The direct reprogramming of a terminally differentiated cell into another lineage using defined combinations of factors has fundamentally changed traditional concepts of the inalterability of differentiated cells. Many studies have achieved direct conversion into various cell types in recent years, and this strategy is considered to be a promising approach for inducing functional cells. Here, we review work on direct reprogramming, from the early pioneering studies to the most recent, including the discovery of novel reprogramming factors, molecular mechanisms, and strategies. We also discuss the applications of direct reprogramming and the perspectives and challenges of this novel technology.
Cell Differentiation ; Regenerative Medicine ; Transcription Factors

Pulmonary arteriovenous malformation (AVM) is a congenital vascular disease in which interventional radiologists can play both diagnostic and therapeutic roles in patient management. The diagnosis of pulmonary AVM is simple and can usually be made based on CT images. Endovascular treatment, that is, selective embolization of the pulmonary artery feeding the nidus of the pulmonary AVM, and/or selectively either the nidus or draining vein, has become a first-line treatment with advances in interventional devices. However, some vascular diseases can simulate pulmonary AVMs on CT and pulmonary angiography.This subset can confuse interventional radiologists and referring physicians. Vascular mimickers of pulmonary AVM have not been widely known and described in detail in the literature, although some of these require surgical correction, while others require regular follow-up. This article reviews the clinical and radiologic features of pulmonary AVMs and their mimickers.

Currently, various types of transarterial treatments are performed for hepatocellular carcinoma from the early to advanced stages. Its indications and efficacy have been widely investigated. However, procedure-related complications have not been updated in the literature, although new types of transarterial treatments, such as drug-eluting bead transarterial chemoembolization and transarterial radioembolization, are common in daily practice. Herein, a comprehensive literature review was carried out, and complications were organized according to the organs affected and treatment modalities.

Mammary gland development and function would not be possible without tissue-specific stem cells. The mammalian reproductive cycles of pregnancy-associated proliferation, lactational differentiation, apoptosis and remodelling following weaning may occur many times during a female's reproductive years. Such processes necessitate a population of tissue-specific stem cells that have a near unlimited capacity to generate the short-lived, differentiated breast cells. In contrast to the functional cells, breast stem cells must last throughout the life of an organism. Because of this longevity, stem cells may accumulate genetic alterations that eventually lead to cancer. Breast tumors contain a population with stem-cell characteristics. Current tumour therapy modalities target proliferative cells, and be successful in causing tumor regression. Targeting these tumor stem cells will be an important goal of future research.
Apoptosis ; Breast Neoplasms ; Breast* ; Longevity ; Mammary Glands, Human ; Neoplastic Stem Cells ; Stem Cells* ; Weaning

BACKGROUND: Parkinson disease (PD) is caused by selective cell death of dopaminergic neurons in the substantia nigra. An early onset form of PD, autosomal recessive juvenile parkinsonism has been associated with a mutation in the parkin gene. The function of parkin is known to remove misfolding proteins and protect cell death. We aimed to investigate the role of parkin against oxidative stress in neuronal cells. METHODS: Parkin knockout embryonic stem cells (PKO ES cells) were differentiated into neurons by adherent monolayer culture method. Oxidative stress was induced by the treatment of 1-methyl-4-phenylpyridinium (MPP+) in neurons derived from wild type and PKO ES cells, and cell viability was examined by MTT assay. After exposure to MPP+, Tuj1-positive cell population was compared between PKO and wild type cells by fluorescence activated cell sorter (FACS) analysis. The activated caspase3 protein level was also measured by Western blot analysis, FACS and immunocytochemistry. RESULTS: There was no difference in the efficiency of neuronal differentiation between wild type and PKO ES cells. After exposure to MPP+, no significant differences were found in cell viability and Tuj1-positive cell population between the two groups determined by MTT assay and FACS analysis, respectively. The activated caspase3 protein levels examined by Western blot analysis, FACS and immunocytochemistry were not changed in PKO cells compared with those of wild type cells after MPP+ treatment. CONCLUSION: These results suggest that PKO neuronal cells including dopaminergic neurons are not sensitive to caspase3-dependent cell death pathway during the response against MPP+-induced oxidative stress.
1-Methyl-4-phenylpyridinium ; Blotting, Western ; Cell Death ; Cell Survival ; Dopaminergic Neurons ; Embryonic Stem Cells ; Fluorescence ; Immunohistochemistry ; Neurons ; Oxidative Stress* ; Parkinson Disease ; Parkinsonian Disorders ; Substantia Nigra

