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Background/Aim: Trabectedin is a DNA-damaging agent and has been approved for the treatment of patients with advanced soft tissue sarcoma. Schlafen 11 (SLFN11) was identified as a dominant determinant of the response to DNA-damaging agents. The aim of the study was to clarify the association between SLFN11 expression and the antitumor activity of trabectedin. Materials and Methods: The antitumor activity of trabectedin was evaluated under different expression levels of SLFN11 regulated by RNA interference and CRISPR-Cas9 systems, and the combined antitumor activity of ataxia telangiectasia and Rad3-related protein kinase (ATR) inhibitor and trabectedin in sarcoma cell lines using in vitro a cell viability assay and in vivo xenograft models. Results: SLFN11-knockdown cell lines had a lower sensitivity to trabectedin, compared to parental cells. ATR inhibitor enhanced the antitumor activity of trabectedin in SLFN11-knockdown cells and in a SLFN11-knockout xenograft model. Conclusion: SLFN11 expression might be a key factor in the antitumor activity of trabectedin.

A reduced-order model ( rom ) of mould heat transfer in the continuous casting of steel is presented and demonstrated for several commercial mould geometries. The rom relies on a physically-based solution of the one-dimensional heat-conduction equation. The up-front cost of the rom is a single three-dimensional finite-element calculation of a small representative portion of the exact mould geometry, which is used to calibrate the geometric parameters of the rom . Specifically, the rom exactly matches the average hot and cold surface temperatures of the mould as computed in the snapshot model. Other features of the rom , namely predictions of the cooling water temperature change and thermocouple temperatures, are derived in a manner consistent with the one-dimensional solution. Combined with models of solidification and mould-metal interfacial phenomena, this accurate and efficient modelling tool can be applied to enable deeper insight into many different aspects of heat transfer and related phenomena in the continuous casting process.

Background: TAS-117 is a potent oral allosteric non-ATP inhibitor selective for AKT. A phase 1 study with TAS-117 is ongoing in patients with endometrial cancer and ovarian clear cell carcinoma. Futibatinib (TAS-120) is a selective, irreversible small-molecule fibroblast growth factor receptor (FGFR) 1-4 inhibitor, with potent antiproliferative activity in preclinical models with FGFR aberrations. Phase 2 studies are ongoing in patients with various FGFR-deregulated cancers. We evaluated the antitumor activity of futibatinib plus TAS-117 in FGFR-aberrant cancer models. Methods: Effects of futibatinib plus TAS-117 were investigated in human endometrial FGFR2-N549K-mutated AN3CA cancer cells and small-cell lung cancer FGFR1-amplified DMS114 cells. Activation of RAS and PI3K pathways was assessed by detecting phosphorylation of ERK1/2, AKT, and S6. Antitumor combination indices (CI) for cell viability over time were determined with the Chou-Talalay median-effect method and CalcuSyn software; a CI Results: Futibatinib and TAS-117 synergistically increased cell death and decreased cell growth in AN3CA (CI Conclusions: Our findings suggest that futibatinib plus TAS-117 has synergistic antitumor effects in FGFR-aberrant tumors. A phase 1/2 study of this combination in advanced solid tumors (JapicCTI-194864) is ongoing. Citation Format: Junya Iwasaki, Takuya Kuramoto, Toshiharu Komori, Hitoshi Saito, Hiroshi Hirai. Synergistic antitumor activity of futibatinib, an FGFR1-4 inhibitor, and TAS-117, a selective AKT inhibitor, in FGFR-deregulated cancer models [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 661.

Primary pulmonary vein stenosis (PVS) is rare within the pediatric population and its pathophysiology remains unclear, especially as to how the histopathology relates to its refractoriness to treatment. We report the case of a 4-month-old girl with primary PVS. The lesion in this patient was characterized by fatal obstruction of intraparenchymal small pulmonary veins, associated with localized stenosis at the four pulmonary veno-atrial junctions. All four localized stenoses underwent transcatheter stent implantation. Although the procedure was technically successful, her clinical status failed to improve, and she died 2 months after stenting. Histopathological examination of lung specimens showed severe luminal obstruction by marked intimal proliferation with fibrosis in the intraparenchymal small pulmonary veins, and these findings were present in every lobe. To the best of our knowledge, the histopathological findings and clinical course in this case, including the response to treatments, are extremely rare. We suggest that the histological findings of the small pulmonary veins are important in deciding the indication and appropriate timing of intervention. Learning objective: The outcome of primary pulmonary vein stenosis has remained poor despite aggressive treatment, while the indication and appropriate timing of intervention has not been clarified. The histological findings of small pulmonary veins are important to predict the response to treatment and outcome, and early intervention might prevent the secondary progression of this disease.>

