Comparison of the risk of ovarian malignancy algorithm and Copenhagen Index for the preoperative assessment of Japanese women with ovarian tumors.

OBJECTIVE: To compare the risk of ovarian malignancy algorithm (ROMA) and Copenhagen Index (CPH-I) in their ability to distinguish epithelial ovarian cancer (EOC) and malignant ovarian tumors (MLOT) from benign ovarian tumors (BeOT) in Japanese women. METHODS: Patients with pathologically diagnosed ovarian tumors were included in this study. The study validated the diagnostic performance of ROMA and CPH-I. RESULTS: Among the 463 Japanese women included in this study, 312 had BeOT, 99 had EOC, and 52 had other MLOT. The receiver-operator characteristic (ROC) area under the curve (AUCs) of ROMA (0.89) and CPH-I (0.89) for distinguishing EOC from BeOT were significantly higher than that of CA125 (0.82) (CA 125 vs. ROMA; p = 0.002, vs. CPH-I; p < 0.001). The ROC-AUCs of ROMA (0.82) and CPH-I (0.81) for distinguishing MLOT from BeOT were significantly higher than that of CA125 (0.75) (CA 125 vs. ROMA: p = 0.003, vs. CPH-I: p < 0.001). The sensitivity (SN)/specificity (SP) of ROMA and CPH-I for distinguishing EOC from BeOT at standard cut-off points were 69%/90%, and 69%/90%, respectively, those for distinguishing MLOT from BeOT were 54%/90%, and 55%/90%, respectively. CONCLUSION: ROMA and CPH-I performed comparably well and better than CA125 in distinguishing EOC from BeOT in Japanese women. ROMA and CHP-I should be used with caution in practical situations, where all histological possibilities for must be considered, because the SNs of ROMA and CPH-I were only 54% and 55%.

Temporal and Directional Cue Effects on the Cocktail Party Problem for Patients With Listening Difficulties Without Clinical Hearing Loss.

OBJECTIVES: To evaluate the listening difficulty in a cocktail party environment in the sound field in order to better demonstrate patients' difficulties listening in noise, and to examine temporal and directional cue effects on the speech intelligibility in patients with listening difficulties in noise in comparison with control subjects. DESIGN: This study examined and analyzed 16 control subjects without any complaints of listening difficulties and 16 patients who had visited the outpatient clinic of the Department of Otolaryngology-Head and Neck Surgery, Tohoku University Hospital, with complaints of listening difficulties, especially in background crowded conditions, despite having relatively good hearing on routine audiograms and speech audiometry. Using five loudspeakers located in front of the subject and at 30° and 60° to the left and right from the front, word intelligibility for the target voice (female talker) presented from one of the loudspeakers in random order with four distractor voices (male talker) was assessed under the following cue conditions: (1) "no additional temporal/directional cue (only talker sex as a cue)"; (2) "fixed temporal cue without directional cue" (white noise bursts [cue sounds] were presented from the five loudspeakers just before word presentation at 500-ms intervals); (3) "directional + variable temporal cues" [cue sounds were presented from the loudspeaker where the next target word would be presented with a variable inter-stimulus interval [ISI] of 500, 1000, 1500, or 2000 ms between the cue sound and word presentation); and (4) "directional + fixed temporal cues" (cue sounds were presented from the loudspeaker where the next target word would be presented with a fixed ISI of 500 ms). RESULTS: The results indicated the following: (1) word intelligibility under distractors was significantly deteriorated in patients with listening difficulties compared with control subjects, although the clinical speech in noise test using the headphone system did not show any significant differences between the two groups; (2) word intelligibility under distractors for patients with listening difficulties was significantly improved with directional cues presented in advance; and (3) under most cue conditions, individual differences in word intelligibility among patients with listening difficulties were significantly correlated with their dichotic listening ability, which is one of the indicators used to assess auditory selective attention ability. CONCLUSIONS: The results of this study indicate the usefulness of the presentation of directional cues for speech comprehension in the cocktail party situation in patients with listening difficulties, as well as the importance of evaluating the degree of listening difficulties spatially in the cocktail party situation.

Loudness functions for patients with functional hearing loss.

