast cancer subtypes caused by different subsets of genetic and epigenetic abnormalities raises the hypothesis that much of the clinically observable plasticity and heterogeneity occurs within, and not across, these major biological subtypes of breast cancer.

/pdf/comprehensive-molecular-portraits-of-human-breast-tumours-4t6h37c9ow.pdf

Comprehensive molecular portraits of human breast tumours

We thank the author for their comments on our article. The questions we asked about light in the bedroom at night were very similar to those used by Stevens in a case–control study of breast cancer. It seems curious that when these measures of exposure showed evidence of an association in that study, they were considered to give “evidence that indicators of exposure to light at night may be associated with the risk of developing breast cancer“, but, apparently, when similar measures of exposure do not show an association they “yield no evidence one way or the other” and are as useful as assessing exposure “on the basis of the flip of a coin”. As in almost all questionnaire epidemiology, the questions give subjective and imperfect measures of exposure, but this does not make them “no evidence”—they are another brick in an imperfect, hard-to-build, wall, in trying to assess the light at night hypothesis.

Response to 'Comment on 'Domestic light at night and breast cancer risk: a prospective analysis of 105 000 UK women in the Generations Study".

Exploiting DNA damage repair defects for effective targeting of acute myeloid leukaemia by PARP inhibitors

&lt;div&gt;Abstract&lt;p&gt;Over one million cases of gastric cancer are diagnosed each year globally, and the metastatic disease continues to have a poor prognosis. A significant proportion of gastric tumors have defects in the DNA damage response pathway, creating therapeutic opportunities through synthetic lethal approaches. Several small-molecule inhibitors of ATR, a key regulator of the DNA damage response, are now in clinical development as targeted agents for gastric cancer. Here, we performed a large-scale CRISPR interference screen to discover genetic determinants of response and resistance to ATR inhibitors (ATRi) in gastric cancer cells. Among the top hits identified as mediators of ATRi response were UPF2 and other components of the nonsense-mediated decay (NMD) pathway. Loss of UPF2 caused ATRi resistance across multiple gastric cancer cell lines. Global proteomic, phosphoproteomic, and transcriptional profiling experiments revealed that cell-cycle progression and DNA damage responses were altered in &lt;i&gt;UPF2&lt;/i&gt;-mutant cells. Further studies demonstrated that UPF2-depleted cells failed to accumulate in G&lt;sub&gt;1&lt;/sub&gt; following treatment with ATRi. UPF2 loss also reduced transcription–replication collisions, which has previously been associated with ATRi response, thereby suggesting a possible mechanism of resistance. Our results uncover a novel role for NMD factors in modulating response to ATRi in gastric cancer, highlighting a previously unknown mechanism of resistance that may inform the clinical use of these drugs.&lt;/p&gt;Significance:&lt;p&gt;Loss of NMD proteins promotes resistance to ATR inhibitors in gastric cancer cells, which may provide a combination of therapeutic targets and biomarkers to improve the clinical utility of these drugs.&lt;/p&gt;&lt;/div&gt; 

Alan Ashworth

Papers

Response to 'Comment on 'Domestic light at night and breast cancer risk: a prospective analysis of 105 000 UK women in the Generations Study".

Exploiting DNA damage repair defects for effective targeting of acute myeloid leukaemia by PARP inhibitors

Data from Resistance to ATR Inhibitors Is Mediated by Loss of the Nonsense-Mediated Decay Factor UPF2

Data from Resistance to ATR Inhibitors Is Mediated by Loss of the Nonsense-Mediated Decay Factor UPF2

Intravascular Folding of a Peripheral Venous VA-ECMO Cannula for Extracorporeal Cardiopulmonary Resuscitation.