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Abstract Background Tumor suppressor p53 is mutated in a wide variety of human cancers and plays a critical role in anoikis, which is essential for preventing tumorigenesis. Recently, we found that a nucleolar protein, Myb-binding protein 1a (MYBBP1A), was involved in p53 activation. However, the function of MYBBP1A in cancer prevention has not been elucidated. Methods Relationships between MYBBP1A expression levels and breast cancer progression were examined using patient microarray databases and tissue microarrays. Colony formation, xenograft, and anoikis assays were conducted using cells in which MYBBP1A was either knocked down or overexpressed. p53 activation and interactions between p53 and MYBBP1A were assessed by immunoprecipitation and western blot. Results MYBBP1A expression was negatively correlated with breast cancer tumorigenesis. In vivo and in vitro experiments using the breast cancer cell lines MCF-7 and ZR-75-1, which expresses wild type p53, showed that tumorigenesis, colony formation, and anoikis resistance were significantly enhanced by MYBBP1A knockdown. We also found that MYBBP1A binds to p53 and enhances p53 target gene transcription under anoikis conditions. Conclusions These results suggest that MYBBP1A is required for p53 activation during anoikis; therefore, it is involved in suppressing colony formation and the tumorigenesis of breast cancer cells. Collectively, our results suggest that MYBBP1A plays a role in tumor prevention in the context of p53 activation.

Abstract Background Liver fibrosis is caused by chemicals or viral infection. The progression of liver fibrosis results in hepatocellular carcinogenesis in later stages. Recent studies have revealed the importance of DNA hypermethylation in the progression of liver fibrosis to hepatocellular carcinoma (HCC). However, the importance of DNA methylation in the early-stage liver fibrosis remains unclear. Methods To address this issue, we used a pathological mouse model of early-stage liver fibrosis that was induced by treatment with carbon tetrachloride (CCl4) for 2 weeks and performed a genome-wide analysis of DNA methylation status. This global analysis of DNA methylation was performed using a combination of methyl-binding protein (MBP)-based high throughput sequencing (MBP-seq) and bioinformatic tools, IPA and Oncomine. To confirm functional aspect of MBP-seq data, we complementary used biochemical methods, such as bisulfite modification and in-vitro-methylation assays. Results The genome-wide analysis revealed that DNA methylation status was reduced throughout the genome because of CCl4 treatment in the early-stage liver fibrosis. Bioinformatic and biochemical analyses revealed that a gene associated with fibrosis, secreted phosphoprotein 1 (Spp1), which induces inflammation, was hypomethylated and its expression was up-regulated. These results suggest that DNA hypomethylation of the genes responsible for fibrosis may precede the onset of liver fibrosis. Moreover, Spp1 is also known to enhance tumor development. Using the web-based database, we revealed that Spp1 expression is increased in HCC. Conclusions Our study suggests that hypomethylation is crucial for the onset of and in the progression of liver fibrosis to HCC. The elucidation of this change in methylation status from the onset of fibrosis and subsequent progression to HCC may lead to a new clinical diagnosis.

Background: Acute type A aortic dissection is treated with an emergency procedure that uses ascending aortic replacement (AAR). However, to avoid a residual dissected aorta with a false lumen, total arch replacement (TAR) is required. The frozen elephant trunk (FET) technique is a promising surgical approach that promotes false lumen obliteration in a single step. Therefore, this retrospective single-center study aimed to evaluate the operative outcomes of AAR and TAR with FET., Methods: Between 2007 and 2021, 143 patients with acute DeBakey type I aortic dissection underwent a central repair using AAR (n = 95) or TAR with FET (n = 43). All perioperative variables, the duration of all-cause mortality, and aortic events defined as dilatation of the distal aorta > 5 cm, new occurrences of aortic dissection, distal aortic surgery, and distal aortic rupture were recorded. We compared these perioperative variables and mid-term results with an additional focus on distal aortic events., Results: Patient background data did not differ between the two groups. Perioperative results for the TAR with FET group vs the AAR group showed similar operative times (306 vs 298 min, P = 0.862), but the TAR group had longer cardiopulmonary bypass times (154 vs 179 min, P < 0.001). The freedom from all-cause death for the TAR vs AAR groups using the Kaplan-Meier method was 81.9% vs 85.4% and 78.0% vs 85.4% (P = 0.407) at 1 and 3 years, respectively. Freedom from aorta-related events was 90.6% vs 97.6% and 69.3% vs 87.0% (P = 0.034) at 1 and 3 years, respectively., Conclusions: TAR with FET had comparable perioperative results to AAR in acute DeBakey type I aortic dissection and was considered a valuable method to avoid aorta-related events in the midterm., (© 2024. The Author(s).)

