M. Oka

Hepatocellular carcinoma has a poor prognosis because of the high intrahepatic recurrence rate. There are technological limitations to traditional methods such as TNM staging for accurate prediction of recurrence, suggesting that new techniques are needed.We investigated mRNA expression profiles in tissue specimens from a training set, comprising 33 patients with hepatocellular carcinoma, with high-density oligonucleotide microarrays representing about 6000 genes. We used this training set in a supervised learning manner to construct a predictive system, consisting of 12 genes, with the Fisher linear classifier. We then compared the predictive performance of our system with that of a predictive system with a support vector machine (SVM-based system) on a blinded set of samples from 27 newly enrolled patients.Early intrahepatic recurrence within 1 year after curative surgery occurred in 12 (36%) and eight (30%) patients in the training and blinded sets, respectively. Our system correctly predicted early intrahepatic recurrence or non-recurrence in 25 (93%) of 27 samples in the blinded set and had a positive predictive value of 88% and a negative predictive value of 95%. By contrast, the SVM-based system predicted early intrahepatic recurrence or non-recurrence correctly in only 16 (60%) individuals in the blinded set, and the result yielded a positive predictive value of only 38% and a negative predictive value of 79%.Our system predicted early intrahepatic recurrence or non-recurrence for patients with hepatocellular carcinoma much more accurately than the SVM-based system, suggesting that our system could serve as a new method for characterising the metastatic potential of hepatocellular carcinoma.

For the recognized importance of knee meniscus function, the treatment of meniscus injury has been changing from resection to repair. However, depending on the type of injury, meniscectomy sometimes cannot be avoided. In such a case, it is important to anticipate the future problem of degenerative change or osteoarthrosis in the knee joint. In consideration of the prognosis and circumstances in such patients, we have developed an artificial meniscus using polyvinyl alcohol-hydrogel (PVA-H) for salvage. We have already reported the results up to 1 year after animal operation. The present study investigated the results in postoperative 2.0 years to assess further the use of artificial meniscus. In the results, the articular cartilage state of knee joint implanted PVA-H meniscus was good even after 2 years, while Osteoarthrosis (OA) change progressed in meniscectomy knee joint. In addition, neither wear, dislocation nor breakage of PVA-H was observed. These results proved that an artificial meniscus using PVA-H can compensate for meniscal function and might be clinically applicable.

The short range part of the interaction between non-strange baryons (N and Δ) is studied in a nonrelativistic quark model. The mass of a quark is assumed to be about one-third of the nucleon mass and the quark-quark interaction consists of a confinement term and the one gluon exchange potential. Baryons are described as clusters of three quarks and the resonating group method, which has been extensively developed in the nuclear cluster model, is used to treat the bound state and scattering problems of two baryons. This paper discusses the formal aspects of the present approach, while the numerical results will be given in the subsequent paper.

The problem of the nuclear force in a nonrelativistic quark model is studied by the resonating group method which has been extensively used in treating the interaction between composite particles. The calculated phase shifts for the 3S1 and 1S0 states of two nucleons indicate the presence of a strong repulsive force at short distance, while an attractive force is predicted for the 7S3((S, T)=(3,0)) state of two Δ's. These features are due to an interplay between the Pauli principle and the spin-spin interaction between quarks.

Single- and double-heavy baryons are studied in the constituent quark model. The model Hamiltonian is chosen as a standard one with two exceptions: (1) the color-Coulomb term depends on quark masses and (2) an antisymmetric $LS$ (spin-orbit) force is introduced. Model parameters are fixed by the strange baryon spectra, $\mathrm{\ensuremath{\Lambda}}$ and $\mathrm{\ensuremath{\Sigma}}$ baryons. The masses of the observed charmed and bottomed baryons are, then, fairly well reproduced. Our focus is on the low-lying negative-parity states, in which the heavy baryons show specific excitation modes reflecting the mass differences of heavy and light quarks. By changing quark masses from the SU(3) limit to the strange quark mass, and, further, to the charm and bottom quark masses, we demonstrate that the spectra change from the SU(3) symmetry patterns to the heavy-quark-symmetry ones.

FoxP3(+) Tregs inhibit immune responses against tumors. KW-0761 is a humanized anti-human CCR4 monoclonal antibody (mAb) that has antibody-dependent cellular cytotoxicity activity. Depletion of CCR4-expressing FoxP3(+) CD4 Tregs by KW-0761 infusion was investigated in solid cancer patients.We conducted a phase Ia clinical trial of KW-0761 infusion in 7 lung and 3 esophageal cancer patients. Toxicity, clinical efficacy, changes in lymphocyte subpopulations, including Tregs, and induction of immune responses were analyzed.The results showed that KW-0761 infusion in a dose range between 0.1 mg/kg and 1.0 mg/kg was safe and well tolerated. No dose-limiting toxicity was observed. Four of 10 patients showed stable disease during treatment and were long survivors. The monitoring of FoxP3(+) Tregs in the peripheral blood mononuclear cells during treatment indicated efficient depletion of those cells, even at the lowest dose of 0.1 mg/kg used. The reduction in Th 1 CD4 T cells and CD8 T cells was limited, whereas a significant reduction was observed with Th 2 and Th 17 CD4 T cells. Immune responses to cancer/testis (CT) antigens and an autoantibody response to thyroid peroxidase were observed in some patients.The findings showed Tregs depletion and the possible occurrence of an immune response following KW-0761 infusion. Combined use of KW-0761 to deplete FoxP3(+) Tregs with other immunotherapies, such as cancer vaccines or checkpoint inhibitors, is a promising approach to augment immune responses.

