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Cetuximab (Cmab) plays an important role in the treatment for recurrent or metastatic head and neck cancer (R/M HNC). To date, however, no safety data on biweekly administration of cetuximab at a dose of 500 mg/mWe retrospectively reviewed the clinical records of five R/M HNC patients who received biweekly Cmab in our institute between January 2016 and September 2021 and compared the safety profile between two phases of weekly 250 mg/mAll patients initially received Cmab in combination with chemotherapy. Chemotherapy consisted of paclitaxel plus carboplatin in two patients, cisplatin + 5-FU in one patient, and paclitaxel in two patients. Three patients switched treatment schedule from weekly Cmab to biweekly Cmab, while two patients received biweekly Cmab after completion of chemotherapy. The main reason for switching to biweekly Cmab was an unacceptably long commuting time to the hospital. The median duration of Cmab was 217 days (49-321) during weekly Cmab with or without chemotherapy and 42 days (28-175) during biweekly Cmab. Median dose of biweekly Cmab was 4 (3-12). During biweekly Cmab, worsened (Grade ≥ 2) toxicities were observed in two patients: one with grade 2 dry skin and the second with grade 2 skin infection. None developed grade ≥ 3 adverse events or discontinued treatment due to Cmab-related adverse events.Biweekly Cmab was well tolerated and did not demonstrate severe toxicities related to Cmab for R/M HNC.

Salivary secretory carcinoma (SASC) is frequently associated with ETV6-neurotrophic tyrosine receptor kinase (NTRK) 3 fusion and more rarely with RET, MET, or ALK rearrangement. We aimed to elucidate the potential diagnostic utility of pan-tropomyosin receptor kinase (Trk) immunohistochemistry and its relationship with the fusion gene subtype in SASC. We examined 33 cases of SASC for immunoexpression of pan-Trk, ALK and ROS1, and gene rearrangement of the ETV6, NTRK3, and RET genes using fluorescence in situ hybridization (FISH) and reverse transcription-polymerase chain reaction (RT-PCR). Thirty (90.9%) of 33 SASCs harbored ETV6-NTRK3 fusion gene transcripts by RT-PCR and/or both ETV6 and NTRK3 gene rearrangements by FISH, and 3 cases (9.1%) had RET gene rearrangement. Most NTRK3-rearranged SASCs (27/33 cases; 81.8%) had conventional ETV6 exon 5-NTRK3 exon 15 fusion, whereas 2 cases (6.1%) had both the conventional fusion and a novel ETV6 exon 4-NTRK3 exon 15 fusion variant. In the remaining one case (3%), only FISH revealed both ETV6 and NTRK3 rearrangements, suggesting an ETV6-NTRK3 fusion with an as yet undetermined break point. All 30 SASCs with ETV6-NTRK3 fusion and/or NTRK3 rearrangement showed nuclear and cytoplasmic immunoreactivity for pan-Trk. In contrast, 3 SASCs with RET rearrangement showed negative or only weak cytoplasmic staining for pan-Trk. There was no case harboring ALK and ROS1 rearrangements. All 17 non-SASC tumors were negative for pan-Trk. The results suggest that nuclear and cytoplasmic immunoreactivity for pan-TRK may be helpful to identify ETV6-NTRK3-fused SASCs and to distinguish them from RET-rearranged SASCs and morphological mimics.

The purpose of this article is to introduce a collaborative online international exchange unit for physical education called CULTURE (Cultural Unit of Learning To Understand, Respect, and Empathize...