OBJECTIVES: To compare the loudness functions (loudness ratings as a function of sound level) obtained from patients diagnosed as having functional hearing loss (FHL) with those for patients with sensorineural hearing loss (SNHL) and healthy volunteers. DESIGN: Loudness functions for a 1000 Hz tone for patients with FHL and SNHL were assessed based on the categorical loudness scaling method. The data were compared with control data obtained in our facilities. STUDY SAMPLE: 18 patients (33 ears) with FHL and 10 patients (19 ears) with SNHL. RESULTS: For patients with SNHL and healthy volunteers, loudness increased progressively with increasing sound level above the audiometric threshold, with no exceptions. However, for about 70% of the patients with FHL, a different type of loudness function was obtained; the thresholds determined from the loudness function, which were defined as the minimum sound levels at which loudness could be judged, were 10 dB or more lower than the audiometric threshold (>10 dB), and/or the loudness ratings were elevated for a sound at the audiometric threshold. CONCLUSIONS: The results support the hypothesis that patients with FHL often make threshold judgments based on a certain loudness.

Antisense Gapmers with LNA-Wings and (S)-5'-C-Aminopropyl-2'-arabinofluoro-nucleosides Could Efficiently Suppress the Expression of KNTC2.

Previously reported (S)-5'-C-aminopropyl-2'-arabinofluoro-thymidine (5ara-T) and newly synthesized (S)-5'-C-aminopropyl-2'-arabinofluoro-5-methyl-cytidine (5ara-MeC) analogs were incorporated into a series of antisense gapmers containing multiple phosphorothioate (PS) linkages and locked nucleic acids (LNAs) in their wing regions. The functional properties of the gapmers were further evaluated in vitro. Compared with the positive control, for the LNA-wing full PS gapmer without 5ara modification, it was revealed that each gapmer could have a high affinity and be thermally stable under biological conditions. Although the cleavage pattern was obviously changed; gapmers with 5ara modification could still efficiently activate E. coli RNase H1. In addition, incorporating one 5ara modification into the two phosphodiester linkages could reverse the destabilization in enzymatic hydrolysis caused by fewer PS linkages. In vitro cellular experiments were also performed, and the Lipofectamine® 2000 (LFA)+ group showed relatively higher antisense activity than the LFA-free group. KN5ara-10, which contains fewer PS linkages, showed similar or slightly better antisense activity than the corresponding full PS-modified KN5ara-3. Hence, KN5ara-10 may be the most promising candidate for KNTC2-targeted cancer therapy.

Extracellular vesicles shed from gastric cancer mediate protumor macrophage differentiation.

BACKGROUND: Peritoneal dissemination often develops in gastric cancer. Tumor-associated macrophages (TAMs) are present in the peritoneal cavity of gastric cancer patients with peritoneal dissemination, facilitating tumor progression. However, the mechanism by which macrophages differentiate into tumor-associated macrophages in the peritoneal cavity is not well understood. In this study, the interplay between gastric cancer-derived extracellular vesicles (EVs) and macrophages was investigated. METHODS: The association between macrophages and EVs in peritoneal ascitic fluid of gastric cancer patients, or from gastric cancer cell lines was examined, and their roles in differentiation of macrophages and potentiation of the malignancy of gastric cancer were further explored. RESULTS: Immunofluorescent assays of the ascitic fluid showed that M2 macrophages were predominant along with the cancer cells in the peritoneal cavity. EVs purified from gastric cancer cells, as well as malignant ascitic fluid, differentiated peripheral blood mononuclear cell-derived macrophages into the M2-like phenotype, which was demonstrated by their morphology and expression of CD163/206. The macrophages differentiated by gastric cancer-derived EVs promoted the migration ability of gastric cancer cells, and the EVs carried STAT3 protein. CONCLUSION: EVs derived from gastric cancer play a role by affecting macrophage phenotypes, suggesting that this may be a part of the underlying mechanism that forms the intraperitoneal cancer microenvironment.

Theoretical and experimental analyses of acoustic characteristics of fine-grain powder considering longitudinal vibration and boundary layer viscosity.