Much evidence indicates that various naturally occurring compounds have an anti-cancer effect, but the detailed mechanisms are not well understood. In this study, we selected anti-cancer phytochemicals such as epigallocatechin-3-gallate (EGCG), resveratrol (RES) and α-mangostin (α-M), all of which are well-characterized chemopreventive agents. We sought to elucidate the mechanism of their anti-cancer effects and the synergistic effects obtained by combined treatment with the anti-cancer drug 5-fluorouracil (5-FU) in three human colon cancer cell lines. The numbers of viable cells were consistently decreased by the treatment with EGCG, RES or α-M at more than 10 μM in all three cell lines tested. All compounds mainly induced apoptosis and suppressed the PI3K/Akt signaling pathway. Additionally, α-M, which had the greatest PI3K/Akt-suppressing activity, also suppressed MAP kinase (MAPK)/Erk1/2 signaling. Importantly, the combination treatment with RES and 5-FU induced a remarkably synergistic enhancement of growth inhibition and apoptosis through the additional suppression of the MAPK/Erk1/2 signaling pathway in colon cancer DLD-1 cells. Interestingly, RES increased the intracellular expression level of miR-34a, which down-regulated the target gene E2F3 and its downstream Sirt1, resulting in growth inhibition. These findings indicate that these compounds functioned as chemosensitizers when combined with anti-cancer drugs through the modulation of apoptotic and growth-related signaling pathways. Also, RES exerted its anti-cancer activity in part through a newly defined mechanism, i.e., the miR-34a/E2F3/Sirt1 cascade.

"Thermie" therapy is one of the folk remedies in Japan and is mainly done by rubbing the skin with special instruments. The therapy is believed to relieve several symptoms which include pain, common cold and ileus. We report here the first two cases of thermie dermatosis in the English published work. The first patient had suffered from poikiloderma-like eruptions for 30 years after the initiation of a thermie therapy. The eruptions were on both the upper back and the abdomen. The second patient presented with a hyperpigmented plaque on the right femoral region, and excoriated papules and a hyperpigmented plaque on the left lower leg. The patient had received thermie therapy for 3 years. The histopathology of the first case revealed features of cutaneous amyloidosis, and, of the second case, superficial dermatitis and hypermelanosis in the epidermal basal layer. A common cause of both cases was regarded as the thermie therapy. This report suggests the importance of getting a thorough history including folk remedies in patients presenting such pigmented lesions.

Five new briarane-type diterpenoids, pachyclavulides E (5), F (6), G (7), H (8) and I (9), were isolated from the Okinawan soft coral Pachyclavularia violacea. The structures of these compounds were elucidated based on the results of spectroscopic analysis. Compound 5 showed a weak growth-inhibitory activity in vitro toward cancer cells.

Four new briarane-type diterpenoids, pachyclavulides A (1), B (2), C (3), and D (4), were isolated from the Okinawan soft coral Pachyclavularia violacea. The structures of these compounds were elucidated on the basis of the results of spectroscopic analysis. The absolute configuration of pachyclavulide A (1) was determined by the X-ray crystallographic analysis of its p-bromobenzoyl ester.

Recently aortic intima-media thickness (IMT) has been used as an earlier marker of preclinical atherosclerosis in high-risk children, such as those with type 1 diabetes mellitus and hypercholesterolemia. Children who were born preterm have an early elevation in insulin resistance, which may be a risk factor for metabolic syndrome in adulthood. However, there is no optimal marker of subsequent cardiovascular disease for children born preterm. In this study, we aimed to evaluate the effect of preterm birth on aortic IMT during the preschool period. Mean aortic IMT was measured by ultrasound in 26 subjects born preterm (gestational age