In CheckMate 141, nivolumab significantly improved overall survival (OS) in patients with platinum-refractory recurrent or metastatic squamous cell carcinomas (R/M SCC) of the head and neck. However, reports on nivolumab for patients with non-SCC and/or a primary subsite excluded from CheckMate 141 are limited.We conducted a retrospective analysis of R/M head and neck cancer patients who received nivolumab. The study subject excluded patients with squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, and larynx.A total of 59 patients were included, consisting of 40 males and 19 females with a median age of 61 years. Half of the patients had non-SCC histology. The main primary site included the sinonasal cavity (n = 18), salivary gland (n = 15), and nasopharynx (n = 13). Three (6.0%) patients achieved a complete response and 5 (10.0%) a partial response, giving an overall response rate (ORR) of 16.6%. Median time-to-treatment failure (TTF) and OS were 3.7 and 16.2 months, respectively. Salivary gland and nasopharyngeal cancer achieved relatively higher ORR (25.0 and 36.4%, respectively). On analysis by primary site, nasopharyngeal cancer showed a significantly better TTF and OS than the other primary sites. On analysis by histological findings, no significant difference in TTF and OS was observed between non-SCC and SCC.Nivolumab for cancers involving the salivary gland/nasopharynx and non-SCC histology showed comparable efficacy to that in CheckMate 141. This result indicates that nivolumab may be effective even for patients not included in CheckMate 141.

The purposes of this paper were to examine Frank Knight’s analysis of the market economy and democratic discussion in terms of the character and function of self-interest, and to clarify the uniqueness of his reflections on self-interest. To this end, the paper organized the significance of the re-examination of Knight’s thought as it has developed over recent years in terms of an assessment of the proper role of self-interest in modern society. Knight’s position could be described as skepticism towards two types of optimism. The first is the optimism of the next generation of Chicago economists who saw wants as a given and affirmed an economic order based on self-interest. The second is the optimism of the liberal institutionalists regarding the control of self-interest. In contrast, Knight’s position was ambivalent, recognizing the need for and difficulty in searching for relatively absolute super-individual norms. Knight’s unique position was based on this skepticism. For him, searching for super-individual norms through discussion was necessary, but desperate in the real world. This attitude differed from that of the Chicago economists, who saw wants driven by self-interest as a given, and that of the liberal institutionalists, who were influenced by Dewey’s optimistic view that self-interest could be controlled positively. Knight’s unique position in the genealogy of self-interest is found in this ambivalent attitude toward both types of optimism, and in his nuanced consideration of a market economy and democratic discussion.

Summary NTRK1/3, ALK, and ROS1 translocations have been reported in a minor subset of papillary thyroid carcinomas (PTCs). We aimed to elucidate the prevalence and clinicopathological characteristics of these gene rearrangements and the utility of immunohistochemistry (IHC) in PTC and anaplastic thyroid carcinoma (ATC). We screened nonradiation-exposed cases of 307 PTCs and 16 ATCs by IHC for pan-Trk, ALK, and ROS1, followed by fluorescence in situ hybridization (FISH). In the PTC group, IHC for pan-Trk, ALK, and ROS1 was positive in 18 cases (5.9%), 1 case (0.3%), and 12 cases (3.9%), respectively. Among the pan-Trk IHC–positive cases (n = 18), 2 cases (11.1%; 0.7% of all PTCs) had NTRK1 or NTRK3 gene rearrangement with conventional PTC histology. The ALK IHC–positive case (n = 1) was the follicular variant of PTC with consistent ALK gene rearrangement. ROS1 gene rearrangement was not detectable in the ROS1 IHC–positive PTCs (0/12) by FISH. Most (approximately 70%) of the pan-Trk or ROS1 IHC–positive/FISH–negative cases had BRAF gene mutation with conventional PTC morphology. In the ATC group, neither ALK nor ROS1 IHC was positive, whereas pan-Trk IHC was positive in 1 case (6.3%) in which NTRK1 gene rearrangement was confirmed by FISH. These results suggest that NTRK, ALK, and ROS1 rearrangements are rare molecular events in nonradiation-exposed Japanese patients with PTC and ATC. Although IHC is not an entirely specific surrogate for these abnormalities and does not serve as a stand-alone companion diagnosis, the combined use of IHC and molecular testing may be helpful for determining promising therapeutic strategies with tyrosine kinase inhibitors.