Surgical approaches of minimally invasive direct coronary artery bypass and left atrial appendage exclusion are different, and issues may arise in cases of concomitant surgery. Moreover, the safety of concomitant procedures has not been established. A man in his 80s with a history of stroke required minimally invasive coronary artery bypass grafting and left atrial appendage closure for the stenosis of the left anterior descending artery and atrial fibrillation. He suffered from bladder bleeding, which required early reduction of anticoagulant and antiplatelet medication. Therefore, he wished for surgical treatment. A lateral incision was necessary for left atrial appendage closure in minimally invasive surgery. We performed totally endoscopic harvest of the internal thoracic artery without a robotic system. This method allowed the incision to be made more laterally. Combining the endoscopic harvest of the internal mammary artery with left atrial appendage closure via lateral incision may be a reasonable technique., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Minimally invasive coronary artery bypass grafting is less invasive. Proximal anastomoses at the ascending aorta, in contrast, are technically difficult to perform because of the limited field of view. A man in his 60s undergoing haemodialysis required minimally invasive coronary artery bypass grafting for left anterior descending artery and circumflex arterial restenosis. We successfully performed minimally invasive coronary artery bypass grafting with a proximal graft anastomosis of the descending aorta. A thoracotomy was performed to extend the lateral approach to the descending aorta. We performed a minithoracotomy using three-dimensional endoscopy for internal thoracic artery harvesting. Endoscopic internal thoracic artery harvesting minimises incision length. The combination of endoscopic and lateral thoracotomy incisions in minimally invasive coronary artery bypass grafting enabled small and lateral thoracotomy incisions., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Stent graft collapse due to aortic dissection is an extremely rare event. Although endovascular aneurysm repair (EVAR) and thoracic endovascular aortic repair (TEVAR) are increasingly being performed, various complications can occur. We report a case of collapse of a stent graft, which was used to repair an abdominal aortic aneurysm (AAA) after TEVAR for thoracic aortic aneurysm (TAA). A 72-year-old man with a 77 mm AAA and 60 mm TAA underwent EVAR and a TEVAR 2 months later, respectively. CT performed after the TEVAR showed thoracic aorta dissection with associated AAA stent graft collapse. The graft collapsed was due to superior mesenteric artery obstruction. An emergency TEVAR was performed, and the procedure improved the collapsed graft; however, the endoleak of the AAA stent graft persisted. The AAA expanded over several days, warranting an open repair. Our case provides an insight into the cautionary indications for endovascular therapy., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Total anomalous pulmonary venous connection (TAPVC) is a rare congenital cardiac anomaly. There are a few reports of untreated TAPVC diagnosed in patients older than 60 years. Herein, we report the successful surgical treatment of TAPVC in a 70-year-old woman. A 70-year-old woman with TAPVC presented with symptoms of acute heart failure. We closed an atrial septal defect and performed tricuspid annuloplasty and commissurotomy of the pulmonary valve. Postoperative CT showed no residual shunt, and the pulmonary veins drained into the left atrium. She had an uneventful postoperative course. This report describes the case of the oldest known patient who underwent surgical treatment for TAPVC. Surviving into adulthood with little or no symptoms is uncommon in patients with TAPVC, and cases of late-onset TAPVC, such as our case, are rare. Nevertheless, close vigilance is necessary to prevent misdiagnosis in patients with this clinical presentation., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: This study aimed to examine the effect of off-pump coronary artery bypass grafting (CABG) in patients who underwent revascularization with bilateral internal thoracic arteries (ITAs)., Methods: Between January 2000 and December 2014, 499 patients underwent isolated CABG with bilateral ITAs for complete revascularization of the left coronary system at our institution. On-pump CABG was performed in 137 patients, and off-pump CABG was performed in 362 patients. We retrospectively compared the clinical outcomes and patency of the ITAs., Results: The off-pump group showed less respiratory failure and required a shorter postoperative stay than the on-pump group. The survival probability, freedom from cardiac events and early graft patency were similar in both groups. Five-year patency of the ITA anastomosed to the left anterior descending artery was significantly greater in the on-pump group than in the off-pump group (98.8% vs 91.2%, P = 0.010). The incidence of string change in the off-pump group was higher than that in the on-pump group (P = 0.017). There was no significant difference between the groups in the 5-year patency of the ITA anastomosed to the left circumflex artery (on-pump group: 93.8%, off-pump group: 91.8%; P = 0.46)., Conclusions: The early graft patency and the late patency of the ITA anastomosed to the left circumflex artery between the groups were similar, implying an equivalent quality of anastomoses. However, the patency of the ITA anastomosed to the left anterior descending artery in the off-pump group showed late deterioration, mainly because of string sign development., (© The Author 2017. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

