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A superfluid helium insert was developed for cryogenic microscopy of millimeter-sized specimens. An optical-interferometric position sensor, cryogenic objective mirror, and piezo-driven cryogenic stage were fixed to an insert holder that was immersed in superfluid helium. The single-component design stabilized the three-dimensional position of the sample, with root-mean-square deviations of (x, lateral) 0.33 nm, (y, lateral) 0.29 nm, and (z, axial) 0.25 nm. Because of the millimeter working range of the optical sensor, the working range of the sample under the active stabilization was (x, y) 5 mm and (z) 3 mm in superfluid helium at 1.8 K. The insert was used to obtain the millimeter-sized fluorescence image of cell nuclei at 1.8 K without a sample exchange.

Solid oxide fuel cells (SOFCs) directly fed with iso-octane are expected to be power sources for mobile devices and automobiles. However, the conventional anode catalysts nickel (Ni) or cerium oxide (CeO 2 ) used for direct feeding of iso-octane do not suppress carbon deposition or generate high power. In this study, we investigated the Ni-CeO 2 /Ni/Ni-yttria-stabilized-zirconia (YSZ) three-layer anode to establish the suppression of carbon deposition and high-power generation in the SOFC. The anode consists of a Ni-CeO 2 catalyst layer as the top layer, an Ni catalyst layer as the second layer, and a Ni-YSZ catalyst layer as the third layer on top of the electrolyte. The concept of the three-layer anode is as follows: fuel reforming occurs in the Ni-CeO 2 layer, the reformed H 2 or CO is electrochemically oxidized in the Ni-YSZ catalyst layer, and the Ni catalyst middle layer prevents the reaction between YSZ and CeO 2 . Scanning electron microscopy and electrochemical characterization confirmed carbon deposition suppression and improved power generation. The anode showed no carbon deposition and generated high-power, 600 mA cm -2 and 150 mW cm -2 , at 950°C and a steam/carbon ratio of 3.0. Additionally, we discuss the fuel reforming reactions on the three-layer electrode by the results of exhaust gas analysis., (© 2022 The Authors.)

Autophagy is a stress-induced lysosomal degradation pathway regulated by evolutionarily conserved autophagy-related (ATG) genes. Recent research has revealed that autophagy plays an important role in the regulation of energy metabolism, development of metabolic tissues, and pathogenesis of metabolic disorders. Bulk and selective degradation by autophagy helps maintain protein homeostasis and physiological function of cells. Aside from classical degradative roles, ATG proteins also carry out non-classical secretory functions of metabolic tissues. In this review, we summarize recent progresses and unanswered questions on the mechanisms of autophagy and ATG proteins in metabolic regulation, with a focus on organelle and nutrient storage degradation, as well as vesicular and hormonal secretion. Such knowledge broadens our understanding on the cause, pathophysiology, and prevention of metabolic diseases including obesity and diabetes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kuramoto and He.)

Objective: Using a self-expanding metal stent as a bridge to surgery (BTS) is considered a reasonable strategy for patients with acute malignant large bowel obstruction. Since postoperative complications have a negative impact on patient survival, we aim to clarify the predictors of complications in patients undergoing BTS using a self-expanding metal stent., Methods: We conducted a retrospective review of 61 patients with colorectal cancer (CRC) who underwent stenting as a BTS at our institution. We analyzed the association of postoperative complications with clinicopathologic, surgical, and patient factors, and with the prestenting or preoperative laboratory data., Results: Both postoperative complications in general and severe complications were significantly associated with a longer stenotic-section length (p = 0.007 and p = 0.003), lower preoperative hemoglobin levels (p < 0.001 and p = 0.081), and lower prestenting hemoglobin levels (p = 0.006 and p = 0.042). Multivariate logistic regression analysis showed that lower prestenting (<13.0 g/dl) and preoperative (<11.5 g/dl) hemoglobin levels were independent predictive factors for postoperative complications (odds ratio [OR]: 4.15; 95% confidence interval [CI]: 1.07-18.90; p = 0.040; and OR: 4.93; 95% CI: 1.35-20.28; p = 0.016). A stenotic-section length of 5.0 cm or greater was predictive of severe complications (OR: 25.67; 95% CI: 1.95-1185.00; p = 0.011)., Conclusions: Our data suggest that lower hemoglobin levels before stenting and a longer length of the stenotic section of bowel might predict postoperative complications in patients with CRC undergoing BTS for obstruction., (© 2022 Wiley Periodicals LLC.)

Background: KRAS is one of the most frequently mutated oncogenes in various cancers, and several novel KRAS G12C direct inhibitors are now in clinical trials. Here, we characterised the anti-tumour efficacy of ASP2453, a novel KRAS G12C inhibitor, in preclinical models of KRAS G12C-mutated cancer., Methods: We evaluated the in vitro and in vivo activity of ASP2453, alone or in combination with targeted agents and immune checkpoint inhibitors, in KRAS G12C-mutated cancer cells and xenograft models. We also assessed pharmacological differences between ASP2453 and AMG 510, another KRAS G12C inhibitor, using an SPR assay, washout experiments and an AMG 510-resistant xenograft model., Results: ASP2453 potently and selectively inhibited KRAS G12C-mediated growth, KRAS activation and downstream signalling in vitro and in vivo, and improved the anti-tumour effects of targeted agents and immune checkpoint inhibitors. Further, ASP2453 had more rapid binding kinetics to KRAS G12C protein and showed more potent inhibitory effects on KRAS activation and cell proliferation after washout than AMG 510. ASP2453 also induced tumour regression in an AMG 510-resistant xenograft model., Conclusions: ASP2453 is a potential therapeutic agent for KRAS G12C-mutated cancer. ASP2453 showed efficacy in AMG 510-resistant tumours, even among compounds with the same mode of action., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Macroautophagy/autophagy is primarily considered as a degradative pathway via the lysosome, yet the secretory functions of autophagy proteins have recently been unveiled. Autophagy proteins have been implicated in metabolic organ development, homeostasis and function, and deficiency in autophagy is associated with metabolic disorders. However, the molecular mechanisms by which autophagy proteins regulate energy metabolism and insulin sensitivity were unclear. We previously showed that systemic activation of autophagy by a hyperactive BECN1 F121A mutant reduces insulin storage in islets but improves insulin sensitivity systemically. In our recent study, we found that BECN1 functions in adipose tissue to systemically regulate energy metabolism. Adipose-specific expression of BECN1 F121A is sufficient to improve systemic insulin sensitivity without negatively affecting pancreatic insulin storage. We demonstrated that BECN1 interacts with exocyst subunit proteins and facilitates the secretion of an adipokine, ADIPOQ (adiponectin, C1Q and collagen domain containing), in adipose tissue. Thus, our findings suggest that BECN1 regulates insulin sensitivity in a non-degradative and non-cell autonomous manner by facilitating ADIPOQ secretion. Our study also highlighted the distinct functions of autophagy proteins in different metabolic tissues.