We present a 76-year-old male patient on chronic dialysis for over 10 years with contained rupture of a mycotic abdominal aortic aneurysm, which was successfully treated by thoracic endovascular aortic repair(TEVAR) and computed tomography(CT) guided percutaneous drainage. Endovascular repair of mycotic aortic aneurysm is nowadays feasible and can be a suitable alternative especially in frail patients.

To reveal the atomistic scale mechanism of buckling of single-walled carbon nanotubes (SWCNTs) under axial compression, we carried out molecular dynamics (MD) simulation and atomistic structural instability (ASI) analysis. The ASI analysis enables us to reveal the development of ‘latent’ instability modes until buckling of structure, which cannot be clarified with MD alone. Euler-type buckling was found in relatively thin and long nanotube models, while buckling triggered by change of cross-sectional shape (i.e., radial buckling) was found in thick and short models. With growing radius, a crossover between the Euler-type and radial buckling modes was clearly found in the ASI analysis. Even when the deformation behavior was apparently the same, the buckling can be triggered by different instability modes. We also analyzed the structural instability using the Flugge theory based on linear continuum mechanics (LCM) to compare the results with the ASI analysis. Initial eigenvalues and development of instability modes were different between the ASI and LCM results, leading to a significant deviation of buckling strain and instability crossover points. We investigated the effect of chirality of CNT which is difficult to explain by LCM.

Differential diagnosis among basal cell adenoma (BCA), basal cell adenocarcinoma (BCAC), adenoid cystic carcinoma (ACC) and pleomorphic adenoma (PA) of the salivary gland can be challenging due to their similar histological appearance. Although frequent nuclear β-catenin expression and CTNNB1 mutations have been reported in BCA, further details of the Wnt/β-catenin signal alterations are unclear. The aim of this study was to assess the diagnostic utility of Wnt/β-catenin signal alteration in BCA and morphological mimics. We performed immunohistochemical staining for β-catenin and mutation analysis for Wnt/β-catenin-related genes (CTNNB1, APC, AXIN1 and AXIN2) in BCA (n = 34), BCAC (n = 3), ACC (n = 67) and PA (n = 31). We also analyzed ACC-specific MYB and MYBL1 gene rearrangements by fluorescence in situ hybridization (FISH). Nuclear β-catenin expression (≥3%) was present in 32/34 cases (94.1%) of BCA, and the nuclear β-catenin labeling index was significantly higher than in other tumor types (p = 0.0001). In BCA, we found mutations in CTNNB1, APC and AXIN1 genes (41.1%, 2.9% and 8.8%, respectively). In BCAC, nuclear β-catenin expression with CTNNB1 mutation was present in 1/3 cases (33.3%). As for ACC, nuclear β-catenin expression was observed in 3/67 cases (4.4%), but all 3 cases harbored either MYB or MYBL1 gene rearrangement. The results suggest that nuclear β-catenin immunoreactivity with appropriate criteria may be helpful to distinguish BCA from histologically similar tumors. However, a minor subset of ACCs with nuclear β-catenin expression require careful diagnosis. In addition, Wnt/β-catenin signal alteration may play a role in the pathogenesis of BCA and BCAC.

Bosentan is a substrate of hepatic uptake transporter organic anion-transporting polypeptides (OATPs), and undergoes extensive hepatic metabolism by cytochrome P450 (P450), namely, CYP3A4 and CYP2C9. Several clinical investigations have reported a nonlinear relationship between bosentan doses and its systemic exposure, which likely involves the saturation of OATP-mediated uptake, P450-mediated metabolism, or both in the liver. Yet, the underlying causes for the nonlinear bosentan pharmacokinetics are not fully delineated. To address this, we performed physiologically based pharmacokinetic (PBPK) modeling analyses for bosentan after its intravenous administration at different doses. As a bottom-up approach, PBPK modeling analyses were performed using in vitro kinetic parameters, other relevant parameters, and scaling factors. As top-down approaches, three different types of PBPK models that incorporate the saturation of hepatic uptake, metabolism, or both were compared. The prediction from the bottom-up approach (models 1 and 2) yielded blood bosentan concentration-time profiles and their systemic clearance values that were not in good agreement with the clinically observed data. From top-down approaches (models 3, 4, 5-1, and 5-2), the prediction accuracy was best only with the incorporation of the saturable hepatic uptake for bosentan. Taken together, the PBPK models for bosentan were successfully established, and the comparison of different PBPK models identified the saturation of the hepatic uptake process as a major contributing factor for the nonlinear pharmacokinetics of bosentan.

