第2卷，第1期

Research misconduct in the field of medical science is on the rise, according to two 2011 reports by Gautam Naik, a science journalist for the Wall Street Journal. He reported that the number of retracted scientific journal articles had surged by 15-fold within the last decade, while the number of publications had risen only 44%. A further analysis within the same period showed that the rise in the fraud-related retractions far exceeded the retractions due to innocent errors. Naik pointed out that, although part of the surge can be attributed to more vigilant journal editors, as well as their advanced validation methods, competitive researchers vying for the stagnant budget and a publication environment preferring positive results may be the major factors driving this trend. Naik further observed: "Science is based on trust, and most researchers accept findings published in peer-reviewed journals. The studies spur others to embark on related avenues of research, so if one paper is later found to be tainted, an entire edifice of work comes into doubt. Millions of dollars' worth of private and government funding may go to waste, and, in the case of medical science, patients can be put at risk." It is apparent that the vital interests of the research community, as well as the trust of the general public, who are both the sponsors and beneficiaries of the scientific progress, are at stake. To turn the tide, the NIH and the journals Nature and Science co-sponsored a workshop in June 2014 to propose new Principles and Guidelines for reporting preclinical research to ensure the transparency and durability of the scientific findings (http://www.nih.gov/about/reportingpreclinical-research.htm). Representatives from more than 30 basic/preclinical science journals participated and co-sponsored the proposed new guidelines. These newly proposed publishing guidelines call for better disclosure of information related to the experimental design, sample collection and statistical data analysis, as well as for better descriptions of the reagents and study materials, which are expected to be shared among peer researchers after the publication. Although the implementation of these guidelines remains challenging, this is a major step forward, with many journal publishers united to raise the standards of scientific publication.

1123

We devoted this short piece to highlight one recent article published in Science, which revisited the anti-cancer efficacy of high-dose vitamin C. Using isogeneic KRAS-and BRAF-mutated colorectal cell lines, the authors were able to demonstrate selective antitumor effects among the KRAS-and BRAF-mutated cells in culture and in ex-planted animal models treated with high-dose vitamin C. Their elegant and in-depth studies unequivocally tied the tumoricidal effect to the heightened sensitivity of the mutant cells due to the increased vitamin C uptake, leading to lethal accumulation of reactive oxygen species (ROS). This report will certainly rekindle enthusiasm in revisiting the case of vitamin C, pushing for more definitive cancer therapy trials.

1219

Ras homolog gene family, member A (RhoA) is a small GTPase that plays critical roles in several essential cell functions, such as migration, adhesion, proliferation, and gene expression. RhoA switches between a GTP-bound active form and a GDP-bound inactive form. The activated RhoA directly interacts with its downstream effectors, such as Rho kinase (ROCK) to regulate actomyosin dynamics, or mDia1 to control stress fiber and filopodia formation. The activity of RhoA is primarily regulated by guanine nucleotide exchange factors (GEFs), GTPase-activating protein (GAP), and guanine nucleotide-dissociation inhibitors (GDIs).

1344

Since the identification of matrix metalloproteinases (MMPs), a family of zinc-dependent endopeptidases, as being a driving factor for cancer progression and patient prognosis, MMPs have been studied extensively. Although early programs targeting MMPs were largely unsuccessful in clinical trials, they remain a viable and highly desirable therapeutic target based on preclinical studies and their role in disease progression. As information regarding the structure and function of these proteinases is compiled and biotechnology evolves, tools to develop better inhibitors are within our grasp. Improved methods for high throughput screening and in silico drug design programs have identified compounds which are highly potent, have high binding affinities, and exhibit favorable pharmacokinetic profiles. More recently, advances in drug delivery methods or compounds which bind outside the active site have brought new light to the field. In this review, we highlight the role of MMPs in cancer, clinical trials for MMP inhibitors, and novel approaches to targeting MMPs in cancer.

1260

Hepatitis C virus (HCV) is a global health burden with an estimated 170-200 million peoples chronically infected worldwide. HCV infection remains as an independent risk factor for chronic hepatitis, liver cirrhosis, hepatocellular carcinoma, and a major reason for liver transplantation. Discovery of direct acting antiviral (DAA) drugs have shown promising results with more than 90% success rate in clearing the HCV RNA in patients, although long-term consequences remain to be evaluated. microRNAs (miRNAs) are important players in establishment of HCV infection and target crucial host cellular factors needed for productive HCV replication and augmented cell growth. Altered expression of miRNAs is involved in the pathogenesis associated with HCV infection by controlling signaling pathways such as immune response, proliferation and apoptosis. miRNA is emerging as a means of communication between various cell types inside the liver. There is likely possibility of developing circulating miRNAs as biomarkers of disease progression and can also serve as diagnostic tool with potential of early therapeutic intervention in HCV associated end stage liver disease. This review focuses on recent studies highlighting the contribution of miRNAs in HCV life cycle and their coordinated regulation in HCV mediated liver disease progression.

