CpG islands frequently contain gene promoters or exons and are usually unmethylated in normal cells. Methylation of CpG islands is associated with delayed replication, condensed chromatin and inhibition of transcription initiation. The investigation of aberrant CpG-island methylation in human cancer has primarily taken a candidate gene approach, and has focused on less than 15 of the estimated 45,000 CpG islands in the genome. Here we report a global analysis of the methylation status of 1,184 unselected CpG islands in each of 98 primary human tumours using restriction landmark genomic scanning (RLGS). We estimate that an average of 600 CpG islands (range of 0 to 4,500) of the 45,000 in the genome were aberrantly methylated in the tumours, including early stage tumours. We identified patterns of CpG-island methylation that were shared within each tumour type, together with patterns and targets that displayed distinct tumour-type specificity. The expression of many of these genes was reactivated by experimental demethylation in cultured tumour cells. Thus, the methylation of particular subsets of CpG islands may have consequences for specific tumour types.

In this article, we first designed and synthesized curcumin-based near infrared (NIR) fluorescence imaging probes for detecting both soluble and insoluble amyloid beta (Aβ) species, and then an inhibitor that could attenuate crosslinking of Aβ induced by copper. According to our previous results and the possible structural stereo-hindrance compatibility of the Aβ peptide and the hydrophobic/hydrophilic property of the Aβ13–20 (HHQKLVFF) fragment, NIR imaging probe CRANAD-58 was designed and synthesized. As expected CRANAD-58 showed significant fluorescence property changes upon mixing with both soluble and insoluble Aβ species in vitro. In vivo NIR imaging revealed that CRANAD-58 was capable of differentiating transgenic and wild type mice as young as 4-months old, the age that lacks apparently visible Aβ plaques and Aβ is likely in its soluble forms. In this report, according to our limited studies on the interaction mechanism between CRANAD-58 and Aβ, we also designed CRANAD-17 to attenuate the crosslinking of Aβ42 induced by copper. It is well known that the coordination of copper with imidazoles on Histidine-13 and 14 (H13, H14) of Aβ peptides could initialize covalent crosslinking of Aβ. In CRANAD-17, a curcumin scaffold was used as an anchoring moiety to usher the designed compound to the vicinity of H13 and H14 of Aβ, and imidazole rings were incorporated to compete with H13/H14 for copper binding. The results of SDS-PAGE gel and Western blot indicated that CRANAD-17 was capable of inhibiting Aβ42 cross-linking induced by copper. This raises a potential for CRANAD-17 to be considered for AD therapy.

The recent success of PD-1 and PD-L1 blockade in cancer therapy illustrates the important role of the PD-1/PD-L1 pathway in the regulation of antitumor immune responses. However, signaling regulated by the PD-1/PD-L pathway is also associated with substantial inflammatory effects that can resemble those in autoimmune responses, chronic infection, and sepsis, consistent with the role of this pathway in balancing protective immunity and immunopathology, as well as in homeostasis and tolerance. Targeting PD-1/PD-L1 to treat cancer has shown benefits in many patients, suggesting a promising opportunity to target this pathway in autoimmune and inflammatory disorders. Here, we systematically evaluate the diverse biological functions of the PD-1/PD-L pathway in immune-mediated diseases and the relevant mechanisms that control these immune reactions.