The alteration of the electronic band gap induced by axial compression of single-wall carbon nanotubes was investigated using molecular dynamics simulation. Beyond a critical level of compressive strain, three classes of buckling modes take place depending on the aspect ratio of the system. Among these three classes, two different shell-buckling modes are found to yield contrasting band-gap modulation behavior as a response to axial compression near the buckling threshold. The potential advantage of using shell buckling to induce gap modulations when designing nanotube-based electromechanical devices is also discussed.

We carried out molecular dynamics (MD) simulation and atomistic instability (ASI) analysis with carbon nanotubes (CNTs) under axial compression to reveal the mechanism of buckling. We investigated the development of instability mode until buckling of structure. For single-walled carbon nanotubes (SWCNTs), Euler-type buckling was found in relatively thin and long nanotubes, while buckling with deformation change of cross-sectional shape (radial buckling) was found in thick and short carbon nanotubes. The crossover between the Euler-type buckling modes and radial buckling modes was clearly seen in the ASI analysis.

The impact of rinsing liquid for Germanium surface after wet chemical treatment is described. The different Ge loss after processing with different rinse (UPW and CO2 water) were determined and the different surface morphologies on the Ge surface after processing with different chemicals (AOM, HF and HCl) were determined by XPS. It was found that the investigation of surface morphology after chemical treatment is necessary to understand the rinse effect and the results showed the CO2 water rinse can decrease and suppress Ge loss at chemical treatment

A rapid repair process of plasma damaged SiCOH in combination with post-etch residue removal has been developed. The carbon depletion layer caused by plasma dry etching was repaired by subsequent surface modifying SAM treatment, which resulted in replenishment of carbon not only on the surface but also a few nm toward the bulk. This repairing technique provides a high-quality hydrophobic surface under conditions of low temperature and short process time. In addition, the SAM layer can be expected to act as an adhesion promotor with metal materials.

Background Differentiating inverted papilloma from squamous cell carcinoma (SCC) is sometimes difficult. We evaluated the clinical usefulness of serum SCCA1 and SCCA2 in the management of patients with inverted papilloma or SCC. Methods Serum and tissue samples for the analysis of SCCA1, SCCA2, and SCC antigen were taken from 18 patients with sinonasal inverted papilloma and 23 cases with sinonasal SCC. The SCCA1, SCCA2, and SCC antigen levels were determined. Results The serum SCCA1 concentration was significantly higher in the inverted papilloma group than in the SCC group, whereas the serum SCCA2 level was significantly higher in the SCC group than in the inverted papilloma group. Conclusion Patients with sinonasal inverted papilloma predominantly express SCCA1 protein, whereas those with SCC predominantly express SCCA2. This suggests that combined measurements of both serum SCCA1 and SCCA2 concentrations can be very useful for distinguishing sinonasal inverted papilloma from SCC.