The 3(rd) English edition of the Japanese classification of biliary tract cancers was released approximately 10 years after the 5(th) Japanese edition and the 2(nd) English edition. Since the first Japanese edition was published in 1981, the Japanese classification has been in extensive use, particularly among Japanese surgeons and pathologists, because the cancer status and clinical outcomes in surgically resected cases have been the main objects of interest. However, recent advances in the diagnosis, management and research of the disease prompted the revision of the classification that can be used by not only surgeons and pathologists but also by all clinicians and researchers, for the evaluation of current disease status, the determination of current appropriate treatment, and the future development of medical practice for biliary tract cancers. Furthermore, during the past 10 years, globalization has advanced rapidly, and therefore, internationalization of the classification was an important issue to revise the Japanese original staging system, which would facilitate to compare the disease information among institutions worldwide. In order to achieve these objectives, the new Japanese classification of the biliary tract cancers principally adopted the 7(th) edition of staging system developed by the International Union Against Cancer (UICC) and the American Joint Committee on Cancer (AJCC). However, because there are some points pending in these systems, several distinctive points were also included for the purpose of collection of information for the future optimization of the staging system. Free mobile application of the new Japanese classification of the biliary tract cancers is available via http://www.jshbps.jp/en/classification/cbt15.html.

Community-acquired pneumonia (CAP) continues to be a major medical problem. Since CAP is a potentially fatal disease, early appropriate antibiotic treatment is vital. Epidemiologic studies have shown that in the combined cause-of-death category, pneumonia ranks fourth as the leading cause of death in Japan. Therefore, the Japanese Respiratory Society (JRS) provided guidelines for the management of CAP in adults in 2000. Because of evolving resistance to antimicrobials and advances in diagnosis, treatment and prevention of CAP, it is felt that an update should be provided every three years so that important developments can be highlighted and pressing questions can be answered. Thus, the guidelines committee updated its guidelines in 2005. The basic policy and main purposes of the JRS guidelines include; 1) prevention of bacterial resistance and 2) effective and long-term use of medical resources. The JRS guidelines have recommended the exclusion of potential and broad spectrum antibiotics, fluoroquinolones and carbapenems, from the list of first-choice drugs for empirical treatment. In addition, the JRS guidelines have recommended short-term usage of antibiotics of an appropriate dose and pathogen-specific treatment using rapid diagnostic methods if possible.

Breast cancer resistance protein (BCRP), an ABC half-transporter, is overexpressed in cancer cell lines selected with doxorubicin/verapamil, topotecan, or mitoxantrone. BCRP-overexpressing cells show cross-resistance to camptothecin derivatives such as irinotecan, SN-38 (the active metabolite of irinotecan), and topotecan. To test whether BCRP confers SN-38 resistance, we selected two SN-38 resistant sublines from PC-6 human small-cell lung cancer cells by SN-38, and then characterized these cells. Compared to PC-6 cells, the resistant sublines PC-6/SN2-5 and PC-6/SN2-5H were approximately 18- and 34-fold resistant, respectively. The intracellular SN-38 accumulation was reduced in the sublines, and BCRP mRNA was overexpressed in proportion to the degree of SN-38 resistance. These findings suggest that BCRP confers SN-38 resistance in the sublines. To confirm this hypothesis, PC-6/SN2-5 cells were transfected with antisense oligonucleotides complementary to portions of BCRP mRNA. The antisense oligonucleotides significantly suppressed BCRP mRNA expression, and enhanced SN-38 sensitivity in the subline. These data indicate that BCRP is directly involved with SN-38 resistance, by efflux transport of SN-38.

An approach to the short range part of baryon-baryon interaction based on a non-relativistic quark model, proposed and formulated in the previous paper, is applied to the case of S-wave relative motion. Repulsive core like interactions appear in most of the spin(S)-isospin(T) states, including the NN system with (S, T) = (1, 0) and (0, 1), while attractive interactions are predicted for the ΔΔ system with (S, T) = (3, 0) and (1, 0). The interaction is mostly due to the Pauli principle between quarks and the spin-spin term in the quark-quark force, and is insensitive to the confinement term. The effect of meson exchanges, which is not included in the present non-relativistic quark model, is studied by simulating it with a phenomenological local potential. Qualitative behaviours of the S-wave NN phase shifts are reproduced in this way.

Ultra-high-strength poly(L-lactide) (PLLA) rods were fabricated using a drawing technique. Rods with a diameter of 3.2 mm and a draw ratio of 2.5:1 showed initial bending strength and modulus values of 240 MPa and 13 GPa, respectively. The purpose of this study was to investigate the in vitro and in vivo degradation of PLLA rods with a draw ratio of 2.5:1. The greater the rod diameter, the longer the bending strength was maintained in phosphate buffered saline at 37 degrees C. The bending strength retention of rods (diam. 3.2 mm) implanted in the subcutis of rabbits was almost equal to that of rods in the in vitro study, while those rods implanted in the medullary cavity of rabbit femora showed a slightly lower bending strength retention. Molecular weight was reduced to the greatest extent in the medullary cavity, followed by in the subcutis and in vitro. The weight of PLLA rods in the medullary cavity was reduced by 22% at 52 weeks and by 70% at 78 weeks after implantation. Histologically, no inflammatory or foreign body reaction was observed in the medullary cavity for 52 weeks. The drawn PLLA rods maintained a bending strength exceeding that of human cortical bone in the medullary canal for a period of 8 weeks, suggesting that the drawn PLLA rods may be useful in the repair of fractured human bones.

