Conclusions: Non-conventional morphological patterns of dysplasia are not uncommon in IBD, detected in 33% of the patients. The higher frequencies of advanced neoplasia (HGD or CRC) and aneuploidy in non-conventional dysplasia, in particular CCD, hypermucinous and GCD variants, suggest that they may have a higher malignant potential than conventional dysplasia or sporadic tubular adenomas, and thus need complete removal and/or careful follow-up.Greater than 40% of non-conventional dysplasia presented as a flat/invisible lesion, suggesting that IBD patients may benefit from random biopsy sampling in addition to targeted biopsies. The majority of nonconventional subtypes appear to develop via the chromosomal instability pathway, whereas an alternative serrated pathway may be responsible for the development of at least a subset of SSL-like and TSA-like dysplasias.

The direct fusion of viral and target cell membranes required for human immunodeficiency virus type 1 (HIV-1) entry is initiated by the primary receptor, CD4, and a chemokine receptor, usually CXCR4 or CCR5. Chemokine receptors are members of the G-protein-coupled receptor (GPCR) superfamily that possess seven transmembrane (TM) domains. Because of its importance in the development of AIDS, CXCR4 has been explored as a new target for drug discovery to combat the AIDS epidemic (3,8,10). As the natural ligands of chemokine receptors, chemokines are small soluble proteins of about 70 amino acid residues that play prominent roles in leukocyte activation and inflammation (5, 11). Most of the known human chemokines are broadly categorized into the CXC and CC chemokines based on the position of two conserved cysteine residues in their amino (N)-terminal domains (3, 11). The natural chemokines of CXCR4 or CCR5 can inhibit HIV-1 infection (4, 13) by blocking HIV-1 gp120 binding sites (2, 14) and/or inducing receptor internalization (1, 9).Despite their important roles in the pathogenesis of AIDS and other human diseases, the lack of receptor selectivity of natural chemokines has made their direct clinical applications problematic. It is common knowledge that a chemokine receptor can often be recognized by multiple ligands, while a chemokine ligand binds to several different receptors (15), illustrating the apparent redundancy and the lack of selectivity in the chemokine ligand-receptor interaction network. As such, we have been working toward the development of a systematic chemical biology approach based on chemokine protein structures and chemistry to generate synthetically and modularly modified (SMM) chemokines that have higher receptor binding selectivity and improved pharmacological profiles compared with natural chemokines. This SMM chemokine approach was recently applied to generate novel ligands selective for CXCR4 or CCR5 by modifying the N-terminal (1-10) sequence module of viral macrophage inflammatory protein II (vMIP-II) or stromal cell-derived factor 1␣ (SDF-1␣) (unpublished data). Importantly, some of these SMM chemokines,

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Aims The pathological features and diagnostic reliability of crypt cell atypia (CCA) arising in inflammatory bowel disease (IBD) and its clinical significance are unknown. Methods and results DNA flow cytometry (FCM) was performed on 14 colon biopsies of CCA from seven IBD patients (male‐to‐female ratio, 5:2; mean age, 53 years; mean IBD duration, 15 years) using paraffin‐embedded tissue. Seven gastrointestinal pathologists were asked to diagnose each biopsy as negative for dysplasia (NEG), indefinite for dysplasia (IND), low‐grade dysplasia (LGD) or high‐grade dysplasia (HGD) by morphology alone, then again with knowledge of FCM results. Aneuploidy was detected in all 14 biopsies, and five of eight biopsies (63%) also showed strong and diffuse nuclear staining for p53 in the areas of CCA. Six (86%) patients developed HGD (n = 5) or adenocarcinoma (n = 1) in the same colonic segment where CCA had been diagnosed within a mean follow‐up time of 27 months. No follow‐up information was available in the remaining one patient. When diagnoses were grouped as NEG or ‘atypical’ (including IND, LGD or HGD), the overall agreement rate of 76% (kappa = 0.51) based on morphology alone improved to 90% (kappa = 0.81) with knowledge of FCM results. Even when categorised as NEG or dysplasia (LGD or HGD) with each of the IND diagnoses reclassified into three categories (NEG, LGD or HGD) based on the degree of suspicion for dysplasia, the overall agreement rate of 63% (kappa = 0.25) based on morphology alone improved to 73% (kappa = 0.46) with knowledge of FCM results. However, when grouped as NEG, LGD or HGD, the overall agreement rate was less than 40% (kappa < 0.09) regardless of knowledge of FCM results. Conclusions The presence of aneuploidy, p53 positivity and development of HGD or adenocarcinoma on follow‐up indicate that CCA likely represents a dysplastic lesion (at least LGD) and is a histological marker of neoplastic progression. Although the grading of CCA, largely based on cytological abnormalities, is subject to significant interobserver variability, CCA can be histologically identified and should lead to a recommendation of increased endoscopic surveillance, especially if aneuploidy is detected.