Right ventricular (RV) function is the predominant determinant of survival in patients with pulmonary arterial hypertension (PAH). In preclinical models, pharmacological activation of BMP (bone morphogenetic protein) signaling with FK506 (tacrolimus) improved RV function by decreasing RV afterload. FK506 therapy further stabilized three patients with end-stage PAH. Whether FK506 has direct effects on the pressure-overloaded right ventricle is yet unknown. We hypothesized that increasing cardiac BMP signaling with FK506 improves RV structure and function in a model of fixed RV afterload after pulmonary artery banding (PAB). Direct cardiac effects of FK506 on the microvasculature and RV fibrosis were studied after surgical PAB in wild-type and heterozygous Bmpr2 mutant mice. RV function and strain were assessed longitudinally via cardiac magnetic resonance imaging during continuous FK506 infusion. Genetic lineage tracing of endothelial cells (ECs) was performed to assess the contribution of ECs to fibrosis. Molecular mechanistic studies were performed in human cardiac fibroblasts and ECs. In mice, low BMP signaling in the right ventricle exaggerated PAB-induced RV fibrosis. FK506 therapy restored cardiac BMP signaling, reduced RV fibrosis in a BMP-dependent manner independent from its immunosuppressive effect, preserved RV capillarization, and improved RV function and strain over the time course of disease. Endothelial mesenchymal transition was a rare event and did not significantly contribute to cardiac fibrosis after PAB. Mechanistically, FK506 required ALK1 in human cardiac fibroblasts as a BMPR2 co-receptor to reduce TGFβ1-induced proliferation and collagen production. Our study demonstrates that increasing cardiac BMP signaling with FK506 improves RV structure and function independent from its previously described beneficial effects on pulmonary vascular remodeling.

Background : Budesonide foam 2 mg twice daily induced complete mucosal healing in patients with mild-to-moderate ulcerative colitis (UC) in a phase 3 study. Post-marketing surveillance is underway to assess the real-world outcomes in UC patients. Research design and methods : The authors performed an interim analysis of post-marketing surveillance in 182 patients with mild-to-moderate UC who received 2 mg budesonide foam rectally. Results : Budesonide foam was prescribed twice daily to 76.4% of patients for 7.6 ± 3.8 weeks (mean ± standard deviation). Seven patients (3.8%) had at least one adverse drug reaction (ADR). A serious ADR of enteritis infectious and glucocorticoid-related ADRs of acne and hypertrichosis were observed in one patient (0.5%) each. The partial Mayo scores significantly decreased from baseline to week 2 in patients with proctitis, left-sided colitis, and pancolitis ( p < 0.01 versus baseline each). Clinical response and remission at week 6 were 75.9% (60/79) and 68.4% (54/79), respectively. At week 6, 72.6% (77/106) of the patients reported as 'good compliance' and 54.7% (58/106) of the patients as 'very easy' for administration, using a self-administered questionnaire. Conclusions : Budesonide foam appeared to be safe, efficacious, and well-accepted in a real-world cohort of patients with UC. Trial registration : JapicCTI-183858.

A 24-year-old man with a history of bloody sputum for 6 months was referred to our hospital with suspected alveolar hemorrhaging due to vasculitis. Chest computed tomography showed ground-glass opacities in both lungs, and an examination of his bronchoalveolar lavage fluid showed alveolar hemorrhaging. However, no evidence of vasculitis was found, and subsequent polysomnographic testing confirmed that he had severe obstructive sleep apnea (OSA). Since the alveolar hemorrhaging improved after the initiation of continuous positive airway pressure treatment, the diagnosis was negative-pressure alveolar hemorrhaging due to severe OSA.

Autophagy dysregulation is implicated in metabolic diseases, including type 2 diabetes. However, the mechanism by which the autophagy machinery regulates metabolism is largely unknown. Autophagy is generally considered a degradation process via lysosomes. Here, we unveil a metabolically important non-cell-autonomous, non-degradative mechanism regulated by the essential autophagy protein Becn1 in adipose tissue. Upon high-fat diet challenge, autophagy-hyperactive Becn1 F121A mice show systemically improved insulin sensitivity and enhanced activation of AMP-activated protein kinase (AMPK), a central regulator of energy homeostasis, via a non-cell-autonomous mechanism mediated by adiponectin, an adipose-derived metabolic hormone. Adipose-specific Becn1 F121A expression is sufficient to activate AMPK in non-adipose tissues and improve systemic insulin sensitivity by increasing adiponectin secretion. Further, Becn1 enhances adiponectin secretion by interacting with components of the exocyst complex via the coiled-coil domain. Together, our study demonstrates that Becn1 improves insulin sensitivity by facilitating adiponectin secretion through binding the exocyst in adipose tissue., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Drug abuse is a foremost public health problem. Cocaine is a widely abused drug worldwide that produces various reward-related behaviors. The mechanisms that underlie cocaine-induced disorders are unresolved, and effective treatments are lacking. Here, we found that an autophagy-related protein Becn2 is a previously unidentified regulator of cocaine reward behaviors. Becn2 deletion protects mice from cocaine-stimulated locomotion and reward behaviors, as well as cocaine-induced dopamine accumulation and signaling, by increasing presynaptic dopamine receptor 2 (D2R) autoreceptors in dopamine neurons. Becn2 regulates D2R endolysosomal trafficking, degradation, and cocaine-induced behaviors via interacting with a D2R-bound adaptor GASP1. Inactivating Becn2 by upstream autophagy inhibitors stabilizes striatal presynaptic D2R, reduces dopamine release and signaling, and prevents cocaine reward in normal mice. Thus, the autophagy protein Becn2 is essential for cocaine psychomotor stimulation and reward through regulating dopamine neurotransmission, and targeting Becn2 by autophagy inhibitors is a potential strategy to prevent cocaine-induced behaviors., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

Cancer stem cells (CSCs), having both self-renewal and tumorigenic capacity, utilize an energy metabolism system different from that of non-CSCs. Lipid droplets (LDs) are organelles that store neutral lipids, including triacylglycerol. Previous studies demonstrated that LDs are formed and store lipids as an energy source in some CSCs. LDs play central roles not only in lipid storage, but also as a source of endogenous lipid ligands, which are involved in numerous signaling pathways, including the peroxisome proliferator-activated receptor (PPAR) signaling pathway. However, it remains unclear whether LD-derived signal transduction is involved in the maintenance of the properties of CSCs. We investigated the roles of LDs in cancer stemness using pancreatic and colorectal CSCs and isogenic non-CSCs. PPARα was activated in CSCs in which LDs accumulated, but not in non-CSCs, and pharmacological and genetic inhibition of PPARα suppressed cancer stemness. In addition, inhibition of both re-esterification and lipolysis pathways suppressed cancer stemness. Our study suggested that LD metabolic turnover accompanying PPARα activation is a promising anti-CSC therapeutic target.