In this article we evaluated the bone-bonding strengths of titanium and titanium alloy implants with and without alkali and heat treatments using the conventional canine femur push-out model. Four kinds of smooth cylindrical implants, made of pure titanium or three titanium alloys, were prepared with and without alkali and heat treatments. The implants were inserted hemitranscortically into canine femora. The bone-bonding shear strengths of the implants were measured using push-out test. At 4 weeks all types of the alkali- and heat-treated implants showed significantly higher bonding strength (2.4-4.5 MPa) than their untreated counterparts (0.3-0.6 MPa). At 12 weeks the bonding strengths of the treated implants showed no further increase, while those of the untreated implants had increased to 0.6-1.2MPa. Histologically, alkali- and heat-treated implants showed direct bonding to bony tissue without intervening fibrous tissue. On the other hand, untreated implants usually had intervening fibrous tissue at the interface between bone and the implant. The early and strong bonding to bone of alkali- and heat-treated titanium and its alloys without intervening fibrous tissue may be useful in establishing cementless stable fixation of orthopedic implants.

In this paper, we provide direct evidence that glutathione S-transferase pi (GSTpi) detoxifies cisplatin (CDDP). We used human colonic cancer HCT8 cells sensitive and resistant to CDDP, the level of cisplatin-glutathione adduct (DDP-GSH) being higher in the resistant cells. There was an overexpression of GSTpi mRNA in these CDDP-resistant cells. Incubation of the cells with CDDP resulted in the formation of DDP-GSH dependent on the CDDP concentration and the incubation time. The formation of DDP-GSH was abolished when the cells were pre-treated with ethacrynic acid or ketoprofen, inhibitors of GSTpi. Purified GSTpi also catalyzed the formation of DDP-GSH in vitro, with an apparent Km of 0.23 mM for CDDP and an apparent Vmax of 4.9 nmol/min/mg protein. The increase in DDP-GSH produced by GSTpi was linear with incubation time up to 3 h and optimal of pH 7.4. A GSTpi transfectant cell line was constructed in HCT8 cells using a pcDNA3.1 (-)/Myc-His B with an expression vector containing cDNA for GSTpi. Transfection of GSTpi cDNA into HCT8 cells resulted in an increase in the expression of GSTpi by 1.4-fold in parallel with an augmentation of the formation of DDP-GSH. These results suggest that GSTpi plays a role in the formation of DDP-GSH and the acquisition of resistance to CDDP in cancer cells.

For development of thin bioactive coatings on metal implants, a dense and uniform apatite layer was coated onto titanium (Ti) implants in situ by using a new biomimetic method, which is composed of apatite nucleation and growth steps in simulated body fluid (SBF). Analysis of the coatings by thin film X-ray diffraction and scanning electron microscopy-energy dispersive X-ray microanalysis (SEM-EMPA) before implantation showed that its characteristics were very similar to those of natural bone. The coated and uncoated rectangular plates were bilaterally implanted into the tibial proximal metaphyses of rabbits. After 6, 10 and 25 weeks post-implantation, the bone bonding and bone formation at the bone-implant interfaces were evaluated by a detachment test and undecalcified histological examination. Mechanical testing in tension showed that the failure load of apatite layer-coated Ti implants was significantly higher than that of uncoated control at each time period (all P < 0.001). Histologically, it was shown that bone was deposited directly onto the apatite coating without any intervening soft tissue, while in the paired controls, interpositional soft tissue was seen at the bone-implant interface. By SEM-EPMA, a uniform calcium- and phosphorus-rich layer was detected between the coated implants and bone, but not in uncoated controls at either earlier or later time periods. The results indicate that the apatite layer deposited on Ti in situ may significantly increase the bone bonding strength by providing a bioactive surface, which allows for an early bone apposition to the implant. In addition, the apatite layer-coated Ti produced by the biomimetic process may fulfil the requirements of favourable thin coatings and strong adhesion at the metal-coating interface.

Abstract Partially stabilized zirconia ceramic is being recognized among ceramics for its high strength and toughness. With this ceramic, is possible to manufacture a 22‐mm‐size femoral head for low friction arthroplasty of the hip joint in association with an ultra‐high‐molecular‐weight polyethylene socket. Wear‐resistant properties of zirconia ceramic were screened on two principally different wear devices. Sterile calf bovine serum, physiological saline, and distilled water were chosen as the lubricant fluid media. Depending on the lubricant medium, the wear factor of polyethylene against zirconia ceramic counterfaces was 40 to 60% less than that against alumina ceramic counterfaces, and 5 to 10 times lower than with the SUS316L metal counterfaces. Polyethylene wear against metal was more susceptible in saline in which it had 2 to 3 times higher wear rate than with serum. On the other hand, different fluid media had little effect on polyethylene wear against ceramic counterfaces. In each set of tests, the wear factor obtained on an unidirectional wear device showed 10 to 15 times higher values, in comparison to the wear factor estimated on a reciprocating wear device.

Overexpression of breast cancer resistance protein (BCRP) ABCG2 reportedly confers cancer cell resistance to camptothecin-based anticancer drugs, such as topotecan and 7-ethyl-10-hydroxycamptothecin (SN-38: the active metabolite of irinotecan). We have recently shown that SN-38-selected PC-6/SN2-5H human lung carcinoma cells overexpressed BCRP with the reduced intracellular accumulation of SN-38 and SN-38-glucuronide (S. Kawabata et al., Biochem. Biophys. Res. Commun. 280, 1216-1223, 2001). In the present study, we have examined whether BCRP transports SN-38 and/or SN-38-glucuronide in vitro, by using plasma membrane vesicles from the parental PC-6 and resistant PC-6/SN2-5H cells, where SN-38 and SN-38-glucuronide accumulation in membrane vesicles was measured by HPLC. Both SN-38 and SN-38-glucuronide were ATP-dependently transported into membrane vesicles prepared from PC-6/SN2-5H cells, whereas no transport activity was observed in membrane vesicles from PC-6 cells. The kinetic parameters of the transport observed in PC-6/SN2-5H vesicles were K(m) = 4.0 microM, V(max) = 714 pmol/mg/min for SN-38 and K(m) = 26 microM, V(max) = 833 pmol/mg/min for SN-38-glucuronide. These findings suggest that BCRP expressed in PC-6/SN2-5H cells transports both SN-38 and SN-38-glucuronide with a higher affinity toward SN-38.