Recently, transcatheter device occlusion has become the first choice treatment for adult persistent ductus arteriosus (PDA). However, various complications such as atrial fibrillation requiring anticoagulation, pulmonary hypertension, and ventricular dysfunction may challenge the interventionist. We report a 61-year-old patient with a large PDA complicated by left ventricular dysfunction, atrial fibrillation, and left atrial thrombus. Computed tomography documented the PDA of Krichenko type A with the narrowest diameter of 8mm. We successfully closed the PDA using an Amplatzer duct occluder under anticoagulation with wafarin. His post-operative course was complicated by ventricular tachycardia and deteriorating left ventricular pump function. Although endomyocardial biopsy from the left ventricle showed myocardial hypertrophy and interstitial fibrosis, possibly caused by chronic volume overload, left ventricular pump function improved dramatically with restoration of sinus rhythm during follow-up. Left ventricular dysfunction, even when associated with histological changes, may be nearly normalized by volume unloading in an adult with a large PDA. Learning objective: Transcatheter device occlusion has become the first choice for adult persistent ductus arteriosus (PDA). It is important to note various complications associated with transcatheter occlusion of PDA in adult, such as arrhythmia, pulmonary hypertension, and ventricular dysfunction. Temporally dysfunction of left ventricular (LV) systolic performance usually occurs following PDA closure, because of reduced muscle fiber stretch by the sudden reduction in LV volume overload and increased LV afterload. Although histological remodeling of LV may be caused by volume overload due to significant left-to-right shunt in adults, volume unloading can, not only prevent further deterioration of LV function, but also may also reverse the substrate of arrhythmia.>

Heat-flow and thermal-stress models of continuous steel slab casting are calibrated with detailed measurements of a breakout and applied to predict longitudinal off-corner crack formation. First, a fluid mass balance is applied together with the measured slide-gate position, mold level, casting speed histories to reconstruct the transient events that occurred during the breakout, including the flow-rate and solidification time histories. An efficient one-dimensional (1-D) heat transfer model of the mold, CON1D, is calibrated to match the measured mold heat flux and thermocouple temperatures, with the help of a full 3-D finite-element model. Using these results, a finite-element thermal-stress model of the solidifying shell was able to match the measured shell thickness profiles, and was applied to reveal insights into interfacial gap conditions and other effects on the formation of off-corner longitudinal cracks and breakouts. Introduction Computational models of heat transfer and thermo-mechanical behavior are useful tools to understand quality problems such as longitudinal cracks in continuous casting of steel. Making accurate, quantitative predictions is difficult, however, because many of the phenomena, such as interfacial heat transfer and crack formation, depend on empirical parameters. One way to meet this challenge is to calibrate the models with measurements on the commercial process. A breakout is the ultimate casting defect. This work performs comprehensive measurements of a breakout at Nippon Steel Yawata Works No.2 strand caster, and presents the casting conditions and data as a benchmark for understanding breakout events, and for model calibration. Finally, the breakout is treated as a longitudinal crack, where the conditions that caused it can be estimated with sufficient accuracy to use as a basis for evaluating hot-tear crack criteria. Breakout Analysis The breakout occurred while casting a 252 x 1360 mm slab of plain carbon steel (0.162%C, 0.71%Mn, 0.016%P, 0.006%S, 0.02%Si, 0.039%Al), under generally steady conditions, given in Table 1, 104 minutes after changing heats. Liquidus and solidus temperatures are 1515.4 and 1479.8 oC. The mold was 258mm thick (top) x 900mm long with 9.5mm taper/side. The mold powder had CaO/SiO2 ratio of 1.2, with a flux solidification temperature of ~1160 oC, and viscosity of 0.6P at 1300oC. The oscillation marks averaged 0.37mm in depth and 3.55mm in width. Supplemental Proceedings: Volume 2: Materials Properties, Characterization, and Modeling TMS (The Minerals, Metals & Materials Society), 2012

We recently reported that both microRNA (miR)-143 and -145 are downregulated in human bladder cancer T24 cells and that miR-143 targets ERK5. In this study, we assessed the anti-tumor effects of combination treatment with miR-143 and -145 on bladder cancer cell lines T24, SNK57, and NKB1, in which the expression levels of miR-143 and -145 are downregulated. The ectopic expression of both miR-143 and -145 led to a significantly synergistic growth inhibition of T24 and NKB1 cells, but not that of SNK57 cells with the levels of miR-143 and -145 higher than those in T24 and NKB1 cells. The MAPK signaling pathway in NKB1 cells and both PI3K/Akt and MAPK signaling pathways in T24 cells were synergistically repressed by the co-treatment with miR-143 and -145. We newly elucidated that miR-143 targeted akt and that miR-145 targeted integrin-linked kinase (ilk) in T24 cells based on the results of a luciferase activity assay. Silencing of ilk significantly inhibited the growth of all the bladder cancer cells tested. Also, the level of phosphorylated ERK1/2 in T24 cells and that of phosphorylated Akt in SNK57 and NKB1 cells were decreased by ilk silencing. This study has provided novel important evidence with regard to the functions of anti-oncogenic miR-143 and -145 and also suggests the possible use of miR-143 and -145 for combination replacement therapy in cancers in which both miRNAs are downregulated.