Mt. Shinmoedake, a part of the Mt. Kirishima cluster of volcanoes in Kyushu, Japan, erupted on 10 March 2018. Our infrasound sensor network located at a distance of more than 200 km from the source detected signals emitted by an explosive eruption of Mt. Shinmoedake. The arrival time of the signals is divided into three time intervals. To reveal how the observed infrasound signals propagated from the source to the sensors, we carry out three-dimensional ray tracing on the basis of the Hamilton equations including the vertical profiles of the temperature and wind around the ray path. We present formulas for calculating travel time and distance of infrasound from a source to an observation site and its turning altitude in the atmosphere. We have identified four kinds of signals, namely, the waves propagated in the troposphere undergoing multiple refraction and those refracting from the stratosphere, the mesosphere, and the lower thermosphere. Brief discussion is devoted to some of the unidentified signals.

Background: Lenvatinib is a novel tyrosine kinase inhibitor that exhibits an antitumor effect on hepatocellular carcinoma (HCC). An established strategy that involves surgery and usage of lenvatinib for advanced HCC remains elusive., Case Presentation: A 58-year-old male patient with advanced HCC and untreated hepatitis B was referred to our hospital. The tumor at the right lobe was 10 cm in diameter with right portal vein thrombus. Because of the possible lung metastasis and concern about the remaining hepatic function after extended right hepatectomy, lenvatinib was initiated before surgery. After the confirmation of a sharp decrease of tumor markers during the 3-week lenvatinib therapy, only a right portal vein transection was done leaving the enlargement of the left lobe for improved post-hepatectomy liver function while lenvatinib therapy was continued. The laparotomy revealed that the tumor was invading the right diaphragm. After 7 weeks of lenvatinib administration after right portal vein transection, an extended right hepatectomy with resection of the tumor-invaded diaphragm was successfully done. The lung nodules that were suspected as metastases had disappeared. The patient has been doing well without any sign of recurrence for 1 year., Conclusion: The strategy involving the induction of lenvatinib to conversion hepatectomy including the portal vein transection was effective for advanced HCC.

Pulmonary arterial hypertension (PAH) is a lethal disease characterized by a progressive increase in pulmonary artery pressure due to an increase in vessel tone and occlusion of vessels. The endogenous vasodilator prostacyclin and its analogs are used as therapeutic agents for PAH. However, their pharmacological effects on occlusive vascular remodeling have not been elucidated yet. Selexipag is a recently approved, orally available and selective prostacyclin receptor agonist with a non-prostanoid structure. In this study, we investigated the pharmacological effects of selexipag on the pathology of chronic severe PAH in Sprague-Dawley and Fischer rat models in which PAH was induced by a combination of injection with the vascular endothelial growth factor receptor antagonist Sugen 5416 and exposure to hypoxia (SuHx). Oral administration of selexipag for three weeks significantly improved right ventricular systolic pressure and right ventricular (RV) hypertrophy in Sprague-Dawley SuHx rats. Selexipag attenuated the proportion of lung vessels with occlusive lesions and the medial wall thickness of lung arteries, corresponding to decreased numbers of Ki-67-positive cells and a reduced expression of collagen type 1 in remodeled vessels. Administration of selexipag to Fischer rats with SuHx-induced PAH reduced RV hypertrophy and mortality caused by RV failure. These effects were probably based on the potent prostacyclin receptor agonistic effect of selexipag on pulmonary vessels. Selexipag has been approved and is used in the clinical treatment of PAH worldwide. It is thought that these beneficial effects of prostacyclin receptor agonists on multiple aspects of PAH pathology contribute to the clinical outcomes in patients with PAH., Competing Interests: All authors are employed by Nippon Shinyaku Co., Ltd. The funders had no role in study design, data collection and analysis, or preparation of the manuscript. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

A 59-year-old female was referred to our hospital due to abnormal upper gastrointestinal(GI)findings in July 2019. Endoscopy showed an advanced type Ⅱ tumor at the esophagogastric junction. The bioptical diagnosis was adenocarcinoma. Computed tomography(CT)and positron emission tomography(PET)revealed a swollen lymph node and abnormal accumulation. Total gastrectomy and Roux-en-Y reconstruction were performed. The final diagnosis was esophagogastric junctional cancer and follicular lymphoma. The chance of encountering double cancer is likely to increase. It is vital to prioritize treatment and determine an appropriate treatment plan according to the clinical stage and prognosis in patients with double cancer.

Aims: The temporal sequence of events underlying functional right ventricular (RV) recovery after improvement of pulmonary hypertension-associated pressure overload is unknown. We sought to establish a novel mouse model of gradual RV recovery from pressure overload and use it to delineate RV reverse-remodelling events., Methods and Results: Surgical pulmonary artery banding (PAB) around a 26-G needle induced RV dysfunction with increased RV pressures, reduced exercise capacity and caused liver congestion, hypertrophic, fibrotic, and vascular myocardial remodelling within 5 weeks of chronic RV pressure overload in mice. Gradual reduction of the afterload burden through PA band absorption (de-PAB)-after RV dysfunction and structural remodelling were established-initiated recovery of RV function (cardiac output and exercise capacity) along with rapid normalization in RV hypertrophy (RV/left ventricular + S and cardiomyocyte area) and RV pressures (right ventricular systolic pressure). RV fibrotic (collagen, elastic fibres, and vimentin+ fibroblasts) and vascular (capillary density) remodelling were equally reversible; however, reversal occurred at a later timepoint after de-PAB, when RV function was already completely restored. Microarray gene expression (ClariomS, Thermo Fisher Scientific, Waltham, MA, USA) along with gene ontology analyses in RV tissues revealed growth factors, immune modulators, and apoptosis mediators as major cellular components underlying functional RV recovery., Conclusion: We established a novel gradual de-PAB mouse model and used it to demonstrate that established pulmonary hypertension-associated RV dysfunction is fully reversible. Mechanistically, we link functional RV improvement to hypertrophic normalization that precedes fibrotic and vascular reverse-remodelling events., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

