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In metal forming processes, the interface between a workpiece and a tool was occasionally observed directly. However, the rolling interface has almost never been observed because of high-speed roll rotation. To achieve the in situ observation, this paper proposes a novel method where one roll is fixed in the space without rotation, while the other roll revolves around the fixed roll with rotation. With passing the gap between the two rolls, a sheet is rolled. A prototype machine with transparent rolls was fabricated, then the interface in solder rolling was successfully observed from the interior of the fixed roll. [ABSTRACT FROM AUTHOR]

With the aim to discover a gastric antisecretory agent more potent than the existing proton pump inhibitors, novel 3,4-dihydro-1 H -spiro(naphthalene-2,2′-piperidin)-1-one derivatives, which could occupy two important lipophilic pockets (described as LP-1 and LP-2) of H + ,K + -ATPase and can strongly bind to the K + -binding site, were designed based on a docking model. Among the compounds synthesized, compound 4d showed a strong H + ,K + -ATPase-inhibitory activity and a high stomach concentration in rats, resulting in potent inhibitory action on histamine-stimulated gastric acid secretion in rats. Furthermore, 4d exerted significant inhibitory action on histamine-stimulated gastric-acid secretion in rats with a rapid onset and moderate duration of action after the administration. These findings may lead to a new insight into the drug design of potassium-competitive acid blockers. [ABSTRACT FROM AUTHOR]

To develop a novel series of CDK8/19 dual inhibitors, we employed structure-based drug design using docking models based on a library compound, 4,5-dihydroimidazolo[3′,4′:3,4]benzo[1,2- d ]isothiazole 16 bound to CDK8. We designed various [5,6,5]-fused tricyclic scaffolds bearing a carboxamide group to maintain predicted interactions with the backbone C O and NH of Ala100 in the CDK8 kinase hinge region. We found that 4,5-dihydrothieno[3′,4′:3,4]benzo[1,2- d ]isothiazole derivative 29a showed particularly potent enzymatic inhibitory activity in both CDK8/19 (CDK8 IC 50 : 0.76 nM, CDK19 IC 50 : 1.7 nM). To improve the physicochemical properties and kinase selectivity of this compound, we introduced a substituted 3-pyridyloxy group into the scaffold 8-position. The resulting optimized compound 52h showed excellent in vitro potency (CDK8 IC 50 : 0.46 nM, CDK19 IC 50 : 0.99 nM), physicochemical properties, and kinase selectivity (only 5 kinases showed <35% unbound fraction at 300 nM. CDK19: 4.6%, CDK8: 8.3%, HASPIN: 23%, DYRK1B: 27%, HIP1: 32%). Based on a docking model of 52h bound to CDK8, we could explain the highly specific kinase activity profile found for this compound, based on the interaction of the pyridyl group of 52h interacting with Met174 of the CDK8 DMG activation loop. In vitro pharmacological evaluation of 52h revealed potent suppression of phosphorylated STAT1 in various cancer cells. The high oral bioavailability found for this compound enabled in vivo studies, in which we demonstrated a mechanism-based in vivo PD effect as well as tumor growth suppression in an RPMI8226 human hematopoietic and lymphoid xenograft model in mouse [T/C: −1% (2.5 mg/kg, qd)]. [ABSTRACT FROM AUTHOR]

Here, we report a case of heparin-induced thrombocytopenia (HIT) associated with polycythemia vera (PV) during the treatment of acute coronary syndrome. An 84-year-old woman with pre-existing PV had an acute myocardial infarction and developed HIT after using heparin. An additional myocardial infarction was caused by HIT, and caused marked damage to her cardiac function. However, she was successfully treated with argatroban infusion and intensive care. In this case, we suspected HIT at an extremely early stage, when the decline in platelet count remained at 16%, which might have prevented further thrombosis. Subsequently, the nadir in the platelet count remained at 32%, which resulted in “intermediate possibility of HIT” according to the 4Ts score; thus, further detailed serological examination may be required for accurate diagnosis of HIT. < Learning objective: The main contribution of our paper is that it reveals that clinicians should exercise caution when treating patients with polycythemia vera (PV) because they are prone to serious thrombotic complications and the presence of PV may obscure the occurrence of heparin-induced thrombocytopenia because of atypical fluctuations in platelet counts. We believe that this contribution is theoretically and practically relevant because it includes findings that could enhance clinical treatment and outcomes among such patients.> [ABSTRACT FROM AUTHOR]