There was a previous study to derive the sound absorption coefficient of the powder layers comprising powder particles with a diameter of a few tens of µm. According to this previous method, the impact of air viscosity at the boundary layer generated in the pores between the powder particles is neglected. Therefore, precision is not guaranteed when the particle diameter is relatively large or when the density is relatively high. In the present study, to obtain the sound absorption coefficient of the powder layer more accurately, in addition to the above-described longitudinal vibration mode, the energy damping property of the boundary layer viscosity was calculated using the transfer-matrix method. As a result, when the longitudinal vibration mode and boundary layer viscosity were considered, the theoretical value tended to be closer to the experimental value than when only the longitudinal vibration was considered.

Interferon-Induced Transmembrane Protein 1 (IFITM1) Promotes Distant Metastasis of Small Cell Lung Cancer.

Small cell lung cancer (SCLC) is a severe malignancy associated with early and widespread metastasis. To study SCLC metastasis, we previously developed an orthotopic transplantation model using the human SCLC cell line DMS273. In the model, metastatic foci were found in distant tissues such as bone and the adrenal gland, similarly as observed in patients with SCLC. In this study, we evaluated the differentially expressed genes between orthotopic and metastatic tumors in the model. We isolated tumor cells from orthotopic and metastatic sites, and the tumor cell RNA was analyzed using DNA microarray analysis. We found that 19 genes in metastatic tumors were upregulated by more than 4-fold compared with their expression in orthotopic tumors. One of these genes encodes a transmembrane protein, interferon (IFN)-induced transmembrane protein 1 (IFITM1), and immunohistochemical analysis confirmed the higher expression of the protein in metastatic sites than in orthotopic sites. IFITM1 was also detected in some SCLC cell lines and lung tumors from patients with SCLC. The overexpression of IFITM1 in DMS273 cells increased their metastatic formation in the orthotopic model and in an experimental metastasis model. Conversely, the silencing of IFITM1 suppressed metastatic formation by DMS273 cells. We also found that IFITM1 overexpression promoted the metastatic formation of NCI-H69 human SCLC cells. These results demonstrate that IFITM1 promotes distant metastasis in xenograft models of human SCLC.

Generation and evaluation of a chimeric antibody against coxsackievirus and adenovirus receptor for cancer therapy.

Coxsackievirus and adenovirus receptor (CAR) is a single-pass transmembrane protein that is associated with adenoviral infection. CAR is involved in the formation of epithelial tight junctions and promotes tumor growth in some cancers. Previously, we developed mouse monoclonal antibodies against human CAR and found that one, mu6G10A, significantly inhibited tumor growth in xenografts of human cancer cells. Herein, we generated and characterized a mouse-human chimeric anti-CAR antibody (ch6G10A) from mu6G10A. ch6G10A had binding activity, inducing antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity, and in vivo anti-tumor activity against CAR-expressing prostate cancer DU-145 cells. In addition, cancer tissue array analysis confirmed that CAR is highly expressed in neuroendocrine lung cancers including small cell lung cancer, and treatment with ch6G10A effectively inhibited in vivo subcutaneous tumor growth of NCI-H69 small cell lung cancer cells in nude mice. Moreover, treatment with mu6G10A effectively inhibited both in vivo orthotopic tumor growth and distant metastatic formation in mouse xenograft models of a highly metastatic subline of human small cell lung cancer DMS273 cells. These results suggest that targeting therapy to CAR with a therapeutic antibody might be effective against several cancer types including small cell lung cancer.

Regulation of homologous recombination by RNF20-dependent H2B ubiquitination.

The E3 ubiquitin ligase RNF20 regulates chromatin structure by monoubiquitinating histone H2B in transcription. Here, we show that RNF20 is localized to double-stranded DNA breaks (DSBs) independently of H2AX and is required for the DSB-induced H2B ubiquitination. In addition, RNF20 is required for the methylation of H3K4 at DSBs and the recruitment of the chromatin-remodeling factor SNF2h. Depletion of RNF20, depletion of SNF2h, or expression of the H2B mutant lacking the ubiquitination site (K120R) compromises resection of DNA ends and recruitment of RAD51 and BRCA1. Consequently, cells lacking RNF20 or SNF2h and cells expressing H2B K120R exhibit pronounced defects in homologous recombination repair (HRR) and enhanced sensitivity to radiation. Finally, the function of RNF20 in HRR can be partially bypassed by forced chromatin relaxation. Thus, the RNF20-mediated H2B ubiquitination at DSBs plays a critical role in HRR through chromatin remodeling.

