The objective of this nationwide case‐control study was to evaluate the risk of specific malignancy in diabetic patients who received thiazolidinediones (TZDs). A total of 606,583 type 2 diabetic patients, age 30 years and above, without a history of cancer were identified from the Taiwan National Health Insurance claims database during the period between January 1 2000 and December 31 2000. As of December 31 2007, patients with incident cancer of liver, colorectal, lung, and urinary bladder were included as cases and up to four age‐ and sex‐matched controls were selected by risk‐set sampling. Logistic regression models were applied to estimate the odds ratio (OR) and 95% confidence interval (CI) between TZDs and cancer incidence. A total of 10,741 liver cancer cases, 7,200 colorectal cancer cases, and 70,559 diabetic controls were included. A significantly lower risk of liver cancer incidence was found for any use of rosiglitazone (OR: 0.73, 95% CI: 0.65‐0.81) or pioglitazone (OR: 0.83, 95% CI: 0.72‐0.95), respectively. The protective effects were stronger for higher cumulative dosage and longer duration. For colorectal cancer, rosiglitazone, but not pioglitazone, was associated with a significantly reduced risk (OR: 0.86; 95% CI: 0.76‐0.96). TZDs were not associated with lung and bladder cancer incidence, although a potential increased risk for bladder cancer with pioglitazone use ≥3 years could not be excluded (OR: 1.56; 95% CI: 0.51‐4.74). Conclusion: The use of pioglitazone and rosiglitazone is associated with a decreased liver cancer incidence in diabetic patients. The effects on occurrence of specific cancer types may be different for pioglitazone and rosiglitazone. (HEPATOLOGY 2012;)

Throughout its complex morphogenesis, the vertebrate skull must at once protect the brain and expand to accommodate its growth. A key structural adaptation that allows this dual role is the separation of the bony plates of the skull with sutures, fibrous joints that serve as growth centers and allow the calvarial bones to expand as the brain enlarges. Craniosynostosis, the premature fusion of one or more calvarial bones with consequent abnormalities in skull shape, is a common developmental anomaly that disrupts this process. We found previously that a single amino acid substitution in the homeodomain of the human MSX2 gene is associated with the autosomal dominant disorder craniosynostosis, Boston type. This mutation enhances the affinity of Msx2 for its target sequence, suggesting that the mutation acts by a dominant positive mechanism. Consistent with this prediction, we showed that general overexpression of Msx2 under the control of the broadly expressed CMV promoter causes the calvarial bones to invade the sagittal suture. Here we use tissue-specific overexpression of Msx2 within the calvarial sutures to address the developmental mechanisms of craniosynostosis and skull morphogenesis. We demonstrate that a segment of the Msx2 promoter directs reporter gene expression to subsets of cells within the sutures. In late embryonic and neonatal stages, this promoter is expressed in undifferentiated mesenchymal cells medial to the growing bone. By P4, promoter activity is reduced in the suture, exhibiting a punctate pattern in undifferentiated osteoblastic cells in the outer margin of the osteogenic front. Overexpression of Msx2 under the control of this promoter is sufficient to enhance parietal bone growth into the sagittal suture by P6. This phenotype is preceded by an increase in both the number and the BrdU labeling of osteoblastic cells in the osteogenic fronts of the calvarial bones. These findings suggest that an important early event in MSX2-mediated craniosynostosis in humans is a transient retardation of osteogenic cell differentiation in the suture and a consequent increase in the pool of osteogenic cells.

The coordinate growth of the brain and skull is achieved through a series of interactions between the developing brain, the growing bones of the skull, and the fibrous joints, or sutures, that unite the bones. These interactions couple the expansion of the brain to the growth of the bony plates at the sutures. Craniosynostosis, the premature fusion of the bones of the skull, is a common birth defect (1 in 3000 live births) that disrupts coordinate growth and often results in profoundly abnormal skull shape. Individuals affected with Boston-type craniosynostosis, an autosomal dominant disorder, bear a mutated copy ofMSX2, a homeobox gene thought to function in tissue interactions. Here we show that expression of the mouse counterpart of this mutant gene in the developing skulls of transgenic mice causes craniosynostosis and ectopic cranial bone. These mice provide a transgenic model of craniosynostosis as well as a point of entry into the molecular mechanisms that coordinate the growth of the brain and skull.

Hepatitis B virus (HBV) X gene encodes a multifunctional protein that can regulate cellular signaling pathways, interact with cellular transcription factors, and induce hepatocellular oncogenesis. In spite of its diverse activities, the precise role of the X protein in the viral life cycle of HBV remains unclear. To investigate this question, we have produced transgenic mice that carry either the wild-type HBV genome or a mutated HBV genome incapable of expressing the 16.5-kDa X protein. Our results indicate that while the X protein is not absolutely essential for HBV replication or its maturation in transgenic mice, it can enhance viral replication, apparently by activating viral gene expression. These results demonstrate a transactivation role of the X protein in HBV replication in transgenic mice.Hepatitis B virus (HBV) is a human pathogen that can cause acute and chronic hepatitis and also hepatocellular carcinoma. This virus is a small DNA virus that belongs to the hepadnavirus family. This family contains a group of closely related viruses that infect primarily the livers of their respective animal hosts. The HBV genome is a 3.2-kb DNA molecule that contains four genes named C, S, P, and X (13). The C gene codes for the core protein and the serum e antigen, the S gene codes for three related viral envelope proteins known as surface antigens, the P gene codes for the viral DNA polymerase, and the X gene codes for a 16.5-kDa protein.The HBV X protein has many activities in vitro (38). It can enhance the expression of RNA polymerase I-, II-, and IIIdependent genes through multiple pathways (31,33,35,36). The X protein does not bind to DNA directly. However, it can bind to different transcription factors, including AP1, AP2, ATF-2, CREB, TBP, TFIIB, and TFIIH, to modify their activities (2,16,21,23,26,30). It also binds to RBP5, a subunit of all three mammalian RNA polymerases (7,21), to the proteasome, p53, a DNA repair protein UV-DDB, and a member of the human voltage-dependent ion channel family HVDAC3 (3,12,17,27,37). The X protein can also activate the ras-rafmitogen-activated protein kinase signaling pathway and the NF-B pathway (4,9,19,22,24,34). These activities are thought to be important for the X protein to induce oncogenesis and apoptosis in cell cultures and in transgenic mice (8,10,18,25,32).In spite of its diverse activities in cultured cells, the role of the X protein in the HBV life cycle remains a mystery. To investigate its possible functions, we produced transgenic mice that carried either the wild-type HBV genome or a mutated HBV genome that expresses all viral proteins except the X protein. The HBV genomic DNA fragment used for producing the transgenic mice is illustrated in Fig. 1. This DNA fragment starts from nucleotide (nt) 1043, which is located upstream of the ENI enhancer and the X promoter, and terminates at nt 1987, which is located downstream of the unique poly(A) site. This DNA fragment is approximately 1.3 times the size of the HBV genome and has been used to generate transgen...

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