The inner cell mass of the mouse blastocyst gives rise to the pluripotent epiblast (EPI), which forms the embryo proper, and the primitive endoderm (PrE), which forms extra-embryonic yolk sac tissues. All inner cells coexpress lineage markers such as Nanog and Gata6 at embryonic day (E) 3.25, and the EPI and PrE precursor cells eventually segregate to exclusively express Nanog and Gata6 , respectively. Fibroblast growth factor (FGF)-extracellular signal-regulated kinase (ERK) signalling is involved in segregation of the EPI and PrE lineages; however, the mechanism involved in Fgf4 regulation is poorly understood. Here, we identified Klf5 as an upstream repressor of Fgf4 Fgf4 was markedly upregulated in Klf5 knockout (KO) embryos at E3.0, and was downregulated in embryos overexpressing Klf5 Furthermore, Klf5 KO and overexpressing blastocysts showed skewed lineage specification phenotypes, similar to FGF4-treated preimplantation embryos and Fgf4 KO embryos, respectively. Inhibitors of the FGF receptor (Fgfr) and ERK pathways reversed the skewed lineage specification of Klf5 KO blastocysts. These data demonstrate that Klf5 suppresses Fgf4-Fgfr-ERK signalling, thus preventing precocious activation of the PrE specification programme., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2017. Published by The Company of Biologists Ltd.)