Background C-reactive protein (CRP) is a prototypic acute phase protein which increases dramatically in the blood during the first 48 h of tissue inflammation and has been recognized as a risk factor for atherosclerosis. CRP interacts with a variety of proteins. Objective To know the role of accumulated CRP in the skin. Methods Interaction of CRP with basal keratinocytes was studied using immunohistochemical method and keratinocyte culture system. Results We found an immunohistochemical deposition of CRP on the basal keratinocyte membrane in some normal human skins (23 out of 46 skins). When added to cultured keratinocytes, heat-denatured but not native CRP was found to adhere to keratinocyte cell membrane after 1 h, then internalized into cytoplasm after 24 h. The heat-denatured CRP recognized at least four keratinocyte polypeptides with the molecular weights of 56, 42, 32 and 24 kDa. Ligand binding assays suggested that multiple populations of receptor-ligand interactions were involved in the binding between CRP and keratinocyte. Cultured dermal microvascular endothelial cells were found to express CRP of which expression was greatly induced by interleukin-1β (IL-1β) treatment, suggesting that the deposited CRP in the basal keratinocytes can be derived from local dermal microvasculatures as well as from systemic circulation (serum). Treatment of cultured keratinocytes with heat-denatured CRP induced interleukin-8 (IL-8) expression, a potent leukocyte chemotactic cytokine. CRP in the medium (liquid phase) and CRP-coated dishes (solid phase) both inhibited the adhesion of keratinocytes in culture. Conclusion Accumulation of CRP may regulate the skin inflammation and keratinocyte proliferation by modulating keratinocyte cytokine expression and adhesion to substrate. [ABSTRACT FROM AUTHOR]

Summary The purpose of this study was to clarify the relationship between the thickness of the deep cervical flexor muscles (longus capitis and longus colli) at rest and sternocleidomastoid activity during the craniocervical flexion test (CCFT). Thirteen healthy males participated in this study. The thickness of the deep cervical flexor muscles was measured by ultrasound imaging in a relaxed supine position. Activity of the sternocleidomastoid was measured by electromyography during the CCFT at five incremental levels (22, 24, 26, 28, and 30 mm Hg). Correlations between normalized muscle thickness relative to body mass index and sternocleidomastoid activity were determined. Significant negative correlations were observed between normalized muscle thickness and activity of the sternocleidomastoid at 26 ( r = −0.622, P = 0.023) and 28 mmHg ( r = −0.653, P = 0.015). Individuals with smaller deep cervical flexor muscles exhibited increased activity in the sternocleidomastoid during the CCFT. [ABSTRACT FROM AUTHOR]

The purpose of this study was to clarify the correlation between neck slope angle and deep cervical flexor muscle thickness in healthy subjects. Forty-two healthy male (20.7 ± 2.6 years old) participated in this study. Neck slope angle was measured in a relaxed sitting posture. The deep cervical flexor muscle thickness was measured in a relaxed supine posture. The correlations between neck slope angle and normalized muscle thickness relative to body mass index were determined using Pearson's correlation coefficient. There was a moderate positive correlation between neck slope angle and normalized muscle thickness ( r = 0.414, P = 0.006). The result demonstrated that participants with lower neck slope angles had smaller muscle thicknesses of the deep cervical flexor muscles. It appears that the deep cervical flexor muscle thickness might be associated with neck slope angle in a relaxed sitting posture. [ABSTRACT FROM AUTHOR]

Background We hypothesized that a development of a novel index based on the combination of left atrial volume (LAV) and left atrial (LA) function evaluated by the time–LA volume curve using speckle tracking echocardiography (STE) would be accurate and useful to estimate pulmonary capillary wedge pressure (PCWP). Our goal was to develop a novel index of PCWP based on a combination of LAV and LA function using STE. Methods A cross-validation study was performed with the patients divided into a training study to define the novel index ( n = 50) and a testing study to validate the index ( n = 196). PCWP was measured by right heart catheterization, and phasic LAV and emptying function (EF) were measured by STE. Results Simple linear regression analysis in the training study revealed that the novel index that best estimated PCWP was the kinetics-tracking index [KT index = log 10 (active LAEF/minimum LAV index)]. Multiple regression analysis revealed that the KT index was the most reliable predictor of PCWP. It had the strongest correlation with PCWP ( r = −0.86, p < 0.001) among all echocardiographic parameters. In the testing study, PCWP estimated by the KT index was also strongly correlated with measured PCWP ( r = 0.92, p < 0.001). These correlations were also strong in the patients with reduced left ventricular ejection fraction (<50%), chronic heart failure, and chronic atrial fibrillation ( r = 0.92, r = 0.91, r = 0.79, p < 0.001, respectively). Conclusions A novel index (KT index) using a combination of LAV and LA function was a powerful and useful predictor of PCWP and may be valuable in routine clinical practice. [ABSTRACT FROM AUTHOR]