Abstract An apatite‐ and wollastonite‐containing glass‐ceramic (A · W‐GC) has been reported to form a tight bond with living bone through an apatite layer formed on its surface. This layer is considered to be formed by dissolution of Ca 2+ and HSiO 3 − ions from the glass‐ceramic into the surrounding body fluids. In order to confirm this proposed mechanism for the surface reaction of A · W‐GC, three kinds of glass in the systems CaOSiO 2 , CaOSiO 2 CaF 2 , and CaOSiO 2 P 2 O 5 were implanted into the tibiae of rabbits for 3 or 8 weeks. Contact microradiography and SEM‐EPMA showed that all three kinds of glass formed a Ca, P‐rich layer in combination with a Si‐rich layer on their surfaces within 3 weeks and formed a direct bond with bone via these layers. The detaching test, performed 8 weeks after implantation, showed that the loads required to detach the implants from the bone were almost equal for the phosphorus‐free and the phosphorus‐containing glasses. It was concluded that even P 2 O 5 ‐free CaO · SiO 2 glass formed a Ca,P‐rich layer on its surface and bonded tightly with living bone. If glasses and glass‐ceramics release at least Ca 2+ and HSiO 3 − ions, this would be sufficient for them to form the Ca,P‐rich layer on their surfaces in vivo , enabling them to bond directly with bone.

Gefitinib (Iressa) is a selective epidermal growth factor receptor tyrosine kinase inhibitor and is used for the treatment of lung cancer. Recently, we discovered that it inhibits the breast cancer resistance protein, which is an ATP-binding cassette transporter. P-glycoprotein (Pgp) also pumps multiple types of drugs out of the cell using energy generated from ATP, and confers multidrug resistance on cancer cells. This study was designed to examine whether gefitinib inhibits the function of Pgp. We used multidrug resistant PC-6/PTX lung cancer and MCF-7/Adr breast cancer cells which overexpress Pgp and measured their drug sensitivity and drug-efflux function by tetrazolium assay and flowcytometry, respectively. In addition, the drug-stimulated ATPase activity of Pgp was measured using insect membranes that express human Pgp. Epidermal growth factor receptor was expressed in MCF-7/Adr, but not in PC-6/PTX cells, and the overexpression of Pgp did not confer resistance to gefitinib to both cell types. However, clinically achievable levels of gefitinib moderately reversed the Pgp-mediated resistance to paclitaxel and docetaxel in Pgp overexpressing cells. In addition, gefitinib increased the intracellular accumulation of the Pgp substrate rhodamine-123 in resistant cells, and activated ATPase in a preparation of pure Pgp-expressing membrane. These findings suggest that gefitinib directly interacts with Pgp and inhibits its function. Gefitinib may clinically inhibit the excretion of Pgp substrate drugs including anticancer agents, and its drug-interaction should therefore be considered.

Abstract Gefitinib (“Iressa”, ZD1839) is an orally active, selective epidermal growth factor receptor tyrosine kinase inhibitor, and the single agent is clinically effective in non–small cell lung cancer. Although gefitinib combined with various cytotoxic agents has been reported to enhance cytotoxicity in vitro and in mouse models, the mechanism remains undetermined. Here, to explore the mechanism with topoisomerase I inhibitors, we focused on the efflux pump of the breast cancer resistance protein (BCRP/ABCG2), and then examined whether gefitinib restored drug sensitivity in multidrug-resistant cancer cells overexpressing BCRP. We used PC-6 human small cell lung cancer cells and multidrug-resistant PC-6/SN2-5H cells selected with SN-38 of the active metabolite of irinotecan, and BCRP-overexpressing MCF-7/MX cells selected with mitoxantrone and BCRP cDNA transfectant MCF-7/clone 8 cells. Drug sensitivity against anticancer drugs was determined by tetrazolium dye assay, and intracellular topotecan accumulation by FACScan. The topotecan transport study was done using the plasma membrane vesicles of PC-6/SN2-5H cells. The resistant PC-6/SN2-5H cells overexpressed BCRP but not epidermal growth factor receptor mRNA. Ten micromoles of gefitinib reversed topotecan, SN-38, and mitoxantrone resistance, and increased the intracellular topotecan accumulation in the resistant cells but not in the parental cells. Furthermore, gefitinib inhibited the topotecan transport into the vesicles, and the Ki value was 1.01 ± 0.09 μmol/L in the Dixon plot analysis, indicating direct inhibition of BCRP by gefitinib. However, gefitinib was not transported into the vesicles with the high-performance liquid chromatography method. These results indicate that gefitinib reverses BCRP-mediated drug resistance by direct inhibition other than competitive inhibition as a BCRP substrate. Combination of gefitinib and topoisomerase I inhibitors could be clinically effective in cancers expressing BCRP.