Objectives: We developed trans-right axillary aortic valve replacement (TAX-AVR) as a more cosmetically superior approach to minimally invasive AVR. We herein retrospectively compared the safety and invasiveness between TAX-AVR and conventional AVR (C-AVR)., Methods: TAX-AVR was performed under femorofemoral cardiopulmonary bypass. Creation of a small right axillary vertical skin incision was followed by anterolateral intercostal thoracotomy. AVR was performed using long-shafted minimally invasive instruments, a knot pusher and endoscopic assistance. From January 2007 to June 2016, 112 patients underwent TAX-AVR and 183 controls underwent first-time, isolated non-emergency C-AVR. The factors used to calculate the European System for Cardiac Operative Risk Evaluation score and Society of Thoracic Surgeons score were adopted for propensity matching. Early mortality and major adverse cardiac and cerebral events were compared. The procedural time, postoperative intensive care unit stay and hospital stay were compared as markers of invasiveness., Results: Propensity matching generated 108 matched pairs with similar backgrounds. Thirty-day mortality occurred in 0 and 1 patient in the TAX-AVR and C-AVR groups, respectively. The major adverse cardiac and cerebral events rates were not significantly different between the groups. The average aortic clamp time was longer (100 vs 94 min), but the intensive care unit stay (1.2 vs 1.8 days) and hospital stay (10.0 vs 12.5 days) were shorter in the TAX-AVR group. Postoperative blood loss, transfusion and atrial fibrillation were lower in the TAX-AVR group. The average prosthesis size was 22 mm in both groups., Conclusions: TAX-AVR is as safe as C-AVR and less invasive in terms of a shorter recovery period., (© The Author 2017. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Objectives: Totally endoscopic minimally invasive mitral valve surgery (MIMVS) is technically demanding and often performed with robotic assistance. We hypothesized that three-port video-assisted thoracic surgery (VATS) would facilitate endoscopic MIMVS and evaluated its feasibility and safety., Methods: From October 2010 to June 2016, we performed first-time MIMVS in 250 consecutive patients (122 male), with median age of 65 years (54-73 years, 25-75 percentile). The thoracic access ports comprised one small (3-5 cm) thoracotomy without a rib spreader plus two trocars (one for the endoscope and one for left-handed instruments), thus establishing triangular three-port VATS. Cannulas, an aortic clamp, and a left atrial retractor were inserted through the thoracotomy, and right-handed instruments were inserted through the remaining space. Cardiopulmonary bypass was established through a groin incision., Results: The etiology of the mitral valve lesion was myxomatous degeneration in 70% of patients, rheumatic disease in 9%, infectious endocarditis in 6%, and other conditions in 15%. Mitral valve repair was performed in 233 patients and replacement in 27. Two patients underwent conversion to replacement after attempted repair. Forty-nine patients underwent tricuspid annuloplasty, and 45 underwent the Maze procedure. One in-hospital death occurred within 30 days. Two patients developed stroke, three underwent re-exploration for bleeding, one developed low output syndrome, and one required new haemodialysis. The aortic clamp, bypass, and total operation times were 119 (94-149), 166 (134-200) and 237 (204-285) min, respectively, median (25-75%). The 5-year survival and reoperation-free rates were 98.3% ± 0.9% and 96.9% ± 1.2%, respectively., Conclusions: Three-port endoscopic MIMVS appears reproducible and safe., (© The Author 2017. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Pluripotency is maintained in mouse embryonic stem (ES) cells and is induced from somatic cells by the activation of appropriate transcriptional regulatory networks. Krüppel-like factor gene family members, such as Klf2, Klf4 and Klf5, have important roles in maintaining the undifferentiated state of mouse ES cells as well as in cellular reprogramming, yet it is not known whether other Klf family members exert self-renewal and reprogramming functions when overexpressed. In this study, we examined whether overexpression of any representative Klf family member, such as Klf1-Klf10, would be sufficient for the self-renewal of mouse ES cells. We found that only Klf2, Klf4, and Klf5 produced leukemia inhibitory factor (LIF)-independent self-renewal, although most KLF proteins, if not all, have the ability to occupy the regulatory regions of Nanog, a critical Klf target gene. We also examined whether overexpression of any of Klf1-Klf10 would be sufficient to convert epiblast stem cells into a naïve pluripotent state and found that Klf5 had such reprogramming ability, in addition to Klf2 and Klf4. We also delineated the functional domains of the Klf2 protein for LIF-independent self-renewal and reprogramming. Interestingly, we found that both the N-terminal transcriptional activation and C-terminal zinc finger domains were indispensable for this activity. Taken together, our comprehensive analysis provides new insight into the contribution of Klf family members to mouse ES self-renewal and cellular reprogramming.