Synthesis and Pharmacological Evaluation of 3-[(4-Oxo-4H-pyrido[3,2-e][1,3]thiazin-2-yl)(phenyl)amino]propanenitrile Derivatives as Orally Active AMPA Receptor Antagonists.

In our search for novel orally active α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonists, we found that conversion of an allyl group in the lead compound 2-[allyl(4-methylphenyl)amino]-4H-pyrido[3,2-e][1,3]thiazin-4-one (4) to a 2-cyanoethyl group significantly increased inhibitory activity against AMPA receptor-mediated kainate-induced toxicity in rat hippocampal cultures. Here, we synthesized 10 analogs bearing a 2-cyanoethyl group and administered them to mice to evaluate their anticonvulsant activity in maximal electroshock (MES)- and pentylenetetrazol (PTZ)-induced seizure tests, and their effects on motor coordination in a rotarod test. 3-{(4-Oxo-4H-pyrido[3,2-e][1,3]thiazin-2-yl)[4-(trifluoromethoxy)phenyl]amino}propanenitrile (25) and 3-[(2,2-difluoro-2H-1,3-benzodioxol-5-yl)(4-oxo-4H-pyrido[3,2-e][1,3]thiazin-2-yl)amino]propanenitrile (27) exhibited potent anticonvulsant activity in both seizure tests and induced minor motor disturbances as indicated in the rotarod test. The protective index values of 25 and 27 for MES-induced seizures (10.7 and 12.0, respectively) and PTZ-induced seizures (6.0 and 5.6, respectively) were considerably higher compared with those of YM928 (5) and talampanel (1).

Experiment and estimation of the sound absorption coefficient for clearance of corrugated honeycomb.

The sound absorption coefficient of thin tubes with a honeycomb-corrugated structure was estimated via theoretical analysis assuming the dimensions of the tube and the known physical properties of air. This analysis yields a propagation constant and characteristic impedance, which can be modeled as a one-dimensional transfer matrix. The sound absorption coefficient is then calculated by the transfer-matrix method and the results of comparison with the experiments are reported. The corrugated clearance was divided into elements for which approximations that assumed the clearance between two planes and took into account the perimeter and cross-sectional area of each element were considered. The theoretical value of the sound absorption coefficient obtained using this method was shown to be in good agreement with the experimental results. The experimental value of the sound absorption coefficient was larger than the theoretical value in the previous method in the analysis wherein each divided element was approximated by the distance between two planes taking into account the thickness and cross-sectional area of the clearance.

Theoretical and experiment analysis on the sound absorption characteristics of a layer of fine lightweight powder.

In this study, the sound absorption characteristics of lightweight powders with a particle size on the order of tens of micrometers have been investigated. Herein, to theoretically determine the sound absorption coefficient of a fine lightweight powder in the longitudinal vibration mode, it was assumed that the powder was continuum and could be treated as a multiple degree-of-freedom damping vibration system. In addition, the acoustic impedance was calculated by assuming proportional viscous damping to determine the sound absorption coefficient. Finally, the theoretical and experimental values were compared. With the presented theoretical analysis, values close to the experimental results were obtained. Among the three calculated values based on proportional viscous damping, i.e., Rayleigh damping, rigidity proportional damping, and mass proportional damping, the results for Rayleigh damping were the closest to the experimental values.

Integrated fluorescent cytology with nano-biologics in peritoneally disseminated gastric cancer.

Gastric cancer patients positive for peritoneal cytology are at increased risk of tumor recurrence, but although a certain proportion of cytology-positive patients relapse rapidly with aggressive progression, others survive longer with conventional chemotherapies. This heterogeneity makes it difficult to stratify patients for more intensive therapy and poses a substantial challenge for the implementation of precision medicine. We developed a new approach to identify biologically malignant subpopulations in cytology-positive gastric cancer patients, using a green fluorescent protein (GFP)-expressing attenuated adenovirus in which the telomerase promoter regulates viral replication (TelomeScan, OBP-401). The fluorescence emitted from TelomeScan-positive cells was successfully quantified using a multi-mode microplate reader. We then analyzed clinical peritoneal washes obtained from 68 gastric cancer patients and found that patients positive for TelomeScan had a significantly worse prognosis. In 21 cytology-positive patients, the median survival time of those who were TelomeScan positive (235 days) was significantly shorter than that for those who were TelomeScan negative (671 days; P = 0.0062). This fluorescent virus-guided cytology detects biologically malignant cancer cells from the peritoneal washes of gastric cancer patients and may thus be useful for both therapy stratification and precision medicine approaches based on genetic profiling of disseminated cells.