Summary The purpose of this study is to assess the reliability of a new ultrasound imaging (USI) parameter and procedure for the evaluation of the size of the deep cervical flexor (DCF) muscles. Thirty-one healthy male subjects (21.6 ± 2.5 years old) participated in this study. Two images of the diagonal dimension (DD) of the DCF of the subjects, at 1.5 fingerbreadths below the laryngeal prominence of the thyroid cartilage in a relaxed state, were taken on separate days with a 1-week interval. The intraclass correlation coefficient between the days was 0.82 (95% confidence interval, 0.65–0.91). The standard error of measurement and minimal detectable change were 0.8 mm and 2.1 mm, respectively. The results indicated that the DD may be used as a reliable USI parameter to measure the DCF thickness in healthy subjects. [ABSTRACT FROM AUTHOR]

Low-intensity ultrasound has been shown to produce a transient pore on cell membranes and allow extracellular materials such as chemotherapeutic drugs, DNA and viruses to enter cells. Boron neutron capture therapy (BNCT) is a selective radiotherapy, if the 10 B concentration is higher in the tumor than in normal tissue. The effect of ultrasound on the uptake of 10 B carrier compounds, boronophenylalanine (BPA) and boronocaptate sodium (BSH), was examined in cell cultures. Cellular 10 B concentrations were increased after the incubation of oral squamous cell carcinoma (SCC) SAS cells with BPA, but not BSH. When cells treated with BPA or BSH were exposed to ultrasound in the presence, but not absence of microbubbles, cellular 10 B concentrations were significantly increased as compared with the untreated control. The suppressive effect of BPA-mediated BNCT on cell viability was more prominent with than without ultrasound. These results suggest that ultrasound is useful to increase the incorporation of boron compounds and enhance the efficiency of BNCT for oral SCC. [ABSTRACT FROM AUTHOR]

Background: Left atrial appendage (LAA) thrombus increases the risk of thromboembolism in atrial fibrillation (AF), and LAA contractile function like emptying fraction (EF) should have physiological importance in thrombus formation. The aim of this study was to validate a velocity vector imaging (VVI) method for quantification of the LAA function and to elucidate echocardiographic parameters that are related to the presence of LAA thrombus in patients with nonvalvular AF. Methods: We measured left atrial (LA) dimension and LAEF by VVI using transthoracic echocardiography, and LAA emptying velocity, spontaneous echo contrast (SEC), and LAAEF by W l using transesophageal echocardiography (TEE) in 142 consecutive patients with nonvalvular AF. The patients were divided into two groups according to the presence (n = 38) or absence (n = 104) of LAA thrombus. Results: There was a good correlation between the VVI method and manual-tracing method for LAAEF and LAEF of patients with AF (r = 0.97, r = 0.96, respectively, p< 0.001). LAAEF in AF with thrombus was significantly reduced compared with AF without thrombus (16.9 ±3.1% and 29.0±9.7%, p<0.001). In multivariate logistic regression analysis, LAAEF, SEC, and prior stroke were independent determinants of LAA thrombus. Using 20% of LAAEF as a cutoff value, the sensitivity was 92% and specificity was 88% for LAA thrombus. Conclusion: The Wl method was reliable in the measurement of LAAEF and LAEF compared with the manual-tracing method. LAAEF assessed by the VVI method using TEE was related to the presence of LAA thrombus. [ABSTRACT FROM AUTHOR]

Abstract: The effect of a strong, lipophilic statin (pitavastatin) on the thoracic aorta has not yet been elucidated. The purpose of the present study was to evaluate the effects of pitavastatin (P) therapy on plaque components and morphology in the thoracic aorta by transesophageal echocardiography (TEE) and clarify the impact of the therapy on media and intima in patients with hypercholesterolemia. Sixty-four media and 64 intima of the thoracic aorta were investigated in 32 patients with hypercholesterolemia. The corrected integrated backscatter (c-IBS) values in the thoracic aortic wall and intima-media thickness (IMT) at the same site were measured before and after P therapy or diet (D) for 7 mo. Moreover, c-IBS values in media were measured in 168 patients without hypercholesterolemia to estimate age-dependent changes. C-IBS values in media were correlated with age (r = 0.84, p < 0.001). C-IBS and IMT of media in the P group significantly decreased from −17.8 ± 2.4 to −20.1 ± 3.7 dB and from 1.7 ± 0.3 to 1.5 ± 0.3 mm, respectively (p < 0.001), whereas those in the D group significantly increased from −18.3 ± 2.0 to −16.7 ± 2.1 dB and from 1.6 ± 0.3 to 1.7 ± 0.2 mm, respectively (p < 0.001). IMT in intima in the P group significantly decreased from 3.7 ± 0.4 to 3.3 ± 0.4 mm (p < 0.001). C-IBS in intima in the P group significantly increased from −10.2 ± 2.2 to −6.9 ± 1.7 dB, which indicated plaque stabilization. Pitavastatin improved the atherosis measured by IMT and sclerosis measured by c-IBS values in the media and induced stabilization and regression of plaques in the intima of the thoracic aorta. (E-mail: masanori@ya2.so-net.ne.jp) [Copyright &y& Elsevier]