Numerous hypotheses have been put forth over the years to explain the development of bipolar disorder. Of these, circadian rhythm hypotheses have gained much importance of late. While the hypothalamus-pituitary-adrenal (HPA) axis hyperactivation hypothesis and the monoamine hypothesis somewhat explain the pathogenic mechanism of depression, they do not provide an explanation for the development of mania/hypomania. Interestingly, all patients with bipolar disorder display significant disruption of circadian rhythms and sleep/wake cycles throughout their mood cycles. Indeed, mice carrying the Clock gene mutation exhibit an overall behavioral profile that is similar to human mania, including hyperactivity, decreased sleep, lowered depression-like behavior, and lower anxiety. It was recently reported that monoamine signaling is in fact regulated by the circadian system. Thus, circadian rhythm instability, imposed on the dysregulation of HPA axis and monoamine system, may in turn increase individual susceptibility for switching from depression to mania/hypomania. In addition to addressing the pathophysiologic mechanism underlying the manic switch, circadian rhythm hypotheses can explain other bipolar disorder-related phenomena such as treatment resistant depression and mixed features.
Animals ; Bipolar Disorder* ; Chronobiology Disorders ; Circadian Rhythm* ; Depression ; Depressive Disorder, Treatment-Resistant ; Humans ; Mice

Remarkable advances have been made recently in the area of liver regeneration. Even though liver regeneration after liver resection has been widely researched, new clinical applications have provided a better understanding of the process. Hepatic damage induces a process of regeneration that rarely occurs in normal undamaged liver. Many studies have concentrated on the mechanism of hepatocyte regeneration following liver damage. High mortality is usual in patients with terminal liver failure. Patients die when the regenerative process is unable to balance loss due to liver damage. During disease progression, cellular adaptations take place and the organ microenvironment changes. Portal vein embolization and the associating liver partition and portal vein ligation for staged hepatectomy are relatively recent techniques exploiting the remarkable progress in understanding liver regeneration. Living donor liver transplantation is one of the most significant clinical outcomes of research on liver regeneration. Another major clinical field involving liver regeneration is cell therapy using adult stem cells. The aim of this article is to provide an outline of the clinical approaches being undertaken to examine regeneration in liver diseases.
Cytokines/metabolism ; Embolization, Therapeutic ; Hepatectomy ; Humans ; Liver/*metabolism/pathology ; Liver Failure/therapy ; *Liver Regeneration ; Liver Transplantation ; Stem Cell Transplantation ; Stem Cells/cytology

PURPOSE: HBV infection acquired later in life elicits an inflammatory response. The quality and intensity of the response determines whether virus clears or persists. Clearance is mediated through antigen-specific cytotoxic T-cells. The immune response often precipitates cholestasis while releasing a number of inflammatory cytokines, such as tumor necrosis factor-alpha and interferon-gamma, which are known to inhibit HBV replication in vivo. Transgenic mice which replicate HBV provide a useful model for studying viral pathogenesis. We try to determine whether cholestasis, apart from inflammation, modulates HBV replication. Method: HBV-expressing female 9-wk old BALD/B6 mice matched for HBeAg titer were utilized. Cholestasis was achieved by mid-length ligation and transection of the common bile duct in anesthesized animals. Sham and ligated animals were sacrificed over at 4 h, 12 h, 24 h, 48 h, and 72 h after operation (4 animals/interval). Sera were assayed for ALT, GGT, and direct bilirubin. Histopathology was obtained. Cytokine profiles for interferons, interleukins and tumor necrosis factor were monitored by RNase protection assay. HBV replication was quantitated by measurement of HBV DNA and RNA using Southern and Northern blotting. RESULTS: Sham-operated animals remained without biochemical, pathological or serological changes. Operated animals demonstrated markedly elevated total bilirubin, ALT and GGT levels. Histologic examination showed marked periductular fibrosis and ductular proliferation and area of focal hepato cellular necrosis. Ribonuclease protection assays demon strated minimal infiltration of CD3 cells, and minimal to no migration of CD4 and CD8 cells. Interferon-gamma mRNA was not detected. TNF-alpha peaked between 1 and 3 days post surgery, but to a much lesser extent than that found in naive virus-challenged animals. Both major HBV RNA species remained unchanged during the experiment. HBV DNA production demonstrated no changes in the quantity of the relaxed circular or single-stranded intermediates for the first 2 days. However, by days 5 and 7, reduction in the quantity of viral intermediates were seen. This diminution did not appear to be due to the presence of inflammatory cytokines or CTLs (cytotoxic T lymphocytes) previously implicated in viral clearance. CONCLUSION: Whereas inflammatory cytokines and cellular immunity are essential for viral attenuation and clearance, Acute cholestasis does not appear to contribute independently to biological modulation of HBV replication.
Animals ; Bilirubin ; Blotting, Northern ; Cholestasis* ; Common Bile Duct ; Cytokines ; DNA ; Female ; Fibrosis ; Hepatitis B e Antigens ; Hepatitis B virus* ; Hepatitis B* ; Hepatitis* ; Humans ; Immunity, Cellular ; Inflammation ; Interferon-gamma ; Interferons ; Interleukins ; Ligation ; Mice ; Mice, Transgenic ; Necrosis ; Ribonucleases ; RNA ; RNA, Messenger ; T-Lymphocytes ; Tumor Necrosis Factor-alpha