Estimation and experiment for sound absorption coefficient of three clearance types using a bundle of nested tubes.

Closely packed nested structure circular tubes form three types of clearances: circular clearances, concentric clearances, and longitudinal clearances. The cross-sectional shape of rice straw, including the above-mentioned three types of clearances, is similar to that of the samples of the present study. Herein, the propagation constant and characteristic impedance of the circular, concentric, and longitudinal clearances surrounded by three cylindrical surfaces are treated as a transfer matrix. Then, by connecting these transfer matrices in parallel, a transfer matrix integrating these clearances is determined, and the sound absorption coefficient is calculated. Test samples that have three types of clearances are also created, and measure their sound absorption coefficients. The contributions of the concentric and circular clearances are significant because of the dimensions of the used tubes. The results of the calculations that took eccentricity into account revealed no significant impact on the sound absorption coefficient in wide-frequency range. The results of the calculations that took flexure into account revealed that the theoretical value was close to the measured value in the low-frequency range.

A silencer incorporated within the thickness of the edge of the door for increasing sound transmission loss.

The present study focuses on a silencer built within the thick portion of a door edge and reports on the results of evaluating silencers by determining sound transmission loss via theoretical analysis and experiments on three types of silencers. The theoretical analysis involved determining the calculated values of sound transmission loss obtained using the transfer matrix method. The change in cross-sectional shape was analyzed by elemental division of the transfer matrix. Using the above, simulations were performed with respect to the optimum shape of the silencer. These theoretical analyses were then compared with the measurement results. Furthermore, the study includes the results of an experiment that attempted to restrain the dip in sound transmission loss by adding a non-woven fabric to the opening of the silencer. In a side branch silencer with an increasing shape wherein the longitudinal cross-section is a linear or an exponential function, the peak of the transmission loss was shifted to the lower frequency side when compared with that in the case of a rectangular side branch silencer. Furthermore, in comparisons between the two, the sound attenuation peak frequency was lower in the case of the exponential shape. The resonance of the side branch was suppressed by adding a non-woven fabric to the opening of the side branch silencer. As a result, the peak and dip of sound attenuation were alleviated, and the sound attenuation characteristics could be adjusted.

Impact of MET inhibition on small-cell lung cancer cells showing aberrant activation of the hepatocyte growth factor/MET pathway.

Small-cell lung cancer (SCLC) accounts for approximately 15% of all lung cancers, and is characterized as extremely aggressive, often displaying rapid tumor growth and multiple organ metastases. In addition, the clinical outcome of SCLC patients is poor due to early relapse and acquired resistance to standard chemotherapy treatments. Hence, novel therapeutic strategies for the treatment of SCLC are urgently required. Accordingly, several molecular targeted therapies were evaluated in SCLC; however, they failed to improve the clinical outcome. The receptor tyrosine kinase MET is a receptor for hepatocyte growth factor (HGF), and aberrant activation of HGF/MET signaling is known as one of the crucial mechanisms enabling cancer progression and invasion. Here, we found that the HGF/MET signaling was aberrantly activated in chemoresistant or chemorelapsed SCLC cell lines (SBC-5, DMS273, and DMS273-G3H) by the secretion of HGF and/or MET copy number gain. A cell-based in vitro assay revealed that HGF/MET inhibition, induced either by MET inhibitors (crizotinib and golvatinib), or by siRNA-mediated knockdown of HGF or MET, constrained growth of chemoresistant SCLC cells through the inhibition of ERK and AKT signals. Furthermore, treatment with either crizotinib or golvatinib suppressed the systemic metastasis of SBC-5 cell tumors in natural killer cell-depleted SCID mice, predominantly through cell cycle arrest. These findings reveal the therapeutic potential of targeting the HGF/MET pathway for inhibition, to constrain tumor progression of SCLC cells showing aberrant activation of HGF/MET signaling. We suggest that it would be clinically valuable to further investigate HGF/MET-mediated signaling in SCLC cells.