Objectives: Few studies have reported the free right internal thoracic artery (RITA) being used in an aorto-coronary fashion. This study aimed to evaluate the free RITA with modified proximal anastomosis in an aorto-coronary fashion., Methods: Between January 2000 and December 2012, 282 patients underwent coronary artery bypass grafting with bilateral internal thoracic arteries for complete revascularization of the left coronary system at our institution. The left internal thoracic artery (LITA) was anastomosed to the left anterior descending artery (LAD) and the RITA was anastomosed to the left circumflex branches (LCX). The RITA was used as a free graft in 213 patients (free group) and as an in situ graft in 69 patients (in situ group). Proximal anastomosis of the free RITA onto the ascending aorta was performed in two different ways. We compared early and late results and graft patency of the free RITA with those of the in situ RITA retrospectively., Results: The numbers of anastomoses per patient and anastomoses of the RITA were larger in the free group than in the in situ group (P < 0.01). There was no significant difference in postoperative survival between the groups (free group: 93.3% vs in situ group: 90.0%, P = 0.82). The 5-year patency of the free RITA was higher than that of the in situ RITA (97.0 vs 80.3%, P = 0.01). The 5-year patency of the free RITA was comparable with that of the in situ LITA anastomosed to the LAD (97.0 vs 92.9%, P = 0.28)., Conclusions: The free RITA anastomosed to the LCX might have better late patency than the in situ RITA. The free RITA with modified proximal anastomosis in an aorto-coronary fashion enables complete revascularization of the left coronary system with the in situ LITA to the LAD., (© The Author 2015. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Estrogens are effective in the treatment of prostate cancer; however, the effects of estrogens on prostate cancer are enigmatic. In this study, we demonstrated that estrogen (17β-estradiol [E2]) has biphasic effects on prostate tumor growth. A lower dose of E2 increased tumor growth in mouse xenograft models using DU145 and PC-3 human prostate cancer cells, whereas a higher dose significantly decreased tumor growth. We found that anchorage-independent apoptosis in these cells was inhibited by E2 treatment. Similarly, in vivo angiogenesis was suppressed by E2. Interestingly, these effects of E2 were abolished by knockdown of either estrogen receptor β (ERβ) or Krüppel-like zinc finger transcription factor 5 (KLF5). Ιn addition, E2 suppressed KLF5-mediated transcription through ERβ, which inhibits proapoptotic FOXO1 and proangiogenic PDGFA expression. Furthermore, we revealed that a nonagonistic ER ligand GS-1405 inhibited FOXO1 and PDGFA expression through the ERβ-KLF5 pathway and regulated prostate tumor growth without ERβ transactivation. Therefore, these results suggest that E2 biphasically modulates prostate tumor formation by regulating KLF5-dependent transcription through ERβ and provide a new strategy for designing ER modulators, which will be able to regulate prostate cancer progression with minimal adverse effects due to ER transactivation., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)

A 50-year old woman presented with arterial thrombosis in the right leg. Echocardiography revealed a mobile left atrial thrombus and severe mitral stenosis. She underwent a left atrial thrombectomy, the maze procedure and mitral valve plasty. Anterior and posterior mitral leaflets arose directly from the anterior papillary muscle, and from the posterior papillary muscle intervened by short chordae. This suggested a hammock mitral valve. A posterior papillary muscle division and commissurotomy were performed. The anterior leaflet was divided off the anterior papillary muscle, then extended by a triangular-shaped autologous pericardial patch and apically reattached. The postoperative mean pressure gradient of the mitral valve was 2.2 mmHg, and there was no regurgitation. The patient was in NYHA Class 1 and in sinus rhythm, 14 months after the operation., (© The Author 2015. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

The 5S ribonucleoprotein particle (RNP) complex, consisting of RPL11, RPL5, and 5S rRNA, is implicated in p53 regulation under ribotoxic stress. Here, we show that the 5S RNP contributes to p53 activation and promotes cellular senescence in response to oncogenic or replicative stress. Oncogenic stress accelerates rRNA transcription and replicative stress delays rRNA processing, resulting in RPL11 and RPL5 accumulation in the ribosome-free fraction, where they bind MDM2. Experimental upregulation of rRNA transcription or downregulation of rRNA processing, mimicking the nucleolus under oncogenic or replicative stress, respectively, also induces RPL11-mediated p53 activation and cellular senescence. We demonstrate that exogenous expression of certain rRNA-processing factors rescues the processing defect, attenuates p53 accumulation, and increases replicative lifespan. To summarize, the nucleolar-5S RNP-p53 pathway functions as a senescence inducer in response to oncogenic and replicative stresses., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Breast cancer is the most common malignancy among women and has poor survival and high recurrence rates for aggressive metastatic disease. Notably, triple-negative breast cancer (TNBC) is a highly aggressive cancer and there is no preferred agent for TNBC therapy. In this study, we show that a novel agent, 2-(4-hydroxy-3-methoxyphenyl)-benzothiazole (YL-109), has ability to inhibit breast cancer cell growth and invasiveness in vitro and in vivo. In addition, YL-109 repressed the sphere-forming ability and the expression of stem cell markers in MDA-MB-231 mammosphere cultures. YL-109 increased the expression of carboxyl terminus of Hsp70-interacting protein (CHIP), which suppresses tumorigenic and metastatic potential of breast cancer cells by inhibiting the oncogenic pathway. YL-109 induced CHIP transcription because of the recruitment of the aryl hydrocarbon receptor (AhR) to upstream of CHIP gene in MDA-MB-231 cells. Consistently, the antitumor effects of YL-109 were depressed by CHIP or AhR knockdown in MDA-MB-231 cells. Taken together, our findings indicate that a novel agent YL-109 inhibits cell growth and metastatic potential by inducing CHIP expression through AhR signaling and reduces cancer stem cell properties in MDA-MB-231 cells. It suggests that YL-109 is a potential candidate for breast cancer therapy.