Introduction Recently the feature size of devices has decreased to Conventional dual-fluid spray is widely used to improve the cleaning efficiency; however, it has not been used on advanced fragile structures because the physical force can easily induce pattern damage. According to a previous paper, smaller droplets at higher velocity are required to reduce pattern damage and to increase particle removal efficiency [1]. In addition, the spray should be able to dissolve the residue. In this paper, we have demonstrated a dual-fluid spray with chemical additive that dissolves the residue and has less pattern damage as an alternative rinse process. Experimental procedures In order to study the characteristics between de-ionized water (DIW) and its chemical additive (Chem. A), a Dynamic Direct Injection system that can mix them at point-of-use and Nanospray as a dual-fluid spray were used. Particle removal efficiency (PRE), CF-polymer removal efficiency (RRE) and distribution of droplets (size and velocity) were investigated. All tests were carried out with DIW, Chem. A and DIW-Chem. A mixtures in a conventional spin processor. (1) SiN PRE vs. pattern damage The number of removed particles was evaluated by an intentional contamination with 45- nm SiN particles on hydrophilic silicon wafer and measured by KLA SP-2. Pattern wafers with aspect ratio 6~7 were prepared as damage test samples. The pattern damage after Nanospray was counted by SEM observation. (2) Residue removal efficiency (RRE) CF-polymer (2x2 cm spots at 37-40 nm thick) was intentionally deposited on low-k material as a test vehicle. The polymer removal efficiency was evaluated by ATR-FTIR spectroscopy. (3) Distribution of droplets (size and velocity) The size (diameter) and velocity of droplets were measured by a droplet measurement system consisting of a laser, high speed camera and image processor. Results and Discussion (1) SiN PRE vs. Pattern damage Fig. 1 shows result of SiN PRE and pattern damage as a function of several Nanospray conditions. The PRE of 100% Chem. A decreased from 50% to 20% compared to DIW; however, its additive mixtures (20% and 40%) showed almost the same PRE as DIW Nanospray. On the other hand, pattern damage was significantly reduced with increasing Chem. A concentration. (2) CF polymer-RRE As shown in Fig. 2, CF-polymer indicates absorbance of functional groups such as C-C, C=O and C-F at the range of 1500 ~ 1900 cm-1. The absorbance of additive mixtures (20% and 40%) or Chem. A Nanospray indicates lower intensity than DIW Nanospray which enables the removal of the CF-polymer by adding Chem. A. (3) Droplets distributions Fig. 3 shows distribution of droplet size as a function of Chem. A concentration. Droplets of DIW Nanospray were widely distributed in size range from 2 to 38µm. In contrast, droplets of Chem.A or its additive mixture Nanospray were much narrower distributed with increasing Chem. A concentration, more than 40% Chem. A Nanospray was achieved in size range from 2 to 17µm.By the addition of the Chem.A to the water, droplet size is decreased than DIW by the role of the surfactant of Chem.A. Therefore, the distribution of large droplets with high kinetic energy decreased and resulted in reduced pattern damage. Conclusions Dual-fluid spray process for post-etch-residue cleaning was developed. An optimized process could enable simultaneous higher PRE and CF-polymer RRE. The additive made smaller droplet size and higher velocity in addition to excellent CF-polymer dissolved characteristics compared to conventional DIW Nanospray. References [1] M. Sato et al, ECS Trans., 41(5) 75-82, 2011 Figure 1

Particle removal without damage to sensitive device structures on semiconductor devices is a necessary process to maximum device yield. The use of an atomized aerosol spray for damage-free particle removal has proven to be one of the more effective strategies. Continued improvements in nozzle design have enabled the use of this technique to 1Xnm technology nodes. Recently, the freezing of water has also shown promise for damage-free particle removal, and the performance of this new technique is compared with aerosol spray cleaning.

This study deals with the process of lexical development by Japanese learners of English in instructional settings. A test was designed to measure their inter-lexical competence (i.e. the ability to use semantically related words differently) about the English basic verbs of sensory perception (e.g. see, listen, smell), which constitutes a conceptual lexical network. Three hundred nineteen university students of different levels of English proficiency participated in this study. The overall results showed that Japanese university students had difficulty in the selective use of basic verbs of perception, and we identified some specific problematic areas. The performance of the participants was discussed in terms of a learning strategy – i.e. the search-translation-equivalent strategy. Pedagogical implications were discussed with reference to core schemas and lexical networks.

