Oct4 suppresses IR­induced premature senescence in breast cancer cells through STAT3- and NF­κB-mediated IL­24 production.

Breast cancer stem cells (BCSCs) are a small subpopulation of breast cancer cells that have been proposed to be a primary cause of failure of therapies, including ionizing radiation (IR). Their embryonic stem-like signature is associated with poor clinical outcome. In the present study, the function of octamer-binding transcription factor 4 (Oct4), an embryonic stem cell factor, in the resistance of BCSCs to IR was investigated. Mammosphere cells exhibited increased expression of stemness-associated genes, including Oct4 and sex­determining region Y­box 2 (Sox2), and were more resistant to IR compared with serum-cultured monolayer cells. IR­resistant MCF7 cells also exhibited significantly increased expression of Oct4. To investigate the possible involvement of Oct4 in IR resistance of breast cancer cells, cells were transfected with Oct4. Ectopic expression of Oct4 increased the clonogenic survival of MCF7 cells following IR, which was reversed by treatment with small interfering RNA (siRNA) targeting Oct4. Oct4 expression decreased phosphorylated histone H2AX (γ-H2AX) focus formation and suppressed IR­induced premature senescence in these cells. Mammosphere, IR­resistant and Oct4­overexpressing MCF7 cells exhibited enhanced phosphorylation of signal transducer and activation of transcription 3 (STAT3) (Tyr705) and inhibitor of nuclear factor κB (NF­κB), and blockade of these pathways with siRNA against STAT3 and/or specific inhibitors of STAT3 and NF­κB significantly increased IR­induced senescence. Secretome analysis revealed that Oct4 upregulated interleukin 24 (IL­24) expression through STAT3 and NF­κB signaling, and siRNA against IL­24 increased IR­induced senescence, whereas recombinant human IL­24 suppressed it. The results of the present study indicated that Oct4 confers IR resistance on breast cancer cells by suppressing IR­induced premature senescence through STAT3- and NF­κB-mediated IL­24 production.

Cardiac surgery-associated acute kidney injury.

Cardiac surgery-associated acute kidney injury (CSA-AKI) is a common and serious postoperative complication of cardiac surgery requiring cardiopulmonary bypass (CPB), and it is the second most common cause of AKI in the intensive care unit. Although the complication has been associated with the use of CPB, the etiology is likely multifactorial and related to intraoperative and early postoperative management including pharmacologic therapy. To date, very little evidence from randomized trials supporting specific interventions to protect from or prevent AKI in broad cardiac surgery populations has been found. The definition of AKI employed by investigators influences not only the incidence of CSA-AKI, but also the identification of risk variables. The advent of novel biomarkers of kidney injury has the potential to facilitate the subclinical diagnosis of CSA-AKI, the assessment of its severity and prognosis, and the early institution of interventions to prevent or reduce kidney damage. Further studies are needed to determine how to optimize cardiac surgical procedures, CPB parameters, and intraoperative and early postoperative blood pressure and renal blood flow to reduce the risk of CSA-AKI. No pharmacologic strategy has demonstrated clear efficacy in the prevention of CSA-AKI; however, some agents, such as the natriuretic peptide nesiritide and the dopamine agonist fenoldopam, have shown promising results in renoprotection. It remains unclear whether CSA-AKI patients can benefit from the early institution of such pharmacologic agents or the early initiation of renal replacement therapy.

Ret finger protein mediates Pax7-induced ubiquitination of MyoD in skeletal muscle atrophy.