A prospective study of the clinical efficacy of an aminoglycoside antibiotic (streptomycin, SM) for the treatment of pulmonary Mycobacterium avium complex (MAC) disease was carried out. In a multicenter trial, patients with pulmonary MAC disease received protocol-guided combined chemotherapy with or without SM. SM was given to the patients intramuscularly 15 mg/kg three times per week for the initial 3 months and three other antibiotics (rifampicin, ethambutol, and clarithromycin) were added and administered for over 24 months after the conversion of MAC strains. From April 1998 to December 2004, 160 HIV-negative patients were enrolled in this trial. Fourteen patients were found to be ineligible because they could not continue the treatment, and they were excluded from the analysis after randomization. Seventy-three patients were assigned to receive combined chemotherapy with SM (group A) and 73 were assigned to receive combined chemotherapy without SM (group B). The median durations of treatment were 27.6 months in group A and 28.4 months in group B. The difference in the backgrounds of the groups was not statistically significant. There were no differences in microbiological and radiological findings between the groups, but the sputum conversion rate for pulmonary MAC disease at the completion of treatment was significantly higher in group A than that in group B. Although, there were no significant differences in the sputum relapse rate and clinical improvement including both clinical symptoms and radiological findings, group A showed better initial microbiological response than group B. As for adverse reactions and abnormal laboratory findings, there were no significant differences between the groups. Based on the results of this double-blind randomized study, we support treatment including SM according to both the American Thoracic Society (ATS) and the Japanese Society for Tuberculosis (JST) guidelines for patients with pulmonary MAC disease without HIV infection.

The non-relativistic quark cluster model is employed to describe the two-baryon systems including hyperons such as Λ, Σ and Ξ. Qualitative discussions about the role of the Pauli principle for quarks and the color magnetic interaction in the baryon-baryon scattering are given. Results of the resonating group method (RGM) calculation show a repulsive interaction at short distances in most of the two-baryon systems with strangeness S = −1 and −2. There appears, however, a sharp resonance in the 1S0ΛΛ scattering at E = 26.3 MeV, which may correspond to the di-hyperon state.

This article evaluates 16 cases of condylar fracture treated surgically, comparing them with the 20 cases treated nonsurgically, with a 2-year follow-up. Although severely displaced and luxated fractures were involved in the surgical group with rigid internal fixation, satisfactory postoperative function and occlusion were achieved at the same level as in the nonsurgical group, without severe complications.

The one-boson exchange potential model for $\Lambda_cN$ is constructed and the possibility of $\Lambda_cN$ bound states is examined. We consider an effective Lagrangian for the charmed baryons, $\Lambda_c$, $\Sigma_c$, and $\Sigma_c^*$, reflecting the heavy quark symmetry, chiral symmetry, and hidden local symmetry. We determine the coupling constants using various methods. With the derived nonrelativistic potentials, we study the bound state problem of the $\Lambda_cN$ system and relevant coupled channel effects. It is found that molecular bound states of $\Lambda_cN$ are plausible, for which the channel couplings of $\Sigma_cN$ and $\Sigma_c^*N$ are essential.

We investigate the anomalous triangle singularity (ATS) and its possible manifestations in various processes. We show that the ATS should have important impact on our understanding of the nature of some newly observed threshold states. Discussions on how to distinguish the ATS phenomena from genuine dynamic pole structures are presented.

Bound states of double-heavy tetraquarks are studied in a constituent quark model. Two bound states are found for isospin and spin-parity I(J^P ) = 0(1^+) in the bb\bar{u}\bar{d} channel. One is deeply bound and compact made of colored diquarks, while the other is shallow and extended as a BB^* molecule. The former agrees well with lattice QCD results. A systematic decrease in the binding energy is seen by replacing one of the heavy quarks to a lighter one. Altogether we find ten bound states. It is shown for the first time that hadrons with totally different natures emerge from a single Hamiltonian.

Our previous study demonstrated that the herbal medicine, Oren-to, had antitumor effects on esophageal cancer cells (ECCs) in vitro. The purpose of this study was to examine which of the seven constituents of Oren-to had antitumor effects on esophageal cancer cells. MTT assay showed that, of the seven constituents, only the aqueous extract of Coptidis Rhizoma had potent inhibitory effect on the proliferation of two types of ECC lines, YES-3 and YES-4. In addition, the proliferation of all six types of ECC lines (YES-1 to YES-6) was inhibited in a dose-dependent manner (P<0.001 for all), when co-cultured at each concentration of Coptidis Rhizoma for 72 h. The ID50 of Coptidis Rhizoma for YES-1 to YES-6 was 2.2 microg/ml, 3.0 microg/ml, 0.25 microg/ml, 2.8 microg/ml, 2.5 microg/ml, and 0.5 microg/ml, respectively, berberine, one of protoberberine components of Coptidis Rhizoma, showed potent antitumor effects on all six types of ECC lines as well as Coptidis Rhizoma. In addition, the ID50 of berberine showed a positive correlation with that of Coptidis Rhizoma in six types of ECC lines examined (r2 = 0.763, P = 0.023). Cell cycle analysis of Coptidis Rhizoma-treated cancer cells showed the accumulation of cells in the G0/G1 phase and relative decrease of the S phase. These results support the possibility that the use of Coptidis Rhizoma containing abundant berberine may be useful as one of alternative therapies for esophageal cancers.

Attempts have been made to develop an artificial articular cartilage on the basis of a new viewpoint of joint biomechanics in which the lubrication and load-bearing mechanisms of natural and artificial joints are compared. Polyvinyl alcohol hydrogel (PVA-H), ‘a rubber-like gel’, was investigated as an artificial articular cartilage and the mechanical properties of this gel were improved through a new synthetic process. In this article the biocompatibility and various mechanical properties of the new improved PVA-H is reported from the perspective of its usefulness as an artifical articular cartilage. As regards lubrication, the changes in thickness and fluid pressure of the gap formed between a glass plate and the specimen under loading were measured and it was found that PVA-H had a thicker fluid film under higher pressures than polyethylene (PE) did. The momentary stress transmitted through the specimen revealed that PVA-H had a lower peak stress and a longer duration of sustained stress than PE, suggesting a better damping effect. The wear factor of PVA-H was approximately five times that of PE. Histological studies of the articular cartilage and synovial membranes around PVA-H implanted for 8–52 weeks showed neither inflammation nor degenerative changes. The artificial articular cartilage made from PVA-H could be attached to the underlying bone using a composite osteochondral device made from titanium fibre mesh. In the second phase of this work, the damage to the tibial articular surface after replacement of the femoral surface in dogs was studied. Pairs of implants made of alumina, titanium or PVA-H on titanium fibre mesh were inserted into the femoral condyles. The two hard materials caused marked pathological changes in the articular cartilage and menisci, but the hydrogel composite replacement caused minimal damage. The composite osteochondral device became rapidly attached to host bone by ingrowth into the supporting mesh. The clinical implications of the possible use of this material in articular resurfacing and joint replacement are discussed.