Recurrent head and neck malignancies (HNM) are often radio-/chemo-resistant and show extensive growth, necessitating a wide resection including surrounding tissues. To avoid severe impairment of oro-facial structures and functions, it is necessary to explore new treatments for HNM. Boron neutron capture therapy (BNCT) is tumor-cell targeted radiotherapy that has significant superiority over conventional radiotherapies in principle. We report here, first in the world, six patients with a recurrent HNM who have been treated with BNCT. The BNCT in combination with boronophenylalanine (BPA) and borocaptate sodium (BSH) was performed using the epithermal neutrons with Kyoto University Research Reactor (KUR). The results of BNCT were as follows: (1) 10B concentration of tumor/normal tissue ratios (T/N ratio) of PET studies were SCC:1.8–4.4, sarcoma:3.1–4.0, parotid tumor:3.5. (2) Relative volume (%) of each tumor to the prior were 6–46%. (3) Remarkable reduction (46–100%) of huge tumor such as 40–675 cm3 (average: 315 cm3), improvement of QOL and very mild side effects were recognized in all cases. These results indicate that BNCT represents a new and promising treatment approach even for a huge or far advanced HNM. [Copyright &y& Elsevier]

The compound biological effectiveness (CBE) value of boronophenylalanine (BPA) for hepatocytes was experimentally determined for the purpose of boron neutron capture therapy (BNCT) for liver tumors. In this study, the critical reevaluation of previous value was performed. In previous experimental studies, the contribution of β component of dose was ignored in the response curve to X-ray. X-ray dose cell survival curves were estimated by combining the α/β values obtained in the ordinary micronucleus (MN) assay with the curve of MN-negative cell fraction (MN(−)F) to dose. This curve was compared to the boron neutron capture reaction (BNCR) dose curve. As a result, the CBE value was 4 at doses close to 0 Gy, decreasing to about 1.0 at doses close to 4.5 Gy. The new value is smaller than the previous value 4.2. This indicates that the bioequivalent dose to normal liver is lower than previously expected. Therefore, higher doses can be given to the tumor. • The CBE value for hepatocytes of BPA was reevaluated. • The curve of MN frequency to X-ray dose was reconstructed into a MN-negative cell fraction curve with β component in the LQ model. • The MN-negative cell fraction curve to BNCR dose, which have essentially only α component, was compared with MN-negative cell fraction curve to X-ray dose. • CBE value decreased with BNCR dose, and DVH in the was constructed. • The bioequivalent dose remarkably reduced by the use of reevaluated variable CBE value of BPA for hepatocytes. [ABSTRACT FROM AUTHOR]

We previously reported that 4-(pyrrolidin-1-yl)benzonitrile derivative 1b was a selective androgen receptor modulator (SARM) that exhibited anabolic effects on organs such as muscles and the central nervous system (CNS), but neutral effects on the prostate. From further modification, we identified that 4-(5-oxopyrrolidine-1-yl)benzonitrile derivative 2a showed strong AR binding affinity with improved metabolic stabilities. Based on these results, we tried to enhance the AR agonistic activities by modifying the substituents of the 5-oxopyrrolidine ring. As a consequence, we found that 4-[(2 S ,3 S )-2-ethyl-3-hydroxy-5-oxopyrrolidin-1-yl]-2-(trifluoromethyl)benzonitrile ( 2f ) had ideal SARM profiles in Hershberger assay and sexual behavior induction assay. Furthermore, 2f showed good pharmacokinetic profiles in rats, dogs, monkeys, excellent nuclear selectivity and acceptable toxicological profiles. We also determined its binding mode by obtaining the co-crystal structures with AR. [ABSTRACT FROM AUTHOR]