Polymerase chain reaction (PCR) is typically used for the early detection of mycoplasma in bovine milk; it requires 3 days to obtain results because of the necessary enrichment process. A more rapid, simple, and accurate detection method is required to directly detect the Mycoplasma bovis (M. bovis) gene in milk. In this study, we assess the utility of combining the following two methods to achieve this goal: the loop-mediated isothermal amplification (LAMP), which is more sensitive than PCR, and the procedure for ultra rapid extraction (PURE), which adsorbs and filters components that inhibit DNA amplification/detection. LAMP was examined using DNA extracts obtained by four methods. This showed that PURE had the highest sensitivity and specificity and that the combination of PURE and LAMP was able to detect M. bovis in milk. We then showed that the detection limit of M. bovis was 10 2 colony-forming units per milliliter of milk using the PURE-LAMP. Finally, the respective sensitivities of the PURE-LAMP and PCR were 57% and 86% for bulk tank milk, 89% and 74% for mature milk, 85% and 92% for colostrum/transitional milk, and 97% and 95% for mastitis milk. The specificity was 100% for all milk samples in both LAMP and PCR. We conclude that PCR was suitable for detecting mycoplasma in bulk tank milk and that the PURE-LAMP could detect mycoplasma within 2 hr and was also effective for mature and mastitis milk.

Glioblastoma multiforme (GBM) is the most malignant primary brain tumour in adults. Since glioma stem cells (GSCs) are associated with therapeutic resistance as well as the initiation and recurrence in GBM, therapies targeting GSCs are considered to be effective for long-term survival in GBM. Several reports suggested that oxidative phosphorylation (OXPHOS) of cancer stem cells is important for their survival; however, the requirement of OXPHOS in GSCs remains unclear. Few effective and safe agents that target GSC mitochondria are available in clinical settings. In this study, we demonstrated that GSCs had high OXPHOS activity compared with isogenic differentiated GSCs and that GSC survival depended on their OXPHOS activity. Remarkably, we showed that complexes III and IV had broad therapeutic windows and that the expression levels of mitochondrial DNA-coded components of complexes III and IV were elevated in GSCs compared with differentiated GSCs. Moreover, our search of the Food and Drug Administration-approved drugs for those targeting GSC mitochondria revealed that verteporfin (Visudyne ® ), a drug approved for macular degeneration, was a novel GSC-specific cytotoxic compound that reduced OXPHOS activity. Importantly, the cytotoxic effect of verteporfin was specific to GSCs without any toxicity to normal cells, and the IC 50 of approximately 200 nm was ten times less than its maximum blood concentration in humans. Overall, these findings indicated that high mitochondrial OXPHOS of GSCs is a potential GSC-specific vulnerability and that clinically available drugs, such as verteporfin, might become novel GSC-specific cytotoxic agents., (© 2019 Federation of European Biochemical Societies.)

Background: Trousseau's syndrome is a cancer-associated thrombosis. Trousseau's syndrome with cholangiocarcinoma is a rare condition with poor prognosis., Case Presentation: A 59-year-old female was admitted to our hospital with abdominal pain, headache, and nausea. Abdominal enhanced computed tomography revealed liver tumor, splenic infarction, and bilateral renal infarction. Multiple acute cerebral infarctions were also detected by magnetic resonance imaging. Her preoperative serum levels of carbohydrate antigen 19-9 (CA19-9) and carcinoembryonic antigen (CEA) were > 120,000 U/mL and 589.6 ng/mL, respectively, which were extremely high. Histopathology after right hepatectomy revealed moderately differentiated adenocarcinoma consistent with intrahepatic cholangiocarcinoma. Her serum levels of CA19-9 were trending down to 9029.2 and 2659.8 U/mL at 1 and 3 weeks after surgery, respectively. However, at 7 weeks after surgery, her CA19-9 levels increased in the presence of positive imaging findings in the remnant liver, hilar lymph nodes, and peritoneal cavity. The initiation of combination chemotherapy including gemcitabine and cisplatin had a significant effect. The patient was doing well at 6 months after the surgery., Conclusion: This rare case of Trousseau's syndrome due to cholangiocarcinoma suggests that extremely high CA19-9 levels might be a pathogenic factor of this syndrome.

Background: Transomental hernias are a rare type of internal hernia. We report two cases of successful cases of laparoscopic repair. One required laparotomy due to concern for intestinal viability., Case Presentation: The first patient was a 67-year-old man who presented with abdominal pain and vomiting. He had no history of laparotomy or abdominal injury. Computed tomography suggested small bowel obstruction and possible intestinal strangulation. Emergent laparoscopy found approximately 200 cm of small bowel was strangulated around the greater omentum. The strangulation was released laparoscopically, but because of the color of the strangulated bowel, laparotomy was performed to evaluate viability. The involved portion of intestine was not resected. The patient experienced transient postoperative paralytic ileus and was discharged on postoperative day 14. The second patient was a 56-year-old man who presented with abdominal pain. Abdominal computed tomography revealed dilatation of the small intestine and a closed loop suggesting ileus due to intestinal strangulation. An emergency laparoscopy found a transomental hernia, and the strangulation was released laparoscopically. Recovery was uneventful, and the patient was discharged on postoperative day 6., Conclusion: Transomental hernia can be successfully treated laparoscopically. In cases where bowel viability is a concern, laparotomy should not be hesitated.

Adenosine monophosphate (AMP)-activated protein kinase (AMPK) plays a key role in maintaining cellular metabolism. AMP or adenosine diphosphate (ADP) levels rise during metabolic stress, such as during nutrient starvation, hypoxia and muscle contraction, and bind to AMPK to induce activity. Recently, activation of AMPK has been considered an attractive therapeutic strategy in the field of human oncology. Structural optimization of lead compound 2, a new type of AMPK activator with potent AMPK activation activity and attractive selective growth inhibition against human cancer cells, improved aqueous solubility, metabolic stability and animal pharmacokinetics (PK) and culminated in the identification of (5-{1-[(6-methoxypyridin-3-yl)methyl]piperidin-4-yl}-1H-benzimidazol-2-yl)(4-{[4-(trifluoromethyl)phenyl]methyl}piperazin-1-yl)methanone ditosylate, ASP4132 (28). Studies on ASP4132 had advanced to clinical trials for the treatment of cancer., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

This study reports the synthesis and evaluation of novel indirect AMP-activated protein kinase (AMPK) activators. The series of compounds selectively inhibited cell growth in several human breast cancer cell lines by activating AMPK. We performed back-up medicinal chemistry synthetic research on ASP4132, a previously reported as a compound for clinical development that acts as an indirect AMPK activator. This led to the successful identification of 4-({4-[5-({1-[(5-ethoxypyrazin-2-yl)methyl]-4-fluoropiperidin-4-yl}methoxy)-3-methylpyridine-2-carbonyl]piperazin-1-yl}methyl)benzonitrile succinate (27b), a potent, highly aqueous soluble and metabolically stable compound in human hepatocytes. Compound 27b also showed weaker human Ether-a-go-go Related Gene (hERG) inhibitory activity than that of compound 13 and ASP4132. Therefore, 27b was a promising AMPK activator and a second-generation clinical candidate for treatment for human cancer.