Objectives: Mitral valve repair is challenging when enough pliable mitral leaflets and chordae are not left intact because of extensive infective endocarditis or chronic sclerotic degeneration. For those cases, we developed a simple method to reconstruct defective leaflets and chordae en bloc with a piece of pericardium, and the mid-term results were evaluated., Methods: From January 2009 to November 2013, 25 patients with the mean age of 63 (range 20-88) years underwent this operation. The causes of mitral regurgitation were infective endocarditis in 8, sclerotic degeneration in 8, leaflet dehiscence of previous repair in 2, mitral annular calcification in 3, rheumatic in 2 and congenital in 2. After complete debridement of infected or consolidated tissue, we reconstructed defective mitral leaflets and chordae en bloc with a piece of glutaraldehyde-treated autologous pericardium. To substitute posterior leaflet and chordae, the pericardium was trimmed into a narrow pentagonal shape. The pointed end was attached directly to the corresponding papillary muscle, basal side edges to remnant leaflets on both sides, and the base to the annulus. For anterior leaflet, the pericardium was trimmed into a triangular shape if the lesion was confined in the left or right half or into a double-triangle shape if the lesion involved whole anterior leaflet. The summit of triangle was fixed to corresponding papillary muscle, and the base to remnant anterior leaflet, thus reconstructing coaptation zone and chordae seamlessly., Results: There was no hospital death, and mitral regurgitation at discharge was none or trivial in all patients. During 1-59 months (mean 12.7) of complete follow-up, death, infection or hemolysis was not observed. In one patient, mitral regurgitation recurred 8 months postoperatively because the fixation suture of the pericardium to the papillary muscle broke. The valve was re-repaired with re-attaching the leg of the pericardium. Regurgitation was less than moderate in all other patients. One patient with rheumatic lesion who underwent anterior leaflet repair and Maze operation suffered minor stroke 1 month postoperatively but fully recovered., Conclusions: Seamless reconstruction of leaflets and chordae with pericardium seemed promising to repair extensively destructed mitral valve., (© The Author 2014. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Ribosome biosynthesis is a major intracellular energy-consuming process. We previously identified a nucleolar factor, nucleomethylin (NML), which regulates intracellular energy consumption by limiting rRNA transcription. Here, we show that, in livers of obese mice, the recruitment of NML to rRNA gene loci is increased to repress rRNA transcription. To clarify the relationship between obesity and rRNA transcription, we generated NML-null (NML-KO) mice. NML-KO mice show elevated rRNA level, reduced ATP concentration, and reduced lipid accumulation in the liver. Furthermore, in high-fat-diet (HFD)-fed NML-KO mice, hepatic rRNA levels are not decreased. Both weight gain and fat accumulation in HFD-fed NML-KO mice are significantly lower than those in HFD-fed wild-type mice. These findings indicate that rRNA transcriptional activation promotes hepatic energy consumption, which alters hepatic lipid metabolism. Namely, hepatic rRNA transcriptional repression by HFD feeding is essential for energy storage., (Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.)