Six patients with acute Type A aortic dissection were medically treated due to advanced age, patient refusal and comorbidity despite surgical indication. Computed tomography after onset revealed a thrombosed false lumen in 3 patients and a patent false lumen with flap in 3 patients. All patients were stable during admission except 1 patient who presented with shock. After admission, treatment including strict control of systolic blood pressure was started according to a predetermined treatment strategy. All patients had no significant complications during hospitalization. All patients survived and returned to their usual activities. Medical treatment for stable elderly patients is a possible therapeutic option for acute Type A aortic dissection.

The CMOS devices with Ge, considered as one of new materials for the later 5-nm generations, has been investigated since Ge should be mandatory material to enhance the electron mobility as replacement for Si. In this paper, we will propose new two techniques for surface preparation and wet cleaning, one of two techniques is in terms of PRE (Particle Removal Efficiency) on Ge surface, and the other is Ge corrosion caused by the dissolved oxygen effect. High PRE without Ge loss was achieved for surface preparation by using O 3 /NH 4 OH mixture. And to add to it, excellent selective Ni removal along germanidation (NiGe generation) without Ge corrosion was realized by reducing dissolved oxygen in chemistry.

of these new materials have necessitated the evaluation of new chemicals and processing methods. The control of the Dissolved Oxygen (DO) concentration to suppress Cu corrosion is well established in BEOL processing and likewise in order to achieve a hydrophobic surface after pre-epi cleaning in FEOL surface preparation [2].

Distant metastasis of primary squamous cell carcinoma (SCC) of the thyroid gland is rare and, to the best of our knowledge, cardiac metastasis has not been reported to date. A 57-year-old man underwent surgery and adjuvant chemoradiotherapy for stage IVA SCC of the thyroid gland. After 3 months, the patient was admitted to the Kyushu University Hospital (Fukuoka, Japan) with subcutaneous hematomas of the left thigh and lower leg, and he was diagnosed with cardiac and mediastinal lymph node metastases of SCC of the thyroid gland with severe disseminated intravascular coagulation (DIC). Echocardiography revealed a mass, 52 mm in greatest diameter, protruding from the interventricular septum towards the right ventricle. Weekly administration of paclitaxel and concurrent irradiation of the cardiac and lymph node metastases were performed. Eighteen days after the initiation of chemoradiotherapy, the DIC and hematomas had significantly improved, and the cardiac metastasis was stable. However, 2 months after admission, the patient developed dyspnea and multiple nodular shadows appeared to be spreading in the subpleura of the lungs bilaterally, which were initially suspected to be pulmonary tumor embolisms. Prednisolone and subsequent administration of lenvatinib were not effective and the patient succumbed to respiratory failure. Severe DIC caused by extremely rare cardiac metastasis of SCC of the thyroid gland was effectively controlled by chemoradiotherapy. However, intensive local control appears to be required for this condition.

The requirement for data on the inhibition and involvement of transporters in the pharmacokinetics of drugs in regulatory applications has increased considerably over the last few decades as the knowledge around drug transporters has evolved and regulatory guidance documents have been regularly updated. Drug interactions guidance from the European Medicines Agency (EMA), US Food and Drug Administration (FDA) and Japanese Ministry of Health, Labour and Welfare (MHLW)/Pharmaceuticals and Medical Devices Agency (PMDA) gives detailed information on the data that are recommended in applications, including decision trees on the need to study specific transporters. This chapter will describe strategies to determine the potential for drug interactions and the exposure of the drug in all sub-populations with altered transport protein activity, and how such data should be presented in the drug labels. Alongside this, the process for submission of new drug applications to respective agencies is described, including processes for obtaining advice from the respective agencies with particular emphasis on transporter mediated interactions.