The uppermost superficial surface layer of articular cartilage, the ‘lamina splendens’ which provides a very low friction lubrication surface in articular joints, was investigated using atomic force microscopy (AFM). Complementary specimens were also observed under SEM at −10 °C without dehydration or sputter ion coating. Fresh adult pig osteochondral specimens were prepared from the patellas of pig knee joints and digested with the enzymes, hyaluronidase, chondroitinase ABC and alkaline protease. Friction coefficients between a pyrex glass plate and the osteochondral specimens digested by enzymes as well as natural (undigested) specimens were measured, using a thrust collar apparatus. Normal saline, hyaluronic acid (HA) and a mixture of albumin, globulin, HA (AGH) were used as lubrication media. The surface irregularities usually observed in SEM studies were not apparent under AFM. The articular cartilage surface was resistant to hyaluronidase and also to chondroitinase ABC, but a fibrous structure was exhibited in alkaline protease enzymes‐digested specimens. AFM analysis revealed that the thickness of the uppermost superficial surface layer of articular cartilage was between 800 nm and 2 μm in adult pig articular cartilage. The coefficient of friction (c.f.) was significantly higher in chondroitinase ABC and alkaline protease enzymes digested specimens. Generally, in normal saline lubrication medium, c.f. was higher in comparison to HA and AGH lubrication media. The role of the uppermost, superficial surface layer of articular cartilage in the lubrication mechanism of joints is discussed.

To identify proteins that could be molecular targets for diagnosis and treatment of hepatitis C virus-related hepatocellular carcinoma (HCV-related HCC), we used a proteomic approach to analyze protein expression in samples of human liver. Twenty-six pairs of tumorous and corresponding nontumorous liver samples from patients with HCV-related HCC and six normal liver samples were analyzed by two-dimensional gel electrophoresis and liquid chromatography-tandem mass spectrometry. One of the numerous spots that showed stronger intensity in tumorous than in nontumorous samples was identified as alpha enolase, a key enzyme in the glycolytic pathway. Expression of this protein increased with tumor dedifferentiation and was significantly higher in poorly differentiated HCC than in well-differentiated HCC. This pattern was reproduced by immunoblot analysis and immunohistochemistry. Expression of alpha enolase also correlated positively with tumor size and venous invasion. These results suggest that alpha enolase is one of the candidates for biomarkers for tumor progression that deserves further investigation in HCV-related HCC.

We study chiral symmetry aspects of the positive and negative parity baryons by identifying them with linear representations of the chiral group $SU(N_{f}) \otimes SU(N_{f})$. It is shown that there are two distinctive schemes: naive and mirror assignments. We construct linear sigma models for baryons in the two assignments and examine their physical implications. Then we investigate properties of the naive and mirror nucleons microscopically by using QCD interpolating fields. Finally, we propose experiments to distinguish the two chiral assignments for the nucleon.

Postlaminectomy deformities were simulated in the cervical or cervicothoracic spine by the use of a displacement incremental method based on finite-element analysis combined with composite material and spanning element theory. The simulation analyses revealed that the primary cause of postlaminectomy deformity was the resection of one or more spinous processes and/or posterior ligaments (ie, ligamenta flava, supraspinous, and interspinous ligaments). After their removal, the tensile stresses that were preoperatively distributed through the posterior ligaments were transferred to the facets. This led to an imbalance of the stresses on the spinal bodies, causing deformity. The gravitational center of the head determined whether the deformity would develop as a kyphosis or increasing lordosis. As the elastic modulus of the soft tissue composites (eg, end plates, ligaments, and facets) increased, a kyphotic deformity changed gradually from swan-neck deformity, to extreme kyphotic deformity with a large curvature, and finally to a straightening deformity. Progressive kyphotic deformity is found only in children.

Gene expression profiles of hepatocellular carcinomas (HCCs) associated with hepatitis B virus (HBV) and hepatitis C virus (HCV) were analyzed and compared. Oligonucleotide microarrays containing >6000 genes and subsequent gene selection by a supervised learning method yielded 83 genes for which expression differed between the two types of HCCs. Expression levels of 31 of these 83 genes were increased in HBV-associated HCCs, and expression levels of the remaining 52 genes were increased in HCV-associated HCCs. The 31 genes up-regulated in HBV-associated HCC included imprinted genes (H19 and IGF2) and genes relating to signal transduction, transcription, and metastasis. The 52 genes up-regulated in HCV-associated HCC included a number of genes responsible for detoxification and immune response. These results suggest that HBV and HCV cause hepatocarcinogenesis by different mechanisms and provide novel tools for diagnosis and treatment of HBV- and HCV-associated HCCs.