Training system for laparoscopy-assisted distal gastrectomy.

PURPOSE: Laparoscopy-assisted distal gastrectomy (LADG) is likely to become a standard procedure for gastric cancer, which highlights the importance of establishing a training system in which even inexperienced surgeons can perform this procedure safely. This study assesses our training system for LADG based on short-term surgical outcomes. METHODS: We evaluated retrospectively the short-term outcomes of 100 consecutive LADGs with curative D1/D1+ lymph node dissection. Our training system was assessed based on the learning curve of trainees, and factors related to achieving good-quality operations were analyzed statistically. RESULTS: Overall, postoperative complications developed in 10 patients (10%), and included one case of anastomotic leakage (1%) and one case of pancreatic fistula (1%). The learning curve of the trainees plateaued after 10 operator cases in terms of operation time. The importance of the trainer's position was also confirmed by the result that the operation time was significantly longer when trainees with ≤10 operator cases performed LADG with a trainer as scopist vs. a trainer as the first assistant. Univariate and multivariate analyses revealed that >10 operator cases were the most important factor for achieving good-quality operations. CONCLUSION: These results show that our current LADG procedure and training system are appropriate and effective.

[Multiple Salvage Radiotherapies for Metachronous Lymph Node Metastasis from Gastric Cancer Contributed to Long-Term Management of Disease].

A 70-year-old man who underwent gastrectomy for Stage III C gastric cancer developed lymph node(LN)metastasis posterior to the pancreatic head 3 years after the radical surgery.He was first treated with radiotherapy(RT)followed by chemotherapy.The irradiated tumor regressed completely.However, the cancer relapsed in a single para-aortic LN and he was treated with RT to the lesion followed by chemotherapy.Although it completely regressed, later, lung metastasis was observed.The lung lesions were well suppressed by switching to docetaxel; however, the cancer relapsed again in a mediastinal LN, and it was not responsive to docetaxel.The growing mediastinal lesion was irradiated again, which resulted in stable disease.The patient has been treated for 4 years and 7 months with all lesions being well-managed, and chemotherapy is being continued.Recurrent gastric cancer after surgery tends to present as multiple lesions; therefore, the principle therapy is systemic chemotherapy and RT is unlikely to be suitable.However, especially in cases of a solitary lesion that is chemo-resistant, RT could be an optimal option and contribute to long-term survival even in patients with recurrent gastric cancer.

A local representation of the head-related transfer function.

Spatial descriptions of the head-related transfer function (HRTF) using spherical harmonics, which is commonly used for the purpose, consider all directions simultaneously. However, in perceptual studies, it is necessary to model HRTFs with different angular resolutions at different directions. To this end, an alternative spatial representation of the HRTF, based on local analysis functions, is introduced. The proposal is shown to have the potential to describe the local features of the HRTF. This is verified by comparing the reconstruction error achieved by the proposal to that of the spherical harmonic decomposition when reconstructing the HRTF inside a spherical cap.

New metastatic model of human small-cell lung cancer by orthotopic transplantation in mice.

Small-cell lung cancer (SCLC) is an aggressive cancer with high metastatic ability and novel strategies against the metastasis are urgently needed to improve SCLC treatment. However, the mechanism of metastasis of SCLC remains largely to be elucidated. For further studies of SCLC metastasis, we developed a new orthotopic transplantation model in mice. We established a GFP-labeled subline from the human SCLC cell line DMS273 and transplanted them orthotopically into the lung of nude mice with Matrigel. The GFP-labeled cells showed significant metastatic activity and formed metastatic foci in distant tissues such as bone, kidney, and brain, as observed in SCLC patients. From a bone metastasis focus of the mouse, we isolated another subline, termed G3H, with enhanced metastatic potential and higher hepatocyte growth factor (HGF) expression than the parental line. Further studies indicated that the HGF/MET signaling pathway was involved in in vitro motility and invasion activities of the G3H cells and treatments with MET inhibitors decreased formation of distant metastases in our orthotopic model using G3H cells. These data indicated that our model mimics the clinical aspect of SCLC such as metastatic tropism and autocrine of HGF/MET signaling. Compared with other orthotopic SCLC models, our model has a superior ability to form distant metastases. Therefore, our model will provide a valuable tool for the study of SCLC metastasis.