Novel 3,5-dimethylpyridin-4(1H)-one scaffold compounds were synthesized and evaluated as AMP-activated protein kinase (AMPK) activators. Unlike direct AMPK activators, this series of compounds showed selective cell growth inhibitory activity against human breast cancer cell lines. By optimizing the lead compound (4a) from our library, 2-[({1'-[(4-fluorophenyl)methyl]-2-methyl-1',2',3',6'-tetrahydro[3,4'-bipyridin]-6-yl}oxy)methyl]-3,5-dimethylpyridin-4(1H)-one (25) was found to have potent AMPK activating activity. Compound 25 also showed good aqueous solubility while maintaining the unique selectivity in cell growth inhibitory activity.

Aim: The purpose of this study was to evaluate the complications and reproductive outcome after uterine artery embolization (UAE) for retained products of conception (RPOC)., Methods: This was a retrospective medical-records review study of 57 women treated for RPOC. Participants were divided into two groups: women who underwent treatment with UAE (UAE group: n = 32, 56.1%) and those without UAE (control group: n = 25, 43.9%). The complications and reproductive outcomes were compared between the two groups. Information on subsequent pregnancies and their outcomes was available for 30 women who attempted to conceive., Results: There were no significant differences in the interval from the last delivery or abortion (40.1 ± 3.4 vs 51.0 ± 5.1 months, respectively; P = 0.16), the rate of severe bleeding under hysteroscopy (18.5 vs 9.1%, respectively; P = 0.65), the conception rate (58.8 vs 61.5%, respectively; P = 1.0) and mean time to conception (9.9 ± 1.6 vs 11.0 ± 2.9 months, respectively; P = 0.17) in women in the UAE group compared with those in the control group. Rates of post-partum hemorrhage (PPH) and manual removal of placenta (25.0% in the UAE group and 16.7% in the control group, respectively) were higher than the general population., Conclusion: Selective UAE for RPOC may be a preferable procedure in women who are suspected as having a risk of severe bleeding under treatment. Women who were treated for RPOC, regardless of UAE, were at risk of PPH and difficulty in removing the placenta in future pregnancies., (© 2019 Japan Society of Obstetrics and Gynecology.)

Objectives: Our objective was to investigate the effectiveness and safety of silodosin in patients with benign prostatic hyperplasia (BPH) who switched to silodosin from another α 1 blocker because of inadequate response., Methods: This was a prospective observational study conducted at 715 medical facilities in Japan in patients with BPH who received an α 1 blocker other than silodosin for at least 3 months but had experienced unsatisfactory treatment outcomes. Patients completed questionnaires, including the International Prostate Symptom Score (IPSS), quality of life (QOL) score and Overactive Bladder Symptom Score (OABSS) at baseline (time of switching) and after 3 months of treatment with silodosin., Results: Overall, 3355 patients were assessed for safety and 3144 patients for effectiveness. Mean ± standard deviation age was 73.1 ± 8.2 years, and most patients had been receiving tamsulosin (53.6%) or naftopidil (45.5%) before silodosin. Silodosin was well tolerated, with an overall incidence of adverse drug reactions of 8.1% and no unexpected safety signals. Significant improvements were observed after switching to silodosin in all effectiveness outcome measures, including total IPSS, all IPSS subscale scores, QOL score, total OABSS, all OABSS subscale scores and residual urine volume. Significant improvements in total IPSS were seen in patients who had been receiving tamsulosin or naftopidil before switching and in almost all other patient subgroups, with the exception of patients with mild symptoms (total IPSS ≤ 7) at baseline., Conclusions: This post-marketing analysis indicates that switching to silodosin from tamsulosin or naftopidil significantly improved symptoms associated with BPH, and silodosin was well tolerated in Japanese patients.

Rationale: Pulmonary arterial hypertension (PAH) is characterized by progressive narrowing of pulmonary arteries, resulting in right heart failure and death. BMPR2 (bone morphogenetic protein receptor type 2) mutations account for most familial PAH forms whereas reduced BMPR2 is present in many idiopathic PAH forms, suggesting dysfunctional BMPR2 signaling to be a key feature of PAH. Modulating BMPR2 signaling is therapeutically promising, yet how BMPR2 is downregulated in PAH is unclear., Objectives: We intended to identify and pharmaceutically target BMPR2 modifier genes to improve PAH., Methods: We combined siRNA high-throughput screening of >20,000 genes with a multicohort analysis of publicly available PAH RNA expression data to identify clinically relevant BMPR2 modifiers. After confirming gene dysregulation in tissue from patients with PAH, we determined the functional roles of BMPR2 modifiers in vitro and tested the repurposed drug enzastaurin for its propensity to improve experimental pulmonary hypertension (PH)., Measurements and Main Results: We discovered FHIT (fragile histidine triad) as a novel BMPR2 modifier. BMPR2 and FHIT expression were reduced in patients with PAH. FHIT reductions were associated with endothelial and smooth muscle cell dysfunction, rescued by enzastaurin through a dual mechanism: upregulation of FHIT as well as miR17-5 repression. Fhit -/- mice had exaggerated hypoxic PH and failed to recover in normoxia. Enzastaurin reversed PH in the Sugen5416/hypoxia/normoxia rat model, by improving right ventricular systolic pressure, right ventricular hypertrophy, cardiac fibrosis, and vascular remodeling., Conclusions: This study highlights the importance of the novel BMPR2 modifier FHIT in PH and the clinical value of the repurposed drug enzastaurin as a potential novel therapeutic strategy to improve PAH.

