Targeting the Mdm2 oncoprotein by drugs has the potential of re-establishing p53 function and tumor suppression. However, Mdm2-antagonizing drug candidates, e. g. Nutlin-3a, often fail to abolish cancer cell growth sustainably. To overcome these limitations, we inhibited Mdm2 and simultaneously a second negative regulator of p53, the phosphatase Wip1/PPM1D. When combining Nutlin-3a with the Wip1 inhibitor GSK2830371 in the treatment of p53-proficient but not p53-deficient cells, we observed enhanced phosphorylation (Ser 15) and acetylation (Lys 382) of p53, increased expression of p53 target gene products, and synergistic inhibition of cell proliferation. Surprisingly, when testing the two compounds individually, largely distinct sets of genes were induced, as revealed by deep sequencing analysis of RNA. In contrast, the combination of both drugs led to an expression signature that largely comprised that of Nutlin-3a alone. Moreover, the combination of drugs, or the combination of Nutlin-3a with Wip1-depletion by siRNA, activated p53-responsive genes to a greater extent than either of the compounds alone. Simultaneous inhibition of Mdm2 and Wip1 enhanced cell senescence and G2/M accumulation. Taken together, the inhibition of Wip1 might fortify p53-mediated tumor suppression by Mdm2 antagonists.

In children with CMV abdominal pain, eyelid swelling, skin rash, fatigue and thrombocytopenia were more common. In children with EBV values of transaminases declined significantly faster.

CYP1A2 -163A/A genotype influence carbamazepine pharmacokinetics. In addition to sex and total carbamazepine daily dose, -163C > A CYP1A2 polymorphism should be considered as a predictor of carbamazepine clearance.

Rosai-Dorfman disease is a rare benign histiocytic disorder that arises predominantly in lymph nodes with fever and malaise, but can affect various organs, with or without lymphadenopathy. Solitary extranodal skeletal lesions are extremely rare. Herein, we describe a case of isolated disease of thoracic spine, with vertebral body fracture. A 14-year-old girl presented with cervical back pain for about one month as the only symptom. There was no lymphadenopathy. Results of laboratory tests were within reference ranges. The radiological examinations revealed collapse, osteolytic lesion and compressive fracture, which reduced vertical diameter of C4 vertebral body. The patient made a complete recovery after a limited C4 laminectomy, spondylodesis C3/C5 vertebra and biopsy of the lesion. Histologically, nonspecific cellular milieu and atypical histiocytic proliferation with emperipolesis, with CD68 and S100 positivity, confirmed a diagnosis of Rosai-Dorfman disease. Isolated extranodal skeletal Rosai-Dorfman disease should be considered among the differential diagnoses of similar changes, such as Langerhans cell histiocytosis, Erdheim-Cheister disease, eosinophilic granuloma, osteomyelitis, metastasis and lymphoma.

Carbamazepine exhibits significant inter-individual variability in its efficacy