Breast cancer is the most frequently diagnosed cancer and the leading cause of death by cancer among females worldwide. An overwhelming majority of these deaths is because of metastasis. Estrogen stimulates and promotes growth of breast tumors, whereas transforming growth factor-beta (TGF-β) signaling promotes invasion and metastasis. We previously reported that estrogen and estrogen receptor alpha (ERα) suppressed breast cancer metastasis by inhibiting TGF-β signaling, whereas antiestrogens that suppress breast cancer growth, such as the selective ER modulator tamoxifen (TAM) or the pure antiestrogen fulvestrant (ICI 182,780), cannot suppress TGF-β signaling or breast cancer invasiveness. Therefore, we predicted that a compound that inhibits TGF-β signaling but does not facilitate ERα signaling would be ideal for suppressing breast cancer invasiveness and growth. In the present study, we identified an ideal candidate compound, N-23. Like estrogen, N-23 strongly decreased expression of TGF-β/Smad target gene plasminogen activator inhibitor-1 (PAI-1), but it did not increase the expression of ERα target gene pS2. While estrogen decreased the levels of phosphorylated Smad2 and Smad3, N-23 had no effect. In addition, TGF-β-dependent recruitment of Smad3 to the PAI-1 gene promoter was inhibited in the presence of estrogen or N-23. We also investigated the effects of N-23 on proliferation, migration, and invasion of breast cancer cells. In contrast to estrogen, N-23 inhibited the cellular proliferation of breast cancer cells. Moreover, we showed that N-23 suppressed the migration and invasion of breast cancer cells to the same extent as by estrogen. Taken together, our findings indicate that N-23 may be a candidate compound that is effective in inhibiting breast cancer progression.

Tetramerization of p53 is crucial to exert its biological activity, and nucleolar disruption is sufficient to activate p53. We previously demonstrated that nucleolar stress induces translocation of the nucleolar protein MYBBP1A from the nucleolus to the nucleoplasm and enhances p53 activity. However, whether and how MYBBP1A regulates p53 tetramerization in response to nucleolar stress remain unclear. In this study, we demonstrated that MYBBP1A enhances p53 tetramerization, followed by acetylation under nucleolar stress. We found that MYBBP1A has two regions that directly bind to lysine residues of the p53 C-terminal regulatory domain. MYBBP1A formed a self-assembled complex that provided a molecular platform for p53 tetramerization and enhanced p300-mediated acetylation of the p53 tetramer. Moreover, our results show that MYBBP1A functions to enhance p53 tetramerization that is necessary for p53 activation, followed by cell death with actinomycin D treatment. Thus, we suggest that MYBBP1A plays a pivotal role in the cellular stress response.

We present a 76-year-old man who underwent two lung resections for metastases originating from cancer of the Ampulla duodeni, 9 years-after pancreaticoduodenectomy with lymphadenectomy. Pancreaticoduodenectomy was performed in 2002; histological examination of the original tumor revealed a stage III tubular adenocarcinoma (pT3, N0, M0). Repetitive lung resection was performed in 2007 (left S8) and 2011 (right S1 and extirpation of a pericardial cyst). Although rarely performed, resection of bilateral pulmonary metastases from carcinoma of the papilla of Vater was done to improve the patient's chances for longterm survival.

The TGF-β superfamily comprises pleiotropic cytokines that regulate SMAD and non-SMAD signaling. TGF-β-SMAD signal transduction is known to be involved in tissue fibrosis, including renal fibrosis. Here, we found that 1,25-dihydroxyvitamin D3-bound [1,25(OH)2D3-bound] vitamin D receptor (VDR) specifically inhibits TGF-β-SMAD signal transduction through direct interaction with SMAD3. In mouse models of tissue fibrosis, 1,25(OH)2D3 treatment prevented renal fibrosis through the suppression of TGF-β-SMAD signal transduction. Based on the structure of the VDR-ligand complex, we generated 2 synthetic ligands. These ligands selectively inhibited TGF-β-SMAD signal transduction without activating VDR-mediated transcription and significantly attenuated renal fibrosis in mice. These results indicate that 1,25(OH)2D3-dependent suppression of TGF-β-SMAD signal transduction is independent of VDR-mediated transcriptional activity. In addition, these ligands did not cause hypercalcemia resulting from stimulation of the transcriptional activity of the VDR. Thus, our study provides a new strategy for generating chemical compounds that specifically inhibit TGF-β-SMAD signal transduction. Since TGF-β-SMAD signal transduction is reportedly involved in several disorders, our results will aid in the development of new drugs that do not cause detectable adverse effects, such as hypercalcemia.