Background/aim: Cancer stem cells (CSCs) are associated with tumorigenesis, recurrence, and metastasis. Cell-cell communication via gap junctions (GJs) between metastatic cancer cells and astrocytes is necessary for brain metastasis. Agents targeting communication between CSCs and astrocytes are expected to suppress brain metastasis., Materials and Methods: Using the A549 CSC, a cancer stem-like cell derived from A549, we examined the effect of AS602801, an anti-cancer stem cell agent whose safety has been confirmed in a phase 2 clinical trial, on GJ communication and connexin expression using a dye-transfer assay and immunoblot analysis, respectively., Results: AS602801 specifically suppressed cell-cell communication in A549 CSCs without any suppression of GJ communication in astrocytes; it also decreased the expression of connexin 43, a constituent of GJs, in A549 CSCs., Conclusion: The anti-cancer stem cell agent, AS602801, is a potential drug candidate against brain metastasis., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Macroscopic diffuse-type hepatocellular carcinoma with concomitant major portal vein tumor thrombus (PVTT) and peritoneal dissemination indicates poor prognosis. Additionally, triple-positive tumor marker status is a predictor of poor outcome even after hepatectomy. Sorafenib is recommended in such patients, but it has limited therapeutic effectiveness., Case Presentation: A 54-year-old man was diagnosed with a liver abscess that was treated by puncture and drainage at a regional hospital. However, the diagnosis was subsequently changed to hepatocellular carcinoma with macroscopic portal vein tumor thrombus, based on the results obtained for the triple-positive tumor markers (alpha-fetoprotein, 45,928 ng/ml; protein induced by vitamin K absence or antagonist-II, 125,350 mAU/ml; and alpha-fetoprotein-L3, 38.3%). As the patient's liver functional reserve was not adequate for curative resection, chemoembolization was performed with a hepatic arterial infusion of cisplatin (50 mg) and 5-FU (1000 mg), followed by mild embolization with cisplatin (50 mg) suspended in lipiodol (5 ml) and starch microspheres (300 mg) containing mitomycin C (4 mg). As the thrombus had progressed to the bifurcation of the right and left portal veins, the right vein was surgically ligated. Three peritoneal nodules could be identified and were removed. Three additional rounds of hepatic arterial chemotherapy/chemoembolization were performed after the initial surgery. At the 2-year evaluation, all tumor markers were observed to have normalized and diagnostic imaging showed complete remission., Conclusions: Complete remission of hepatocellular carcinoma with macroscopic portal vein tumor thrombus and peritoneal dissemination was obtained with a treatment regimen that involved four rounds of hepatic arterial infusion chemotherapy and transient chemoembolization, portal vein ligation, and the removal of peritoneal dissemination. This regimen can be recommended for patients with advanced hemiliver lesions who cannot undergo curative resection.

Use of epidermal growth factor receptor (EGFR) inhibitors represented by gefitinib and erlotinib has become the standard of treatment for non-small-cell lung cancers (NSCLCs) with activating EGFR mutations. However, the majority of NSCLCs, which overexpress EGFR without such mutations, are resistant to EGFR inhibitors, and the mechanism(s) behind such primary resistance of NSCLCs without activating EGFR mutations to EGFR inhibitors still remains poorly understood. Here in this study, we show that glucose metabolism mediated by GLUT1, a facilitative glucose transporter, is involved in gefitinib resistance of NSCLC cells. We found that GLUT1 expression and glucose uptake were increased in resistant NSCLC cells after gefitinib treatment and that genetic as well as pharmacological inhibition of GLUT1 sensitized not only NSCLC cells with primary resistance but also those with acquired resistance to gefitinib. In vivo , the combination of systemic gefitinib and a GLUT1 inhibitor, both of which failed to inhibit tumor growth when administered alone, significantly inhibited the growth of xenograft tumors formed by the implantation of NSCLC cells with wild-type EGFR (wt-EGFR). Since our data indicated that GLUT1 was similarly involved in erlotinib resistance, our findings suggest that the activity of GLUT1-mediated glucose metabolism could be a critical determinant for the sensitivity of NSCLC cells to EGFR inhibitors and that concurrent GLUT1 inhibition may therefore be a mechanism-based approach to treating NSCLCs resistant to EGFR inhibitors, including those with wt-EGFR., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interest.

Background/aim: Poorly differentiated hepatocellular carcinoma (HCC) is a malignant phenotype following radiofrequency ablation, but not liver resection. This study aimed to identify prognostic parameters that could predict poorly differentiated HCC., Patients and Methods: Between 2007-2014, 158 HCC patients undergoing liver resection were enrolled that not the Milan criteria. Laboratory data were measured including three tumor markers and inflammatory factors (neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio, and monocyte/lymphocyte ratio. Preoperative parameters to predict poorly differentiated HCC were assessed by multivariate logistic regression analysis., Results: Poorly differentiated HCC was observed in 28 (17.7%) patients. In multivariate analysis, two or three positive tumor markers and high NLR (≥2.33) were independent predictors of poorly differentiated HCC. Recurrence-free and overall survival were comparable despite these significant predictors., Conclusion: The preoperative status of two or three positive tumor markers and high NLR facilitated selecting HCC patients with poorly differentiated disease, which will assist making therapeutic decisions for HCC patients., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

The near-Earth asteroid (3200) Phaethon is the parent body of the Geminid meteor stream. Phaethon is also an active asteroid with a very blue spectrum. We conducted polarimetric observations of this asteroid over a wide range of solar phase angles α during its close approach to the Earth in autumn 2016. Our observation revealed that Phaethon exhibits extremely large linear polarization: P = 50.0 ± 1.1% at α = 106.5°, and its maximum is even larger. The strong polarization implies that Phaethon's geometric albedo is lower than the current estimate obtained through radiometric observation. This possibility stems from the potential uncertainty in Phaethon's absolute magnitude. An alternative possibility is that relatively large grains (~300 μm in diameter, presumably due to extensive heating near its perihelion) dominate this asteroid's surface. In addition, the asteroid's surface porosity, if it is substantially large, can also be an effective cause of this polarization.

Autophagy, a stress-induced lysosomal degradative pathway, has been assumed to exert similar metabolic effects in different organs. Here, we establish a model where autophagy plays different roles in insulin-producing β cells versus insulin-responsive cells, utilizing knockin (Becn1 F121A ) mice manifesting constitutively active autophagy. With a high-fat-diet challenge, the autophagy-hyperactive mice unexpectedly show impaired glucose tolerance, but improved insulin sensitivity, compared to mice with normal autophagy. Autophagy hyperactivation enhances insulin signaling, via suppressing ER stress in insulin-responsive cells, but decreases insulin secretion by selectively sequestrating and degrading insulin granule vesicles in β cells, a process we term "vesicophagy." The reduction in insulin storage, insulin secretion, and glucose tolerance is reversed by transient treatment of autophagy inhibitors. Thus, β cells and insulin-responsive tissues require different autophagy levels for optimal function. To improve insulin sensitivity without hampering secretion, acute or intermittent, rather than chronic, activation of autophagy should be considered in diabetic therapy development., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background/Aim: The sacrifice of a major hepatic vein can cause hepatic venous congestion (HVC). We evaluated the effects of HVC on regional liver function using the liver uptake value (LUV), that was calculated from 99m Tc-labeled-galactosyl-human-serum-albumin ( 99m Tc-GSA) single-photon emission computed tomography (SPECT) /contrast-enhanced computed tomography (CE-CT) fused images. Patients and Methods: Sixty-two patients underwent 99m Tc-GSA SPECT/CE-CT prior to hepatectomy for liver cancer and at 7 days after surgery were divided into groups with (n=8) and without HVC (n=54). In the HVC group, CT volume (CTv) and LUV were separately calculated in both congested and non-congested areas. Results: The remnant LUV/CTv of the HVC group was significantly smaller than that of the non-HVC group (p<0.01). The mean functional ratio was 0.47±0.05, and all ratios were ≥0.39. Conclusion: After hepatectomy with sacrifice of major hepatic vein, liver function per unit volume in the congested areas was approximately 40% of that in the non-congested areas., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