We have attempted to develop an artificial articular cartilage on the basis of a new viewpoint of joint biomechanics in which lubrication and load-bearing mechanisms of natural and artificial joints are compared. We investigated poly(vinyl alcohol)-hydrogel (PVA-H) which has been recognized as a rubber-like gel and have improved the mechanical properties of this gel through a new synthetic process. In this article we report the biocompatibility and various mechanical properties of the new, improved PVA-H from the aspect of its usefulness as artificial articular cartilage. As regards the lubrication, we measured the change of thickness and fluid pressure of the gap formed between a glass plate and the specimen under loading and found that the PVA-H had a thicker fluid film under higher pressure than polyethylene (PE). The momentary stress transmitted through the specimen revealed that PVA-H had a lower peak stress and a longer duration of sustained stress than PE, suggesting a better damping effect. The wear factor of PVA-H was approximately five times as large as that of PE. Histological findings of the articular cartilage and synovial membranes around the PVA-H implanted for 8-52 weeks showed neither inflammatory nor degenerative changes. The PVA-H artificial articular cartilage could be attached to the underlying bone using an osteochondral composite material. Although there remain still some problems to solve, PVA-H seems to be a very interesting and promising material which meets the requirements of artificial articular cartilage.

To identify proteins linked to the pathogenesis of hepatocellular carcinoma (HCC) associated with hepatitis C virus (HCV), we profiled protein expression levels in samples of HCC. To identify essential proteins, ten samples of HCV-related HCC were analyzed by two-dimensional gel electrophoresis and matrix-assisted laser desorption/ionization-time of flight mass spectrometry. These experiments revealed increased levels of nine proteins in cancerous tissues compared to levels in corresponding noncancerous liver tissues. We focused on four members of the heat shock protein 70 family: 78 kDa glucose-regulated protein (GRP78), heat shock cognate 71 kDa protein (HSC70), 75 kDa glucose-regulated protein (GRP75), and heat shock 70 kDa protein 1 (HSP70.1). These results were confirmed by immunoblot analysis. In an additional 11 samples, the same expression patterns of these four proteins were observed. In total, 21 samples showed statistically significant up-regulation of GRP78, GRP75 and HSP70.1 in cancerous tissues. HSC70 showed a tendency toward overexpression. There has been no report describing overexpression of these four proteins simultaneously in HBV-related HCC as well as nonviral HCC. Our results suggest that these four proteins play important roles in the pathogenesis of HCV-related HCC and could be molecular targets for diagnosis and treatment of this disease.

Abstract The objectives of this study were to investigate the biocompatibility, phase stability, and wear properties of a newly developed Ce‐TZP/Al 2 O 3 nanocomposite, as compared to conventional ceramics, and to determine whether the new composite could be used as a bearing material in total joint prostheses. In tests of mechanical properties, this composite showed significantly higher toughness than conventional Y‐TZP. For biocompatibility tests, cylindrical specimens of both the Ce‐TZP/Al 2 O 3 nanocomposite and monolithic alumina were implanted into the paraspinal muscles of male Wistar rats. The tissue reactions were almost the same, and at 24 weeks after implantation, thin fibrous capsules with almost no inflammation were observed around both of them. There were no significant differences in membrane thickness between the two ceramics. After hydrothermal treatment in 121 °C vapor for 18 h, the new composite showed complete resistance to aging degradation, whereas Y‐TZP showed a phase transformation of 25.3 vol% (initial 0.4%) to the monoclinic form. According to the results of pin‐on‐disk tests, the wear rates of Ce‐TZP/Al 2 O 3 nanocomposite and alumina were 0.55 ± 0.04 × 10 −7 and 2.12 ± 0.37 × 10 −7 mm 3 /Nm, respectively. The results of this study suggest that the Ce‐TZP/Al 2 O 3 nanocomposite is a promising alternative ceramic component for total joint replacement. © 2002 Wiley Periodicals, Inc. J Biomed Mater Res (Appl Biomater) 63: 262–270, 2002

Background and Study Aims: The technique of endoscopic submucosal dissection (ESD) has recently been developed for en-bloc resection of gastric tumors. For oncological reasons and in order to improve the patients’ quality of life, it may be desirable to use the same technique for rectal neoplasia. Patients and Methods: Thirty-five consecutive patients with rectal neoplasia who had a preoperative diagnosis of large intraepithelial neoplasias with submucosal fibrosis or located on the rectal folds were enrolled. ESD was carried out with the same technique previously described for the stomach, with some modifications. The efficacy, complications, and follow-up results of the treatment were assessed. Results: The rates of en-bloc resection and en-bloc plus R0 resection were 88.6 % (31 of 35) and 62.9 % (22 of 35), respectively. Hemoglobin levels did not drop by more than 2 g/dl in any of the patients after ESD. None of the patients had to receive blood transfusions or undergo emergency colonoscopy due to bleeding during ESD or hematochezia after ESD. Perforation during ESD occurred in two patients (5.7 %), who were managed with conservative medical treatment after endoscopic closure of the perforation. Excluding three patients in whom additional surgery was carried out, all but one of 32 patients were free of recurrence during a mean follow-up period of 36 months (range 12 - 60 months). The exception was a patient in whom a multiple-piece resection was required; the recurrent (residual) tumor, found 2 months after ESD, was a small adenoma that was again treated endoscopically. Conclusions: ESD is applicable in the rectum with promising results, but the technique is still at a developmental stage and patients should be informed of the potential risks.

