De novo variants of CSNK2B cause a new intellectual disability-craniodigital syndrome by disrupting the canonical Wnt signaling pathway

CSNK2B encodes for casein kinase II subunit beta (CK2b), the regulatory subunit of casein kinase II (CK2), which is known to mediate diverse cellular pathways. Variants in this gene have been recently identified as a cause of Poirier-Bienvenu neurodevelopmental syndrome (POBINDS), but functional evidence is sparse. Here, we report five unrelated individuals: two of them manifesting POBINDS, while three are identified to segregate a new intellectual disability-craniodigital syndrome (IDCS), distinct from POBINDS. The three IDCS individuals carried two different de novo missense variants affecting the same codon of CSNK2B. Both variants, NP_001311.3; p.Asp32His and NP_001311.3; p.Asp32Asn, lead to an upregulation of CSNK2B expression at transcript and protein level, along with global dysregulation of canonical Wnt signaling. We found impaired interaction of the two key players DVL3 and b-catenin with mutated CK2b. The variants compromise the kinase activity of CK2 as evident by a marked reduction of phosphorylated b-catenin and consequent absence of active b-catenin inside nuclei of the patient-derived lymphoblastoid cell lines (LCLs). In line with these findings, whole-transcriptome profiling of patient-derived LCLs harboring the NP_001311.3; p.Asp32His variant confirmed a marked difference in expression of genes involved in the Wnt signaling pathway. In addition, whole-phosphoproteome analysis of the LCLs of the same subject showed absence of phosphorylation for 313 putative CK2 substrates, enriched in the regulation of nuclear b-catenin and transcription of the target genes. Our findings suggest that discrete variants in CSNK2B cause dominant-negative perturbation of the canonical Wnt signaling pathway, leading to a new craniodigital syndrome distinguishable from POBINDS

Rationale and techniques of cytoreductive surgery and peritoneal chemohyperthermia

The evolution of loco-regional treatments has occurred in the last two decades and has deeply changed the natural history of primitive and secondary peritoneal surface malignancies. Several phase II-III studies have proved the effectiveness of the combination of cytoreductive surgery with peritoneal chemohyperthermia. Cytoreductive surgery allows the reduction of the neoplastic mass and increases tumoral chemosensitivity. The development of chemohyperthermia finds its origins in the necessity to exceed the limits of intraperitoneal chemotherapy performed in normothermia. It permits a continuous high concentration gradient of chemotherapeutic drugs between the peritoneal cavity and the plasma compartment to and a more uniform distribution throughout the abdominal cavity compared to systemic administration

Odontogenic Epithelium: Immunolabeling of Ki-67, EGFR and Survivin in Pericoronal Follicles, Dentigerous Cysts and Keratocystic Odontogenic Tumors

The aim of this study was to evaluate the biological profile of odontogenic epithelium by immunolabeling of epidermal growth factor receptor (EGFR), Ki-67 and survivin in keratocystic odontogenic tumors (KOT), dentigerous cysts (DC), and pericoronal follicles (PF). Immunohistochemical analysis was performed in 13 KOTs, 14 DCs and 9 PFs. Immunolabeling was analyzed in the basal and suprabasal layers of KOTs and DCs, and in the islands of odontogenic epithelium and/or reduced enamel epithelium of PFs. KOTs showed the highest proliferation rate among the three groups, mainly in suprabasal layers. EGFR immunolabeling was observed mainly in the cytoplasm in basal and suprabasal layers of KOTs and in the suprabasal layer of DCs. Immunolabeling in both membrane and cytoplasm was greater in PFs. In PFs, membrane-only staining was observed. Survivin immunolabeling showed a greater percentage of positive cells (scoring +++) in the suprabasal layer of KOTs. In DCs, both layers showed similar percentages of cells scoring +++; PFs showed the highest percentage of these cells. In KOTs, epithelial cells showed stimulus-independent neoplastic proliferative characteristics, suggesting the presence of a suprabasal proliferative compartment, maintained by inhibition of apoptosis. In DCs, the basal layer seemed to proliferate in response to stimulus. Although PFs showed low proliferative activity, the expression of EGFR indicates that some cells have a high capacity to respond to stimuli, which could probably explain the origin of odontogenic lesions

Selective compounds define Hsp90 as a major inhibitor of apoptosis in small-cell lung cancer

The heat shock protein 90 (Hsp90) has a critical role in malignant transformation. Whereas its ability to maintain the functional conformations of mutant and aberrant oncoproteins is established, a transformation-specific regulation of the antiapoptotic phenotype by Hsp90 is poorly understood. By using selective compounds, we have discovered that small-cell lung carcinoma is a distinctive cellular system in which apoptosis is mainly regulated by Hsp90. Unlike the well-characterized antiapoptotic chaperone Hsp70, Hsp90 is not a general inhibitor of apoptosis, but it assumes this role in systems such as small-cell lung carcinoma, in which apoptosis is uniquely dependent on and effected through the intrinsic pathway, without involvement of caspase elements upstream of mitochondria or alternate pathways that are not apoptosome- channeled. These results provide important evidence for a transformation- specific interplay between chaperones in regulating apoptosis in malignant cells. © 2007 Nature Publishing Group