Background: The potential exists for microcirculatory impairment during rotational coronary atherectomy (RA) due to embolization of plaque debris, platelet aggregation, or vasospasm. This prospective randomized pilot study aimed to confirm favorable effects of nicorandil during RA compared with verapamil. Methods: We randomly assigned 200 patients with 219 coronary lesions planned to undergo RA with intracoronary infusion of nicorandil cocktail (100 patients, 109 lesions), which contained nicorandil 24 mg, nitroglycerin 5 mg, and heparin 10000 U in 1000 mL saline, or verapamil cocktail (100 patients, 110 lesions), which contained verapamil 10 mg instead of nicorandil. Drug cocktails were infused through a 4F Teflon sheath of the rotablator system during RA. The primary end point was incidence of no-reflow/slow-flow phenomenon; secondary end points were those of continuous ST elevation, Q-wave myocardial infarction (MI), and non–Q-wave MI. Results: Group baseline and coronary angiographic characteristics were similar. Rotational atherectomy was performed successfully, and no patients died or required emergency coronary artery bypass grafting. Incidence of no-reflow/slow-flow phenomenon was significantly lower in the nicorandil group (nicorandil 5/109 lesions, verapamil 13/110 lesions, P < .005). Incidences of persistent ST-segment elevation and non–Q-wave MI were significantly lower in the nicorandil group (ST-segment elevation: nicorandil 3/100 patients, verapamil 10/100 patients, P < .05; non–Q-wave MI: nicorandil 2/100, verapamil 9/100 patients, P < .05). One patient each in the 2 groups experienced Q-wave MI. Conclusion: Our findings suggest that continuous intracoronary infusion of nicorandil during RA prevents acute periprocedural complications. Nicorandil should be used as adjunctive treatment during RA. [Copyright &y& Elsevier]

Abstract: The retinoic acid (RA, a vitamin A metabolite) receptor (RAR) is a transcription factor. Vitamin A/RA administration improves the Alzheimer's disease (AD)- and age-related attenuation of memory/learning in mouse models. Recently, a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) was identified as a key molecule in RA-mediated anti-AD mechanisms. We investigated the effect of chronic administration of the RAR agonist Am80 (tamibarotene) on ADAM10 expression in senescence-accelerated mice (SAMP8). Moreover, we estimated changes in the expression of the amyloid precursor protein (APP), amyloid beta (Aβ), and hairy/enhancer of split (Hes), which are mediated by ADAM10. Spatial working memory and the levels of a hippocampal proliferation marker (Ki67) were also assessed in these mice. ADAM10 mRNA and protein expression was significantly reduced in the hippocampus of 13-month-old SAMP8 mice; their expression improved significantly after Am80 administration. Further, after Am80 administration, the expression levels of Hes5 and Ki67 were restored and the deterioration of working memory was suppressed, whereas APP and Aβ levels remained unchanged. Our results suggest that Am80 administration effectively improves dementia by activating the hippocampal ADAM10–Notch–Hes5 proliferative pathway. [Copyright &y& Elsevier]

Accumulation of degenerated elastic fibers in the sun-exposed skin designated as actinic elastosis is a histological hallmark of photodamaged skin. Previous studies have indicated that the elastic fibers of actinic elastosis interact with lysozyme and are modified by Nɛ-(carboxymethyl)lysine (CML), one of the major advanced glycation end products (AGEs). We studied here how CML modification of elastin is involved in the pathogenesis of actinic elastosis. The CML-modified insoluble elastin became resistant to neutrophil elastase digestion, which was reversed by treatment with aminoguanidine, a potent inhibitor of AGE formation. In a temperature-dependent aggregation assay, CML-modified elastin rapidly formed self-aggregates, the size of which was larger than unmodified elastin. The elastic fiber sheets prepared from CML-modified α-elastin showed 3D wider diameter, tortuous appearance, and decreased elasticity on tensile tests. The CML-modified α-elastin, but not unmodified α-elastin, was found to bind to lysozyme in vitro, supporting the immunohistochemical findings that the antibodies for lysozyme and CML reacted simultaneously with the elastic fibers of actinic elastosis and UV-irradiated skin. The glycated elastin is likely to cause the accumulation of abnormally aggregated elastic fibers and unusual interaction with lysozyme in actinic elastosis. [ABSTRACT FROM AUTHOR]

Boron neutron capture therapy (BNCT) is a unique radiation therapy in which boron compounds are trapped into tumor cells. To determine the biodistribution of boronophenylalanine (BPA) in nude mice carrying oral squamous cell carcinoma (SCC), BPA was administered at a dose of 250 mg/kg body weight intraperitoneally. Two hours later, 10B concentration in the tumor was 15.96 ppm and tumor/blood, tumor/tongue, tumor/skin and tumor/bone 10B concentration ratios were 6.44, 4.19, 4.68 and 4.56, respectively. Two hours after the administration of borocaptate sodium (BSH) at a dose of 75 mg/kg body weight, 10B concentration in the tumor was 3.61 ppm, and tumor/blood, tumor/tongue, tumor/skin and tumor/bone 10B concentration ratios were 0.77, 1.05, 0.60 and 0.59, respectively. When cultured oral SCC cells were incubated with BPA or BSH for 2 h and then exposed to thermal neutrons, the proportion of survival cells that were capable of forming cell colonies decreased exponentially, depending on 10B concentration. BPA-mediated BNCT was more efficient than BSH-mediated BNCT. Addition of boron compounds in the cell suspension during neutron irradiation enhanced the cell-killing effect of the neutrons. These results indicate that BPA is more selectively incorporated into human oral SCC as compared with normal oral tissues, and that both extra- and intra-cellular BPA contribute to the cell-killing effect of BNCT. BPA may be a useful boron carrier for BNCT in the treatment of advanced oral SCC. [Copyright &y& Elsevier]