A 70-year-old man with a growing liver tumor had undergone subtotal gastrectomy with pancreaticoduodenectomy for gastric cancer (T4b P0 H0 N1, Stage IIIB) 30 months before admission to our hospital. Enhanced computed tomography revealed two hypervascular nodules in segments 4 and 8. After histological diagnosis of small liver metastases from gastric cancer in segment 8, the patient underwent open microwave coagulation therapy (MCT) for the tumor (diameter: 30 mm) in segment 4. MCT was performed by using 1.5-cm and 3-cm monopolar needle electrodes with 22 times of puncture under the condition of 100 W × 60 sec. Liver abscess developed at the MCT site; however, it was decreased with percutaneous drainage. The patient is alive, without tumor recurrence even after 15 years since the MCT. This successful case proves that appropriate MCT is a promising treatment for patients with gastric liver metastases., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: A hepatic sclerosed hemangioma (HSH) is a very rare benign liver tumor. The correct preoperative diagnosis of HSH is very difficult because its features of imaging are similar to those of intrahepatic cholangiocarcinoma or colorectal liver metastasis., Case Presentation: We experienced five patients who were diagnosed histologically with HSH. The preoperative diagnoses were HSH in two patients, cavernous hemangioma in one, intrahepatic cholangiocarcinoma in one, and colorectal liver metastasis in one. All patients were treated with hepatectomy (one laparoscopic and four laparotomies), and the diagnosis was completed by histological investigation of the resected specimen. In particular, we investigated the apparent diffusion coefficient (ADC) mean value using diffusion-weighted sequences of magnetic resonance imaging (DW-MRI). The average of the ADC mean (ADC mean ) value of HSH was 1.94 × 10 -3  mm 2 /s (range 1.73-2.10 × 10 -3  mm 2 /s), which was higher than the value of common malignant liver tumors. Interestingly, the ADC mean values were almost the same between the degenerate (1.90 ± 0.17 × 10 -3  mm 2 /s) and the non-degenerate areas (1.95 ± 0.26 × 10 -3  mm 2 /s) in HSH., Conclusions: The ADC mean value seemed to be quite useful to preoperatively distinguish HSH from other malignant liver tumors.

Background/aim: To investigate the utility of adjuvant hepatic arterial infusion chemotherapy (HAIC) following hepatectomy for patients with hepatocellular carcinoma (HCC) with intrahepatic dissemination (IHD) after local ablation therapy., Patients and Methods: Twelve patients with HCC with IHD were divided into two groups: HAIC group (n=6) underwent hepatectomy followed by HAIC; and the non-HAIC group (n=6) underwent hepatectomy alone. HAIC with cisplatin and 5-fluorouracil was started within a month and was continued for a month: Results: At the first local ablation, tumors close to the major portal vein and insufficient ablation were recognized in eight (67.7%) and six (58.3%) of the patients, respectively. In the HAIC group, the 1-, 3-, and 5-year disease-free and overall survival rates were 50.0%, 16.7%, and 16.7%, and 83.3%, 83.3% and 62.5%, respectively. Three patients in the HAIC group remain alive after 10 years of follow-up., Conclusion: Hepatic resection with short-term postoperative HAIC may provide excellent outcomes in patients with HCC and IHD., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Macroautophagy/autophagy abnormality has been recently associated with metabolic disorders, such as type 2 diabetes (T2D). However, the effect of autophagy activation in systemic energy metabolism was poorly understood. In our recent study, we demonstrated that autophagy plays different roles in distinct metabolic tissues, using an autophagy-hyperactive mouse model. In insulin-producing β cells, excess autophagy degrades insulin-containing vesicles (a process termed vesicophagy), resulting in decreased insulin contents and systemic glucose intolerance; whereas in insulin-responsive cells, activating autophagy decreases endoplasmic reticulum (ER) stress and improves insulin sensitivity.

Background/aim: Olanzapine, an atypical antipsychotic, is now increasingly used as an off-label indication for the management of cancer patients with chemotherapy-induced nausea and vomiting (CINV). However, how olanzapine affects cancer cells per se remains poorly understood., Materials and Methods: The effects of olanzapine treatment and survivin knockdown, alone or in combination with chemotherapeutic agents, on survivin expression and cell viability were investigated in human cancer cell lines., Results: Olanzapine reduced survivin expression in lung and pancreatic cancer stem cell (CSC) lines and sensitized them to chemotherapeutic agents such as 5-fluorouracil, gemcitabine, and cisplatin in a survivin expression-dependent manner. Olanzapine also reduced survivin expression and chemosensitized serum-cultured, non-CSC ovarian cancer cells that expressed survivin., Conclusion: Olanzapine may benefit cancer patients not only as an antiemetic for CINV, but also by enhancing the effects of chemotherapeutic agents through down-regulation of survivin, which has been implicated in multidrug chemoresistance., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

CEP-1347 is a mixed lineage kinase inhibitor tested in a large-scale phase 2/3 clinical trial in early Parkinson's disease, in which its safety and tolerability, but nevertheless not efficacy, was demonstrated. Here we identify by drug repositioning CEP-1347 as a potential anti-cancer stem cell drug. In vitro , CEP-1347 efficiently induced differentiation and inhibited the self-renewal and tumor-initiating capacities of human cancer stem cells from glioblastoma as well as from pancreatic and ovarian cancers at clinically-relevant concentrations, without impairing the viability of normal fibroblasts and neural stem cells. In vivo , a 10-day systemic administration of CEP-1347 at a dose that was less than 1/10 the mouse equivalent of the dose safely given to humans for 2 years was sufficient to effectively reduce tumor-initiating cancer stem cells within established tumors in mice. Furthermore, the same treatment protocol significantly extended the survival of mice receiving orthotopic implantation of glioma stem cells. Together, our findings suggest that CEP-1347 is a promising candidate for cancer stem cell-targeting therapy and that further clinical and preclinical studies are warranted to evaluate its efficacy in cancer treatment., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interest.