MicroRNAs regulate gene expression by repressing translation or directing sequence-specific degradation of their complementary mRNA. We recently reported that miR-203 is down-regulated, and its exogenous expression inhibits cell growth in canine oral malignant melanoma tissue specimens as well as in canine and human malignant melanoma cells. A microRNA target database predicted E2F3 and ZBP-89 as putative targets of microRNA-203 (miR-203). The expression levels of E2F3a, E2F3b, and ZBP-89 were markedly up-regulated in human malignant melanoma Mewo cells compared with those in human epidermal melanocytes. miR-203 significantly suppressed the luciferase activity of reporter plasmids containing the 3′-UTR sequence of either E2F3 or ZBP-89 complementary to miR-203. The ectopic expression of miR-203 in melanoma cells reduced the levels of E2F3a, E2F3b, and ZBP-89 protein expression. At the same time, miR-203 induced cell cycle arrest and senescence phenotypes, such as elevated expression of hypophosphorylated retinoblastoma and other markers for senescence. Silencing of E2F3, but not of ZBP-89, inhibited cell growth and induced cell cycle arrest and senescence. These results demonstrate a novel role for miR-203 as a tumor suppressor acting by inducing senescence in melanoma cells.

Enantioselective preparation of the six-membered ring of pachyclavulide B, a briarane-type diterpenoid, was achieved. The key step is desymmetrization of an achiral symmetric substrate by enantiogroup- and diastereoselective epoxidation. The asymmetric epoxidation proceeded with up to 99% de and 94% ee.

We recently reported that microRNA (miR)-145 is downregulated and induces apoptosis in human bladder cancer cells. Also, it is suggested that the ectopic expression of miR-145 induces apoptosis with the induction of TRAIL expression in several cancer cells. Here, we demonstrated a novel mechanism of apoptosis induction by miR-145 in bladder cancer cells. Exogenous miR-145 in T24 and NKB1 cells markedly increased the expression levels of interferon (IFN)-β, 2′–5′-oligoadenylate synthetase 1, which lies upstream of 2′–5′ oligoadenylates/RNase L system, and TRAIL, and induced apparent caspase-dependent apoptosis that was suppressed by cotreatment with a pan-caspase inhibitor; moreover, these expression levels were reduced by cotreatment with an miR-145 inhibitor. The apoptosis did not depend on Toll-like receptor 3 (TLR3) expression, because TLR3-silencing failed to inhibit IFN-β induction by miR-145. Then, we focused on the suppressor of cytokine signaling 7 (socs7), whose expression level was upregulated in bladder cancer cells compared with its level in normal human urothelial cells, as a putative target gene involved in IFN-β induction by miR-145. Expectedly, exogenous miR-145 decreased the expression level of SOCS7, and socs7-silencing enhanced IFN-β induction by transfection with a TLR3 ligand, polyinosinic acid-polycytidylic acid (PIC). The results of a luciferase reporter assay revealed that miR-145 targeted socs7. In addition, socs7-silencing significantly decreased the level of p-Akt and suppressed the growth of T24 cells. Furthermore, exogenous miR-145 or socs7-silencing promoted nuclear translocation of STAT3. In conclusion, the machinery of IFN-β induction through the regulation of SOCS7 by miR-145 was closely associated with the induction of apoptosis. Moreover, exogenous miR-145 promoted IFN-β induction by targeting socs7, which resulted in the nuclear translocation of STAT3. Additionally, our data indicate that SOCS7 functioned as an oncogene, the finding that revealed a novel mechanism of carcinogenesis in bladder cancer cells.

The color Doppler flow imaging (CDFI) technique was used to study the dynamics of cerebrospinal fluid (CSF) flow in 13 infants with intracranial hemorrhage. CDFI was performed 46 times in 6 intraventricular hemorrhage (IVH) patients and 7 subarachnoid hemorrhage (SAH) patients with or without subdural hemorrhage during different stages. CSF flow was observed in 8 infants with IVH (5) or SAH (3) on CDFI. CSF flow in the aqueduct, third ventricle and foramen of Monro was visualized in both the upward and downward directions, primarily reflecting respiration and/or cardiac pulsation in the acute stage. It is suggested that CDFI may allow evaluation of the CSF flow dynamics and an early diagnosis of intracranial hemorrhage in infants.