Purpose: To investigate the mutagenic effect in boron neutron capture therapy (BNCT), Chinese hamster ovary cells were incubated with 10 B-enriched borocaptate sodium (BSH) or para-boronophenylalanine (BPA) before exposure to thermal neutrons, and the occurrence of mutations at the hypoxanthine-guanine phosphoribosyl transferase (HPRT) locus was measured.Methods and Materials: BSH or BPA was added to cells 20 h or 2 h before irradiation and removed before irradiation. Cells were irradiated with thermal neutrons. The biologic end point of cell survival was measured by colony formation assay. The mutagenicity was calculated from the mutation frequency at the HPRT locus.Results: The mutagenicity of BSH and BPA was similar to that of 10B boric acid when the cells were irradiated with neutrons at an isosurvival dose after 2-h preincubation. Preincubation with BSH for 20 h, compared with preincubation for just 2 h, had no effect on either cytotoxicity or mutagenicity in BNCT. However, with BPA, 20-h preincubation, compared with 2-h preincubation, caused an increase in the cell killing effect, but a decrease in the mutagenic effect of the BNCT.Conclusion: After 20-h incubation, BPA was less mutagenic than BSH. The mutagenic study of electroporated BPA or BSH revealed a reduced mutagenicity. These results suggest that the retention of these boron compounds in the cells causes a more accurate assault on the cell and lessens the chance of misrepair after neutron irradiation. [Copyright &y& Elsevier]

• Accelerator-BNCT produced tumor response in 71% of head and neck patients. • BNCT showed no serious adverse events such as grade 4 or 5, except hyperamylasemia. • The results support a pivotal role of accelerator BNCT in cancer treatment. Boron neutron capture therapy (BNCT) can be performed without reactors due to development of cyclotron-based epithermal neutron source (C-BENS), which is optimized for treatment for deeper-seated tumors. The purpose of this study was to evaluate efficacy and safety of cyclotron-based BNCT with borofalan (10B) for recurrent or locally advanced head and neck cancer. In this open-label, phase II JHN002 trial of BNCT using C-BENS with borofalan (10B), patients with recurrent squamous cell carcinoma (R-SCC) or with recurrent/locally advanced non-squamous cell carcinoma (R/LA-nSCC) of the head and neck were intravenously administered 400 mg/kg borofalan (10B), followed by neutron irradiation. The tumor dose was determined passively as the mucosal maximum dose of 12 Gy-Eq. The primary endpoint was the objective response rate (ORR). Post-trial observational JHN002 Look Up study was planned for evaluating locoregional progression-free survival (LRPFS). Eight R-SCC and 13 R/LA-nSCC patients were enrolled. All R-SCC patients had prior radiotherapy with a median dose of 65.5 Gy (range, 59.4–76.0 Gy). The ORR for all patients was 71%, and complete response/partial response were 50%/25% in R-SCC and 8%/62% in R/LA-nSCC. The 2-year overall survival for R-SCC and R/LA-nSCC were 58% and 100%, respectively. The median LRPFS was 11.5 months for R-SCC. Frequently observed adverse events included alopecia (95%), hyperamylasemia (86%), and nausea (81%). These data suggest that BNCT using C-BENS with borofalan (10B) is a promising treatment option for patients with R-SCC or R/LA-nSCC of the head and neck. [ABSTRACT FROM AUTHOR]

With the aim to discover a novel excellent potassium-competitive acid blocker (P-CAB) that could perfectly overcome the limitations of proton pump inhibitors (PPIs), we tested various approaches based on pyrrole derivative 1 as a lead compound. As part of a comprehensive approach to identify a new effective drug, we tried to optimize the duration of action of the pyrrole derivative. Among the compounds synthesized, fluoropyrrole derivative 20j , which has a 2-F-3-Py group at position 5, fluorine atom at position 4, and a 4-Me-2-Py sulfonyl group at the first position of the pyrrole ring, showed potent gastric acid-suppressive action and moderate duration of action in animal models. On the basis of structural properties including a slightly larger C log P value (1.95), larger log D value (0.48) at pH 7.4, and fairly similar pKa value (8.73) compared to those of the previously optimized compound 2a , compound 20j was assumed to undergo rapid transfer to the stomach and have a moderate retention time there after single administration. Therefore, compound 20j was selected as a new promising P-CAB with moderately long duration of action. [ABSTRACT FROM AUTHOR]