We carried out further research into the prefrontal hemodynamics corresponding to changes in a women's auditory sense during pregnancy and child raising. A total of forty-six volunteers took part in our experiment, and we divided them into several groups in accordance with the progress of their child raising. For the auditory tasks performed by the volunteers, we used two auditory stimulations: the sound of baby crying, and a classical music as a control. Hemodynamic changes at the prefrontal regions were measured using a 2 ch functional near-infrared spectroscopy (fNIRS) along with a 47 ch fNIRS instrument equipped with 3×5 probes (22 ch). Judging the results of the female groups about their prefrontal hemodynamics, there were almost no significant differences across the groups in the dynamics with the music task. However, in the section of the baby crying task, their hemodynamics were regarded as significant compared to the control. Concerning the time scale of the changes in the hemodynamic response to the two tasks, especially in the postnatal group, we took notice of the possibility that higher activations were clearly observed at the right sides of their brains than their left sides. Our experimental results not only demonstrated that postnatal women within one and a half years of their childbearing might have acute ears, but also revealed the hemispheric asymmetry in their prefrontal hemodynamics, as compared to pregnant and nonpregnant volunteers. We inferred that the pregnancy-inducing expression of such women's special capabilities is definitely due to a boost-up of a built-in female disposition, which is destined for expressions of maternal love.

Currently, there is no established therapeutic option for high-grade meningioma recurring after surgery and radiotherapy, and few chemotherapeutic agents are in development for the treatment of high-grade meningioma. Here in this study, we screened a panel of chemotherapeutic agents for their possible antitumor activity in high-grade meningioma and discovered that high-grade meningioma cells show a preferential sensitivity to antimetabolites, in particular, to gemcitabine. In vitro , gemcitabine inhibited the growth of high-grade meningioma cells effectively by inducing S-phase arrest and apoptotic cell death. In vivo , systemic gemcitabine chemotherapy suppressed not only tumor initiation but also inhibited the growth and achieved a long-term control of established tumors in xenograft models of high-grade meningioma. Histological analysis indicated that systemic gemcitabine blocks cell cycle progression and promotes apoptotic cell death in tumor cells in vivo . Together, our data demonstrate that gemcitabine exerts potent antitumor activity against high-grade meningioma through cytostatic and cytotoxic mechanisms. We therefore propose gemcitabine is a promising chemotherapeutic agent that warrants further investigation as a treatment option for high-grade meningioma., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interest.

Hepatic resection (HR) and radiofrequency ablation (RFA) are popular local therapies for early-stage hepatocellular carcinoma (HCC). Alpha-fetoprotein, Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein, and des-c-carboxy prothrombin are well-known and useful tumor markers for HCC. The positive number status of these tumor markers has recently been demonstrated as beneficial for predicting outcome for HCC patients treated with local therapy. Although the normal ranges reported have differed by institution, the positivity of tumor markers is consistent and can easily be assessed. Kumamoto and Wakayama's group clearly demonstrated the following: 1) Regardless of the degree of tumor stage, a triple-positive tumor marker profile can predict poor outcome in HCC patients undergoing HR; 2) For RFA alone, HCC patients with double- and triple-positive status, having less than three lesions and lesions ≤3 cm in diameter show comparably insufficient outcomes; 3) For HCC patients with lesions ≤5 cm in Child-Pugh grade A, HR is preferred over RFA; 4) Microvascular invasion rates increased even in the double-positive patients, while poorly differentiated HCC was frequently observed only in the triple-positive patients; and 5) RFA with chemoembolization, anatomical liver resection, and postoperative adjuvant chemoembolization or hepatic arterial chemotherapy might improve the outcome for patients with highly malignant HCC with multiple positive tumor markers. However, the impacts of these therapies still need to be evaluated in prospective comparative studies., Competing Interests: The authors have no conflict of interests related to this publication.

Glioblastoma multiforme is the most malignant primary intrinsic brain tumor. Glioma stem cells (GSCs) are associated with chemoradiotherapy resistance and the recurrence of glioblastomas after conventional therapy. The targeting of GSCs is potentially an effective treatment for the long-term survival of glioblastoma patients. Licochalcone A, a natural chalconoid from licorice root, exerts anticancer effects; however, its effect on GSCs remains unknown. We found that Licochalcone A induced massive caspase-dependent death in GSCs but not in differentiated GSCs nor normal somatic and neural stem cells. Prior to cell death, Licochalcone A caused mitochondrial fragmentation and reduced the membrane potential and ATP production in GSCs. Thus, Licochalcone A induces mitochondrial dysfunction and shows promise as an anticancer stem cell drug.

Selexipag (NS-304; [2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N- (methylsulfonyl)acetamide]) is a novel, orally available non-prostanoid prostacyclin receptor (IP receptor) agonist that has recently been approved for the treatment of pulmonary arterial hypertension (PAH). We examined the effect of the active metabolite of selexipag, MRE-269, and IP receptor agonists that are currently available as PAH therapeutic drugs on the relaxation of rat, porcine and human pulmonary artery. cAMP formation in human pulmonary artery smooth muscle cells was induced by all test compounds (MRE-269, epoprostenol, iloprost, treprostinil and beraprost sodium) and suppressed by IP receptor antagonists (CAY10441 and 2-[4-(1H-indol-4-yloxymethyl)-benzyloxycarbonylamino]-3-phenyl-propionic acid). MRE-269 induced endothelium-independent vasodilation of rat extralobar pulmonary artery (EPA). In contrast, endothelial denudation or the addition of a nitric oxide synthase inhibitor markedly attenuated the vasodilation of EPA induced by epoprostenol, treprostinil and beraprost sodium but not iloprost. The vasorelaxant effects of MRE-269 on rat small intralobar pulmonary artery (SIPA) and EPA were the same, while the other IP receptor agonists induced less vasodilation in SIPA than in EPA. Furthermore, a prostaglandin E receptor 3 antagonist enhanced the vasodilation induced by all IP receptor agonists tested except MRE-269. We also investigated the relaxation induced by IP receptor agonists in pulmonary arteries from non-rodent species and found similar vasodilation modes in porcine and human as in rat preparations. These results suggest that MRE-269, in contrast to other IP receptor agonists, works as a selective IP receptor agonist, thus leading to pronounced vasorelaxation of rat, porcine and human pulmonary artery., (Copyright © 2016 Elsevier B.V. All rights reserved.)