MENX is a recessive multiple endocrine neoplasia-like syndrome in the rat. The tumor spectrum in MENX overlaps those of human multiple endocrine neoplasia (MEN) types 1 and 2. We mapped the MenX locus to the distal part of rat chromosome 4, excluding the homologs of the genes responsible for the MEN syndromes ( RET and MEN1 ) and syndromes with an endocrine tumor component ( VHL and NF1 ). We report the fine mapping of the disease locus and the identification of a homozygous frameshift mutation in Cdkn1b , encoding the cyclin-dependent kinase inhibitor p27 ^Kip1 . As a consequence of the mutation, MENX-affected rats show dramatic reduction in p27 ^Kip1 protein. We have identified a germ-line nonsense mutation in the human CDKN1B gene in a MEN1 mutation-negative patient presenting with pituitary and parathyroid tumors. Expanded pedigree analysis shows that the mutation is associated with the development of an MEN1-like phenotype in multiple generations. Our findings demonstrate that germ-line mutations in p27 ^Kip1 can predispose to the development of multiple endocrine tumors in both rats and humans.

Papillary thyroid carcinoma (PTC) is clinically heterogeneous. Apart from an association with ionizing radiation, the etiology and molecular biology of PTC is poorly understood. We used oligo-based DNA arrays to study the expression profiles of eight matched pairs of normal thyroid and PTC tissues. Additional PTC tumors and other tissues were studied by reverse transcriptase–PCR and immunohistochemistry. The PTCs showed concordant expression of many genes and distinct clustered profiles. Genes with increased expression in PTC included many encoding adhesion and extracellular matrix proteins. Expression was increased in 8/8 tumors for 24 genes and in 7/8 tumors for 22 genes. Among these genes were several previously known to be overexpressed in PTC, such as MET , LGALS3 , KRT19 , DPP4 , MDK , TIMP1 , and FN1 . The numerous additional genes include CITED1 , CHI3L1 , ODZ1 , N33 , SFTPB , and SCEL . Reverse transcriptase–PCR showed high expression of CITED1 , CHI3L1 , ODZ1 , and SCEL in 6/6 additional PTCs. Immunohistochemical analysis detected CITED1 and SFTPB in 49/52 and 39/52 PTCs, respectively, but not in follicular thyroid carcinoma and normal thyroid tissue. Genes underexpressed in PTC included tumor suppressors, thyroid function-related proteins, and fatty acid binding proteins. Expression was decreased in 7/8 tumors for eight genes and decreased in 6/8 tumors for 19 genes. We conclude that, despite its clinical heterogeneity, PTC is characterized by consistent and specific molecular changes. These findings reveal clues to the molecular pathways involved in PTC and may provide biomarkers for clinical use.

Most mammalian cells exhibit transient delays in the G ₁ and G ₂ phases of the cell cycle after treatment with radiation or radiomimetic compounds. p53 is required for the arrest in G ₁ , which provides time for DNA repair. Recently, a role of p53 in the G ₂ /M transition has also been suggested. However, it has been reported that the presence of functional p53 does not always correlate with the induction of these checkpoints. To precisely assess the role of p53 in activating cell cycle checkpoints and in cell survival after radiation, we studied the response of two isogenic human fibrosarcoma cell lines differing in their p53 status (wild type or mutant). We found that when irradiated cells undergo a wild-type p53-dependent G ₁ arrest, they do not subsequently arrest in G ₂ . Moreover, wild-type p53 cells irradiated past the G ₁ checkpoint arrest in G ₂ but do not delay in the subsequent G ₁ phase. Furthermore, in these cell lines, which do not undergo radiation-induced apoptosis, the wild-type p53 cell line exhibited a greater radioresistance in terms of clonogenic survival. These results suggest that the two checkpoints may be interrelated, perhaps through a control system that determines, depending on the extent of the damage, whether the cell needs to arrest cell cycle progression at the subsequent checkpoint for further repair. p53 could be a crucial component of this control system.

Chemokine ligand-receptor interactions play a pivotal role in cell attraction and cellular trafficking, both in normal tissue homeostasis and in disease. In cancer, chemokine receptor-4 (CXCR4) expression is an adverse prognostic factor. Early clinical studies suggest that targeting CXCR4 with suitable high-affinity antagonists might be a novel means for therapy. In addition to the preclinical evaluation of [⁶⁸Ga]Pentixafor in mice bearing human lymphoma xenografts as an exemplary CXCR4-expressing tumor entity, we report on the first clinical applications of [⁶⁸Ga]Pentixafor-Positron Emission Tomography as a powerful method for CXCR4 imaging in cancer patients. [⁶⁸Ga]Pentixafor binds with high affinity and selectivity to human CXCR4 and exhibits a favorable dosimetry. [⁶⁸Ga]Pentixafor-PET provides images with excellent specificity and contrast. This non-invasive imaging technology for quantitative assessment of CXCR4 expression allows to further elucidate the role of CXCR4/CXCL12 ligand interaction in the pathogenesis and treatment of cancer, cardiovascular diseases and autoimmune and inflammatory disorders.