A boron delivery system with high therapeutic efficiency and low adverse effects is crucial for a successful boron neutron capture therapy (BNCT). In this study, we developed boron cluster-containing redox nanoparticles (BNPs) via polyion complex (PIC) formation, using a newly synthesized poly(ethylene glycol)-polyanion (PEG-polyanion, possessing a 10 B-enriched boron cluster as a side chain of one of its segments) and PEG-polycation (possessing a reactive oxygen species (ROS) scavenger as a side chain of one of its segments). The BNPs exhibited high colloidal stability, selective uptake in tumor cells, specific accumulation, and long retention in tumor tissue and ROS scavenging ability. After thermal neutron irradiation, significant suppression of tumor growth was observed in the BNP-treated group, with only 5-ppm 10 B in tumor tissues, whereas at least 20-ppm 10 B is generally required for low molecular weight (LMW) 10 B agents. In addition, increased leukocyte levels were observed in the LMW 10 B agent-treated group after thermal neutron irradiation, and not in BNP-treated group, which might be attributed to its ROS scavenging ability. No visual metastasis of tumor cells to other organs was observed 1 month after irradiation in the BNP-treated group. These results suggest that BNPs are promising for enhancing the BNCT performance. [ABSTRACT FROM AUTHOR]

Boron neutron capture therapy (BNCT) is a cellular-level particle radiation therapy that combines the selective delivery of boron compounds to tumour tissue with neutron irradiation. Previously, high doses of one of the boron compounds used for BNCT, L-BPA, were found to reduce the boron-derived irradiation dose to the central nervous system. However, injection with a high dose of L-BPA is not feasible in clinical settings. We aimed to find an alternative method to improve the therapeutic efficacy of this therapy. We examined the effects of oral preloading with various analogues of L-BPA in a xenograft tumour model and found that high-dose L-phenylalanine reduced the accumulation of L-BPA in the normal brain relative to tumour tissue. As a result, the maximum irradiation dose in the normal brain was 19.2% lower in the L-phenylalanine group relative to the control group. This study provides a simple strategy to improve the therapeutic efficacy of conventional boron compounds for BNCT for brain tumours and the possibility to widen the indication of BNCT to various kinds of other tumours. [ABSTRACT FROM AUTHOR]

Malignant peripheral nerve sheath tumors (MPNST) are relatively rare neoplasms with poor prognosis. At present there is no effective treatment for MPNST other than surgical resection. Nonetheless, the anti-tumor effect of boron neutron capture therapy (BNCT) was recently demonstrated in two patients with MPNST. Subsequently, tumor-bearing nude mice subcutaneously transplanted with a human MPNST cell line were injected with p -borono- L -phenylalanine ( L -BPA) and subjected to BNCT. Pathological studies then revealed that the MPNST cells were selectively destroyed by BNCT. [ABSTRACT FROM AUTHOR]

Brain radiation necrosis is the most serious late adverse event that occurs after 6 months following radiation therapy. Effective treatment for this irreversible brain necrosis has not been established yet. This study tries to establish brain radiation necrosis mouse model using proton or helium beam. The right cerebral hemispheres of C57BL/6J mouse brains were irradiated at doses of 40, 50, 60 Gy with charged particles. In 60 Gy group, brain necrosis that recapitulates human disease was detected after 8 months. [ABSTRACT FROM AUTHOR]

Clear cell sarcoma (CCS) is a rare malignant tumor with a poor prognosis. In the present study, we established a lung metastasis animal model of CCS and investigated the therapeutic effect of boron neutron capture therapy (BNCT) using p -borono- l -phenylalanine ( l -BPA). Biodistribution data revealed tumor-selective accumulation of 10 B. Unlike conventional gamma-ray irradiation, BNCT significantly suppressed tumor growth without damaging normal tissues, suggesting that it may be a potential new therapeutic option to treat CCS lung metastases. [ABSTRACT FROM AUTHOR]