A 64-year-old woman was referred to our hospital with palpitation and exertional dyspnea. An electrocardiogram showed sinus rhythm, but supraventricular tachycardia was recorded on Holter monitoring. Multidetector computed tomography revealed a small left ventricular outpouching in the apex, with a narrow connection to the ventricle and normal coronary arteries. Surgery for the left ventricular pouch was performed successfully. Histological examination demonstrated that the left ventricular diverticulum consisted of three layers of the ventricular wall, with the myocardial layer mostly replaced by fibrous tissue. The patient has been well after surgery.

Objective The aim of this study was to investigate the clinical features and prognosis of patients with squamous cell carcinoma (SCC) associated with sinonasal inverted papilloma (IP). Methods The medical records of 95 patients who were diagnosed with IP or SCC associated with IP were retrospectively reviewed. Out of 95 patients, 15 were diagnosed with SCC associated with IP. The clinical characteristics, treatment modalities, and survival outcomes of the patients were analyzed. Results The incidence of SCC associated with IP was 15.8%. Although differential diagnosis between IP and SCC associated with IP is difficult, epistaxis may be the specific symptom in SCC associated with IP cases. The 3-year disease-specific survival rate was higher in cases with T1, 2 and 3 than in cases with T4. There was no significant difference in survival rate between maxillary sinus and other primary sites. On the other hand, there was a significant difference in survival rate between the microscopic SCC with IP cases and the other cases. In addition, the patients with 70 years old with a 3-year disease free survival of 80% versus 0%. Conclusions Some T4 patients were found to have a highly aggressive disease. Therefore, complete surgical resection followed by chemo-radiation therapy is the recommended treatment for patients with T4 disease to control of the primary tumor site.

Since Tetramethylammonium Hydroxide (TMAH) became widely used as a silicon etchant, e.g. the dummy gate removal for gate-last approach (RMG) [1, or Si fin formation on FinFET [, some careful preparations and optimizations have required implementation. These adaptations have involved not only chemical-related issues, but also hardware-related in order to satisfy the necessary process performance.

Since in vitro cell culture models often show altered apical transporter expression, they are not necessarily suitable for the analysis of renal transport processes. Therefore, we aimed here to investigate the usefulness of primary-cultured rat proximal tubular cells (PTCs) for this purpose. After isolation of renal cortical cells from rat kidneys, PTCs were enriched and the gene expression and function of apical transporters were analyzed by means of microarray, RT-PCR and uptake experiments. RT-PCR confirmed that the major apical transporters were expressed in rat PTCs. Na(+)-dependent uptake of α-methyl-d-glucopyranoside (αMG), ergothioneine and carnitine by the PTCs suggests functional expression of Sglts, Octn1 and Octn2, respectively. Inhibition of pH-dependent glycylsarcosine uptake by low concentration of cephalexin, which is a β-lactam antibiotics recognized by Pepts, indicates a predominant role of high affinity type Pept2, but not low affinity type Pept1, in the PTCs. Moreover, the permeability ratio of [(14)C]αMG (apical to basolateral/basolateral to apical) across PTCs was 4.3, suggesting that Sglt-mediated reabsorptive transport is characterized. In conclusion, our results indicate that rat PTCs in primary culture are found to be a promising in vitro model to evaluate reabsorption processes mediated at least by Sglts, Pept2, Octn1 and Octn2.

The physiological function of organic anion transporter OAT2 (SLC22A7) remains unclear, but since OAT2 transports purine derivatives, it may be involved in renal handling of uric acid, the final metabolite of purine derivatives. In the present study, we studied uric acid transport in stably OAT2-expressing HEK293 cells (HEK293/OAT2). OAT2 mediated uptake, but not efflux, of [(14)C]uric acid. Uric acid transport was saturable with K(m) of 1168+/-335 muM (mean and S.E.M.) and V(max) of 2.57+/-0.350 nmol/min/mg protein. The [(14)C]uric acid uptake was sensitive to Cl(-) and was enhanced at acidic pH. In cis-inhibition assay, [(14)C]uric acid uptake was inhibited by several mono- or dicarboxylic acids, but it was not trans-stimulated by any of the compounds tested. The pattern of inhibition of OAT2-mediated uric acid transport by various drugs was different from that of OAT1- or OAT3-mediated transport. Furthermore, OAT2-mediated transport of uric acid was inhibited by an antiuricosuric drug, pyrazinecarboxylic acid. These results revealed distinct characteristics of uric acid transport via OAT2 compared with other uric acid transporters, suggesting that OAT2 plays a role in renal uric acid uptake from blood as a first step of tubular secretion. OAT2 may therefore be a potential target for regulating serum uric acid level.