1241

Approximately 10 years ago, the Wnt signaling pathway effector TCF7L2 (ZTCF-4) was recognized as a type 2 diabetes (T2D) risk gene through a genome wide association study (GWAS). As the correlation between TCF7L2 polymorphisms and T2D susceptibility has been reproducibly observed by numerous follow-up investigations among different ethnic groups, great efforts have been made to explore the function of TCF7L2 in metabolic organs including the pancreas, liver and adipose tissues. Although these explorations have enriched our general knowledge on the Wnt signaling cascade in metabolic homeostasis, studies conducted to date have also generated controversial suggestions. Here I will provide a brief review on the Wnt signaling pathway as well as the milestone GWAS discovery and the follow-up studies. I will then discuss the two different opinions on the correlation between TCF7L2 variants and T2D risk, a gain-of-function event versus a loss-of-function event. This will be followed by summarizing the relevant investigations on the metabolic function of hepatic TCF7L2 and presenting our view on the discrepancy and perspectives.

1185

Current reconstructive approaches to large craniofacial skeletal defects are often complicated and challenging. Critical-sized defects are unable to heal via natural regenerative processes and require surgical intervention, traditionally involving autologous bone (mainly in the form of nonvascularized grafts) or alloplasts. Autologous bone grafts remain the gold standard of care in spite of the associated risk of donor site morbidity. Tissue engineering approaches represent a promising alternative that would serve to facilitate bone regeneration even in large craniofacial skeletal defects. This strategy has been tested in a myriad of iterations by utilizing a variety of osteoconductive scaffold materials, osteoblastic stem cells, as well as osteoinductive growth factors and small molecules. One of the major challenges facing tissue engineers is creating a scaffold fulfilling the properties necessary for controlled bone regeneration. These properties include osteoconduction, osteoinduction, biocompatibility, biodegradability, vascularization, and progenitor cell retention. This review will provide an overview of how optimization of the aforementioned scaffold parameters facilitates bone regenerative capabilities as well as a discussion of common osteoconductive scaffold materials.

1311

One of the simplest models for examining the interplay between bone formation and resorption is the junction between the cranial bones. Although only roughly a quarter of patients diagnosed with craniosynostosis have been linked to known genetic disturbances, the molecular mechanisms elucidated from these studies have provided basic knowledge of bone homeostasis. This work has translated to methods and advances in bone tissue engineering. In this review, we examine the current knowledge of cranial suture biology derived from human craniosynostosis syndromes and discuss its application to regenerative medicine.

1226

Osteoarthritis (OA) is the most common form of joint disease and the leading cause of chronic disability in middle-aged and older populations. The development of diseasemodifying therapy for OA currently faces major obstacles largely because the regulatory mechanisms for the function of joint tissue cells remain unclear. Previous studies have found that the alterations in gene expression of specific transcription factors (TFs), pro-or antiin flammatory cytokines, matrix proteinases and extracellular matrix (ECM) proteins in articular cartilage may be involved in the development of OA. However, the regulatory mechanisms for the expression of those genes in OA chondrocytes are largely unknown. The recent advances in epigenetic studies have shed light on the importance of epigenetic regulation of gene expression in the development of OA. In this review, we summarize and discuss the recent studies on the regulatory roles of various epigenetic mechanisms in the expression of genes for specific TFs, cytokines, ECM proteins and matrix proteinases, as well the significance of these epigenetic mechanisms in the pathogenesis of OA.

1211

Due to a blood supply shortage, articular cartilage has a limited capacity for selfhealing once damaged. Articular chondrocytes, cartilage progenitor cells, embryonic stem cells, and mesenchymal stem cells are candidate cells for cartilage regeneration. Significant current attention is paid to improving chondrogenic differentiation capacity; unfortunately, the potential chondrogenic hypertrophy of differentiated cells is largely overlooked. Consequently, the engineered tissue is actually a transient cartilage rather than a permanent one. The development of hypertrophic cartilage ends with the onset of endochondral bone formation which has inferior mechanical properties. In this review, current strategies for inhibition of chondrogenic hypertrophy are comprehensively summarized; the impact of cell source options is discussed; and potential mechanisms underlying these strategies are also categorized. This paper aims to provide guidelines for the prevention of hypertrophy in the regeneration of cartilage tissue. This knowledge may also facilitate the retardation of osteophytes in the treatment of osteoarthritis.

1181

Sustained, high level transgene expression in mammalian cells is desired in many cases for studying gene functions. Traditionally, stable transgene expression has been accomplished by using retroviral or lentiviral vectors. However, such viral vector-mediated transgene expression is often at low levels and can be reduced over time due to low copy numbers and/or chromatin remodeling repression. The piggyBac transposon has emerged as a promising nonviral vector system for efficient gene transfer into mammalian cells. Despite its inherent advantages over lentiviral and retroviral systems, piggyBac system has not been widely used, at least in part due to their limited manipulation flexibilities. Here, we seek to optimize piggyBac-mediated transgene expression and generate a more efficient, user-friendly piggyBac system. By engineering a panel of versatile piggyBac vectors and constructing recombinant adenoviruses expressing piggyBac transposase (PBase), we demonstrate that adenovirus-mediated PBase expression significantly enhances the integration efficiency and expression level of transgenes in mesenchymal stem cells and osteosarcoma cells, compared to that obtained from co-transfection of the CMV-PBase plasmid. We further determine the drug selection timeline to achieve optimal stable transgene expression. Moreover, we demonstrate that the transgene copy number of piggyBac-mediated integration is approximately 10 times higher than that mediated by retroviral vectors. Using the engineered tandem expression vector, we show that three transgenes can be simultaneously expressed in a single vector with high efficiency. Thus, these results strongly suggest that the optimized piggyBac system is a valuable tool for making stable cell lines with sustained, high transgene expression.

1154