Skeletal muscle atrophy results from the net loss of muscular proteins and organelles and is caused by pathologic conditions such as nerve injury, immobilization, cancer, and other metabolic diseases. Recently, ubiquitination-mediated degradation of skeletal-muscle-specific transcription factors was shown to be involved in muscle atrophy, although the mechanisms have yet to be defined. Here we report that ret finger protein (RFP), also known as TRIM27, works as an E3 ligase in Pax7-induced degradation of MyoD. Muscle injury induced by sciatic nerve transection up-regulated RFP and RFP physically interacted with both Pax7 and MyoD. RFP and Pax7 synergistically reduced the protein amounts of MyoD but not the mRNA. RFP-induced reduction of MyoD protein was blocked by proteasome inhibitors. The Pax7-induced reduction MyoD was attenuated by RFP siRNA and by MG132, a proteasome inhibitor. RFPΔR, an RFP construct that lacks the RING domain, failed to reduce MyoD amounts. RFP ubiquitinated MyoD, but RFPΔR failed to do so. Forced expression of RFP, but not RFPΔR, enhanced Pax7-induced ubiquitination of MyoD, whereas RFP siRNA blocked the ubiquitination. Sciatic nerve injury-induced muscle atrophy as well the reduction in MyoD was attenuated in RFP knockout mice. Taken together, our results show that RFP works as a novel E3 ligase in the Pax7-mediated degradation of MyoD in response to skeletal muscle atrophy.

Cardiac surgery-associated acute kidney injury.

Cardiac surgery-associated acute kidney injury (CSA-AKI) is a common and serious postoperative complication of cardiac surgery requiring cardiopulmonary bypass (CPB), and it is the second most common cause of AKI in the intensive care unit. Although the complication has been associated with the use of CPB, the etiology is likely multifactorial and related to intraoperative and early postoperative management including pharmacologic therapy. To date, very little evidence from randomized trials supporting specific interventions to protect from or prevent AKI in broad cardiac surgery populations has been found. The definition of AKI employed by investigators influences not only the incidence of CSA-AKI, but also the identification of risk variables. The advent of novel biomarkers of kidney injury has the potential to facilitate the subclinical diagnosis of CSA-AKI, the assessment of its severity and prognosis, and the early institution of interventions to prevent or reduce kidney damage. Further studies are needed to determine how to optimize cardiac surgical procedures, CPB parameters, and intraoperative and early postoperative blood pressure and renal blood flow to reduce the risk of CSA-AKI. No pharmacologic strategy has demonstrated clear efficacy in the prevention of CSA-AKI; however, some agents, such as the natriuretic peptide nesiritide and the dopamine agonist fenoldopam, have shown promising results in renoprotection. It remains unclear whether CSA-AKI patients can benefit from the early institution of such pharmacologic agents or the early initiation of renal replacement therapy.

Evaluation of a new polysulfone hemofilter for continuous renal replacement therapy.

New strategies using continuous renal replacement therapy as a tool to achieve immunomodulation in septic acute kidney injury have been proposed. The hypothesis is based on the possibility to remove inflammatory mediators and oxidants in a wide spectrum of molecular weights, thanks to new, highly permeable synthetic membranes. A new polysulfone hemofilter with high permeability and a sharp high cut-off membrane (CUREFLO™; Asahi Kasei Kuraray Medical Co., Ltd., Tokyo, Japan) has been evaluated in this study to assess IL-6 and advanced oxidation protein product removal in critically ill patients undergoing continuous renal replacement therapy. Unit performance, sieving coefficients and clearances were evaluated in fourteen patients undergoing continuous veno-venous hemofiltration and continuous veno-venous hemodialysis.

Dermatomyositis associated with hepatitis B virus-related hepatocellular carcinoma.

Dermatomyositis (DM) is an idiopathic inflammatory myopathy (IIM) with typical cutaneous manifestations. It has been proposed that DM may be caused by autoimmune responses to viral infections, and previous studies have also shown that an association between DM and malignancy. However, chronic hepatitis B virus (HBV) infection associated with DM and hepatocellular carcinoma (HCC) is rarely encountered. The authors report a case of DM and HCC in a patient with a HBV infection. A 58-year-old man presented erythematous skin rashes on a sun-exposed area of 2 year's duration, and recent proximal muscle weakness. His medical history revealed that he had a chronic HBV infection. A diagnosis of DM relies on proximal muscle weakness, elevated muscle enzymes, myopathic changes (demonstrated by electromyography), muscle biopsy evidence of myositis, and its characteristic cutaneous findings. A Liver mass in the left lobe visualized by abdominal computed tomography was confirmed histologically as HCC. This case suggests that DM associated with HCC might be caused by a HBV infection.