To understand the mechanism of cell death induced by boron neutron capture reaction (BNCR), we performed proteome analyses of human squamous tumor SAS cells after BNCR. Cells were irradiated with thermal neutron beam at KUR after incubation under boronophenylalanine (BPA)(+) and BPA(−) conditions. BNCR mainly induced typical apoptosis in SAS cells 24 h post-irradiation. Proteomic analysis in SAS cells suggested that proteins functioning in endoplasmic reticulum, DNA repair, and RNA processing showed dynamic changes at early phase after BNCR and could be involved in the regulation of cellular response to BNCR. We found that the BNCR induces fragments of endoplasmic reticulum-localized lymphoid-restricted protein (LRMP). The fragmentation of LRMP was also observed in the rat tumor graft model 20 hours after BNCT treatment carried out at the National Nuclear Center of the Republic of Kazakhstan. These data suggest that dynamic changes of LRMP could be involved during cellular response to BNCR. [ABSTRACT FROM AUTHOR]

Salvage surgery after radiation therapy is known to be associated with a high incidence of postoperative complications. We describe a case of a successful salvage surgery after BNCT. In our patient with head and neck carcinoma, cervical lymph node recurrence with adhesion to a large vessel occurred after conventional radiotherapy. This lesion responded well to BNCT. Salvage surgery was subsequently performed to remove the residual tumor. Histopathologically, the isolated tissue contained tumor cells in its center and the surrounding tissue showed severe fibrosis. However, the tissue outside of the irradiation area had almost no fibrosis. BNCT may facilitate salvage surgery after radiotherapy because it causes less injury to the surrounding tissue than conventional radiotherapy. Our experience suggests that BNCT may be a feasible preoperative treatment in patients with inoperable lesions or in those who strongly desire preservation of function. • In our patient with head and neck carcinoma, cervical lymph node recurrence with adhesion to a large vessel occurred after conventional irradiation. • This lesion responded well to BNCT irradiation and was subsequently treated by tumor resection. • Tissues surrounding the tumor could easily be detached. • Histopathologically, the isolated tissue contained tumor cells in its center and the surrounding tissue showed severe fibrosis. • However, the tissue outside of the irradiation area had almost no fibrosis. [ABSTRACT FROM AUTHOR]

Objective To characterize the preoperative factors affecting renal cell carcinoma patients as predictive of post–radical nephrectomy (RN) mild (M-decline) or severe (S-decline) renal functional decline and to elucidate the histopathologic features of the resected normal kidney cortex, as well as the occurrence of cardiovascular disease (CVD) in both M-decline and S-decline patients. Materials and Methods M-decline and S-decline were categorized as a percentage of postoperative estimated glomerular filtration rate decline of <20 and of >40, respectively. The preoperative factors analyzed were patient demographics, comorbidities, and radiographic findings, including remnant kidney status and tumor size. The factors based on postoperative information analyzed were tumor and normal cortex pathology and CVD events. Results In 175 patient cohort, 21 and 32 cases were categorized as M-decline and S-decline, respectively. Absence of comorbidities, larger remnant kidney volume (RKV)/body surface area (BSA) ratio, and larger tumor diameter were significantly predictive of M-decline, whereas smaller tumor diameter was significantly predictive of S-decline. The global glomerulosclerosis extent in nephrectomized normal cortex of S-decline cases was significantly higher than in other types of cases. No CVD event was observed in M-decline cases. Conclusion This is the first report to identify the RKV/BSA ratio as a promising predictor of post-RN degree of renal functional decline. Post-RN prevention of life-threatening outcomes according to preoperative and postoperative information, including the degree of post-RN renal functional decline and histopathology of the nephrectomized normal cortex, should be considerable in future urological tasks. [ABSTRACT FROM AUTHOR]

Carboranyl-containing chlorins have emerged as promising dual sensitizers for use in both photodynamic therapy (PDT) and boron neutron capture therapy (BNCT), by virtue of their known tumor affinity, low cytotoxicity in dark conditions, and their strong absorptions in the red region of the optical spectrum. Tetrakis( p-carboranylthio-tetrafluorophenyl)chlorin (TPFC) is a new synthetic carboranyl-containing chlorin of high boron content (24% by weight). To evaluate TPFC's applicability as sensitizer for both PDT and BNCT, we performed an in vitro and in vivo study using F98 rat glioma cells and F98 rat glioma-bearing brain tumor models. For the in vivo BNCT study, we used boronophenylalanine (BPA), which is currently used in clinical BNCT studies, via intravenous administration (i.v.) and/or used TPFC via convection-enhanced delivery (CED), a method for local drug infusion directly into the brain. In the in vitro PDT study, the cell surviving fraction following laser irradiation (9 J/cm2) was 0.035 whereas in the in vitro BNCT study, the cell surviving fraction following neutron irradiation (thermal neutron = 1.73 × 1012 n/cm2) was 0.04. In the in vivo BNCT study, the median survival time following concomitant administration of BPA (i.v.) and TPFC (CED) was 42 days (95% confidence interval; 37-43 days). © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:962-970, 2015 [ABSTRACT FROM AUTHOR]