The liver is the largest organ in the body; it has a complex architecture, wide range of functions and unique regenerative capacity. The growing incidence of liver diseases worldwide requires increased numbers of liver transplant and leads to an ongoing shortage of donor livers. To meet the huge demand, various alternative approaches are being investigated including, hepatic cell transplantation, artificial devices and bioprinting of the organ itself. Adult hepatocytes are the preferred cell sources, but they have limited availability, are difficult to isolate, propagate poor and undergo rapid functional deterioration in vitro. There have been efforts to overcome these drawbacks; by improving culture condition for hepatocytes, providing adequate extracellular matrix, co-culturing with extra-parenchymal cells and identifying other cell sources. Differentiation of human stem cells to hepatocytes has become a major interest in the field of stem cell research and has progressed greatly. At the same time, use of decellularized organ matrices and 3 D printing are emerging cutting-edge technologies for tissue engineering, opening up new paths for liver regenerative medicine. This review provides a compact summary of the issues, and the locations of liver support systems and tissue engineering, with an emphasis on reproducible and useful sources of hepatocytes including various candidates formed by differentiation from stem cells.
Adult ; Bioprinting ; Extracellular Matrix ; Hepatocytes ; Humans ; Incidence ; Liver Diseases ; Liver Transplantation* ; Liver* ; Liver, Artificial ; Regenerative Medicine ; Stem Cell Research ; Stem Cells ; Tissue Donors ; Tissue Engineering*

BACKGROUNDS/AIMS: Although perioperative therapies have improved greatly, pancreatectomies still often need blood transfusions. However, the morbidity from blood transfusions, the poor prognosis of blood transfused patients, high cost, and decreasing supply of blood products is accelerating transfusion-free (TF) surgery in the patients who have pacreatectomies. The aim of this study was to assess the feasibility of TF pancreatectomies for patients who are Jehovah's Witness. METHODS: We investigated the possibility of TF pancreatectomies for the Jehovah's Witness patients undergoing pancreatectomies between January 2007 and Februay 2014. There were 4 cases of Whipple's operation, 4 of pylorus-preserving pancreaticoduodenectomy, 2 of radical antegrade modular pancreatosplenectomy and 1 of laparoscopic distal pancreatectomy. All were performed by one surgeon. RESULTS: Most of the TF pancreatecomies patients received perioperative blood augmentation and intraoperative acute normovolemic hemodilution (ANH). They received no blood transfusions at any time during their hospitalization, and pre- and intra-operative data and outcomes were acceptably favorable. CONCLUSIONS: To the best of our knowledge, this report is the first successful consecutive pancreatectomy program for Jehovah's Witness not involving blood transfusion. TF pancreatectomy can be performed successfully in selected Jehovah's Witness. Postoperative prognosis and outcomes should be confirmed in follow up studies.
Blood Transfusion ; Bloodless Medical and Surgical Procedures ; Follow-Up Studies ; Hemodilution ; Hospitalization ; Humans ; Pancreatectomy* ; Pancreaticoduodenectomy ; Prognosis