[Show abstract][Hide abstract] ABSTRACT: Liver regeneration, following partial hepatectomy (PHx), occurs through precisely controlled and synchronized cell proliferation, in which quiescent hepatocytes undergo one to two rounds of replication, with restoration of liver mass and function. We previously demonstrated that loss of the Smad3/4 adaptor protein β-2 spectrin (β2SP) is associated with faster entry into S phase, and hepatocellular cancer formation. These observations led us to further pursue the role of β2SP in cell cycle progression in vivo. Liver regeneration studies with PHx in β2SP(+/-) mice reveal a surprising and significant decrease in liver/body weight ratio at 48 hours after PHx in β2SP(+/-) mice in comparison to wildtype mice. At 48 hours after PHx we also observe decreased levels of cyclin E (2.4-fold, P < 0.05), Cdk1 (7.2-fold, P < 0.05), cyclin A, pRb (Ser249/Thr252), proliferative cell nuclear antigen (PCNA), cyclin D1 with elevated levels of pCdk1 (Thr14) (3.6-fold, P < 0.05). Strikingly, at 24 hours elevated levels of p53 (4-fold, P < 0.05), phospho-p53 (ser15 and ser20), and p21 (200-fold, P < 0.05) persisting to 48 hours after PHx further correlated with raised expression of the DNA damage markers pChk2 (Thr68) and γH2AX (S139). However, compromised cell cycle progression with loss of β2SP is not rescued by inhibiting p53 function, and that G(2) /M phase arrest observed is independent and upstream of p53. CONCLUSION: β2SP deficiency results in dysfunctional hepatocyte cell cycle progression and delayed liver regeneration at 48 hours after PHx, which is p53-independent. β2SP loss may increase susceptibility to DNA damage, impair cell cycle progression, and ultimately lead to hepatocellular cancer.
[Show abstract][Hide abstract] ABSTRACT: Colorectal cancer (CRC) is the second leading cause of death from cancer in the United States. Aggressive research in the last decade has led to a wealth of information about this disease; for example, we now know that more than 80% of sporadic colon tumors contain mutations in the Wnt and TGFβ signaling pathways. The latest avenue of research is revealing the existence of and role for the cancer stem cell (CSC) model, which promotes the idea that malignancies originate from a small fraction of cancer cells that show self-renewal and multi- or pluripotency. The model also endorses that CSCs are capable of initiating and sustaining tumor growth. The body of evidence in favor of the CSC model is rapidly growing and includes analyses from flow cytometry of numerous CSC biomarkers, abnormal signaling pathways, symmetric division, dietary augmentation, and analysis of the behavior of these cells in spheroid culture formation. Although the incidence of death from CRC remains high, fervent research, both basic and translational, is beginning to improve patient outcomes. This paper focuses on stem cell biology in the context of CRC to help understand the mechanisms leading to tumor development and therapy resistance, with possible therapeutic indications.
[Show abstract][Hide abstract] ABSTRACT: Fulminant hepatic failure is a disease with high mortality. Prior to orthotopic liver transplantation (OLT), the mortality
rate was greater than 80%. With improved intensive care, however, several series report a survival rate of 60% (1). At present,
standard therapy is liver transplantation and approximately 6% of OLTs performed in the United States are for fulminant hepatic