L-Citrulline has diagnostic potential for renal function, because its plasma concentration increases with the progression of renal failure. Although L-citrulline extracted by glomerular filtration in kidney is mostly reabsorbed, the mechanism involved is not clearly understood. The present study was designed to characterize L-citrulline transport across the apical membranes of renal epithelial tubular cells, using primary-cultured rat renal proximal tubular cells, as well as the human kidney proximal tubular cell line HK-2. L-Citrulline was transported in a Na+-dependent manner from the apical side of both cell types cultured on permeable supports with a microporous membrane. Kinetic analysis indicated that the transport involves two distinct Na+-dependent saturable systems and one Na+-independent saturable system in HK-2 cells. The uptake was competitively inhibited by neutral and cationic, but not anionic amino acids. Relatively large cationic and anionic compounds inhibited the uptake, but smaller ones did not. In HK-2 cells, mRNA expression of SLC6A19 and SLC7A9, which encode B0AT1 and b0,+AT, respectively, was detected by RT-PCR. In addition, L-citrulline transport was significantly decreased in HK-2 cells in which either SLC6A19 or SLC7A9 was silenced. Hence, these results suggest that amino acid transporters B0AT1 and b0,+AT are involved in the reabsorption of L-citrulline in the kidney, at least in part, by mediating the apical membrane transport of L-citrulline in renal tubule cells. Copyright © 2009 John Wiley & Sons, Ltd.

A 37-year-old male was transferred to our hospital with a diagnosis of acute myocardial infarction and a mass in the ascending aorta. Echocardiography revealed dyskinesia on the left ventricular apex and a floating mass lesion just above the aortic valve. Acute myocardial infarction was considered to be caused by embolism from the floating mass in the ascending aorta. Emergency surgery was successfully performed and histological examination showed the extirpated mass in the ascending aorta was thrombus. The patient has been well on oral anticoagulant and no recurrence has been seen on echocardiogram 4 years after the operation.

Serum uric acid (SUA) is currently recognized as a risk factor for cardiovascular disease. It has been reported that an angiotensin II receptor blocker (ARB), losartan, decreases SUA level, whereas other ARBs, such as candesartan, have no lowering effect. Because the renal uric acid transporter (URAT1) is an important factor controlling the SUA level, we examined the involvement of URAT1 in those differential effects of various ARBs on SUA level at clinically relevant concentrations. This study was done by using URAT1-expressing Xenopus oocytes. Losartan, pratosartan, and telmisartan exhibited cis-inhibitory effects on the uptake of uric acid by URAT1, whereas at higher concentrations, only telmisartan did, and these ARBs reduced the uptake in competitive inhibition kinetics. On the other hand, candesartan, EXP3174 [2-n-butyl-4-chloro-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yI)methyl]imidazole-5-carboxylic acid] (a major metabolite of losartan), olmesartan, and valsartan were not inhibitory. Preloading of those ARBs in the oocytes enhanced the URAT1-mediated uric acid uptake, showing a trans-stimulatory effect. The present study is a first demonstration of the differential effects of ARBs on URAT1 that some ARBs are both cis-inhibitory and trans-stimulatory, depending on concentration, whereas others exhibit either a trans-stimulatory or cis-inhibitory effect alone, which could explain the clinically observed differential effects of ARBs on SUA level. Furthermore, it was found that such differential effects of ARBs on URAT1 could be predicted from the partial chemical structures of ARBs, which will be useful information for the appropriate use and development of ARBs without an increase of SUA.