ADP ribosyl cyclase synthesizes the novel secondary messenger cyclic ADP ribose (cADPR) utilizing NAD as a substrate. The enzyme shares extensive sequence similarity with two lymphocyte antigens, CD38 and BST-1, which hydrolyse as well as synthesize cADPR. The crystal structure provides a model for these cell surface enzymes. Cyclase contains two spatially separated pockets composed of sequence conserved residues, suggesting that the cyclization reaction may entail use of distinct sites. The enzyme dimer encloses a cavity which may entrap the intermediate, ADP ribose.

The Wnt/Frizzled (FZD) signaling cascade is important for cell fate determination during embryonic development as well as maintaining tissue homeostasis in the adult. In addition to these physiologic roles, studies have shown that deregulation of Wnt/FZD signaling occurs during carcinogenesis. As an example, over 90% of the colorectal cancers have mutations in adenomatous polyposis coli (APC) or beta-catenin genes. In addition, hepatocellular carcinoma (HCC) is another tumor with frequent aberrant activation of beta-catenin signaling. Nuclear and/or cellular beta-catenin accumulation, a hallmark of the activated canonical Wnt/FZD signaling, has been observed in 33-67% of tumors. However, mutations of APC and/or beta-catenin genes are found only in about 20-30% of HCCs, suggesting that the predominant mechanism(s) activating Wnt/FZD signaling pathway may be different from that found in colorectal cancers. There is accumulating evidence to suggest that regulatory mechanisms other than mutations involving beta-catenin or proteins in its destruction complex, many of which involve upstream components of the Wnt/FZD cascade, are important in HCC. Furthermore, information on the target genes of Wnt/FZD signaling and their roles in hepatocarcinogenesis is limited despite the recent discovery of several candidate genes. This review focuses on the alterations of Wnt/FZD signaling pathways and their relationship to the pathogenesis of HCC. A better understanding of the precise mechanisms of altered Wnt/FZD signaling may provide new molecular targets for therapy of HCC.

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In contrast to the usual slow disease progression in myofibrillar myopathies, patients with Bag3opathy often have a rapidly progressive and more severe phenotype with a worse prognosis. We describe a Chinese patient, born to non-consanguineous parents, who first presented at age 6 with clumsy walking and difficult climbing staircase. With a history of restrictive lung disease previously diagnosed as asthma, she progressed rapidly with proximal myopathy, rigid spine and bilateral tightening of the Achilles tendons requiring surgical elongation. Hypertrophic cardiomyopathy with restrictive physiology was shown by echocardiogram. Moreover, prolonged QT interval was also noted in the patient. Family history was unremarkable yet her father was incidentally found to have prolonged QT interval. Mutation analysis with genomic DNA of the proband showed heterozygous de novo known mutation c.626C>T (p.Pro209Leu) and a germline variation c.772C>T (p.Arg258Trp) in BAG3. Her father was found to be a carrier of c.772C>T. Muscle biopsy findings were suggestive of myofibrillar myopathy on light microscopy and ultrastructural studies. To our knowledge, this is the first Chinese case of Bag3opathy so far reported.