Abstract Matrix metalloproteinase (MMP)‐1 and MMP‐3 genes are associated with tumor cell invasion and metastasis with their promoter polymorphisms influencing the level of transcription. Our study explored the association of these polymorphisms with colorectal cancer risk in a Japanese population. DNA was extracted from peripheral blood of 101 patients with colorectal cancer and 127 age‐ and gender‐matched healthy volunteers. Genotyping was carried out using PCR‐RFLP and direct sequencing. In the MMP‐1 gene polymorphism, the frequency of the 2G/2G genotype that is associated with higher enzyme activity was significantly increased in colorectal cancer patients when compared to controls ( p = 0.0067; OR = 2.077; 95% CI = 1.221–3.534). With regard to the MMP‐3 polymorphism, unexpectedly, the frequency of the 6A/6A genotype causing lower enzyme activity was significantly increased in patients ( p = 0.0129; OR = 2.110; 95% CI = 1.165–3.822). Because the loci for the 2 MMP genes are closely linked, we examined linkage disequilibrium between the 2 loci using expectation‐maximization algorithm. We found that the 2 loci were in linkage disequilibrium and that 2G‐6A haplotype was significantly increased in patients compared to controls ( p = 0.0010; OR = 1.949; 95% CI = 1.305–2.911). Our present data suggest that the MMP‐1 and MMP‐3 promoter polymorphisms may be associated with a colorectal cancer susceptibility in Japanese. © 2002 Wiley‐Liss, Inc.

The bone-bonding behavior of three kinds of bioactive ceramics coated on titanium alloy by the plasma-spray technique was investigated. Titanium alloy (Ti-6A1-4V) coated with BioglassR (45S5), apatite-wollastonite containing glass ceramic (AW), or β-tricalcium phosphate (TCP) was prepared, and rectangular specimens were implanted into the tibial bones of mature male rabbits, which were sacrificed 8 or 24 weeks after implantation. The tibiae containing the implants were dissected out and subjected to detachment tests to measure the failure load. The bone-implant interface was investigated by Giemsa surface staining, contact microradiography, and scanning electron microscopy-electron probe microanalysis (SEM-EPMA). Eight weeks after implantation, the failure loads for implants coated with BioglassR, AW, and TCP were 1.04 ± 0.94, 2.03 ± 1.17, and 3.91 ± 1.51 kg, respectively, and 24 weeks after implantation, the respective failure loads were 2.72 ± 1.33, 2.39 ± 1.30, and 4.23 ± 1.34 kg. Failure loads of AW- and TCP-coated implants did not increase significantly with time. After the detachment test, breakage of the coating layer was observed. Bioactive ceramics can act as stimulants that induce bonding between bone and metal implants. However, failure load of metal implants coated with the bioactive ceramics was lower than that of bulk AW or TCP. It appears impossible to obtain a higher failure load using a bioactive-ceramic coating on titanium alloy. Histologically, the coating layer was found to become detached from the metal implant and the bone tissue bonded to the coating layer. SEM-EPMA observation revealed breakage of the coating layer, although bonding between bone and the coating layer was evident. A Ca-P-rich layer was observed at the interface between bone and the AW coating, and a Ca-P-rich and a Si-rich layer were observed at the interface between bone and the BioglassR coating. For clinical application, it would seem better to use coated metal implants for short-term implantation. However, there is a possibility of breakage of the coating layer because of both dissolution of the bioactive ceramic and mechanical weakness at the interface between the coating layer and the metal implant. © 1996 John Wiley & Sons, Inc.

We prepared a composite of D,L-lactic acid oligomer and dideoxykanamycin B for use as a biodegradable antibiotic delivery system with sustained effect. The composite was implanted in the distal portion of the rabbit femur, and the effective concentration of the antibiotic was measured in the cortex, the cancellous bone, and the bone marrow. In all bone tissues around the implant, the concentration of antibiotic exceeded the minimum inhibitory concentration for the common causative organisms of osteomyelitis for six weeks. Most of the implant material had been absorbed and the bone marrow had been repaired to a nearly normal state within nine weeks of implantation. The implant caused no systemic side effects, and it is likely to prove clinically useful as a drug delivery system for treating chronic osteomyelitis.

This study was carried out to investigate the effects of the alkali and heat treatments on the bone-bonding behavior of porous titanium implants. Porous titanium implants had a 4.6 mm solid core and a 0.7 mm thick porous outer layer using pure titanium plasma-spray technique. Three types of porous implants were prepared from these pieces: 1. control implant (CL implant) as manufactured 2. AW-glass ceramic bottom-coated implant (AW implant) in which AW-glass ceramic was coated on only the bottom of the pore of the implant 3. alkali- and heat-treated implant (AH implant), where implants were immersed in 5 mol/L NaOH solution at 60°C for 24 h and subsequently heated at 600°C for 1 h. The implants were inserted into bilateral femora of six dogs hemi-transcortically in a randomized manner. At 4 weeks, push-out tests revealed that the mean shear strengths of the CL, AW, and AH implants were about 10.8, 12.7, and 15.0 MPa, respectively. At 12 weeks there was no significant difference between the bonding strengths of the three types of the porous implants (16.0–16.7 MPa). Histologically and histomorphologically, direct bone contact with the implant surface was significantly higher in the AH implants than the CL and AW implants both at 4 and 12 weeks. Thus, the higher bonding strength between bone and alkali- and heat-treated titanium implants was attributed to the direct bonding between bone and titanium surface. In conclusion, alkali and heat treatments can provide porous titanium implants with earlier stable fixation. © 2000 John Wiley & Sons, Inc. J Biomed Mater Res 54: 198–208, 2001

Abstract Zirconia has received special attention, mainly because of its high strength and toughness. However, there is some controversy about the time‐dependent deterioration of its mechanical properties. To examine the change in mechanical properties of zirconia ceramics in vivo and in vitro , tetragonal zirconia polycrystal pieces were introduced into the medullary cavity of the tibia in Japanese rabbits and animals were sacrificed after 2, 4 and 6 weeks and 6, 12, and 30 mo, respectively. Alumina ceramic and hydroxyapatite (HAP) pieces were used as controls to investigate the differences in biocompatibility. Zirconia showed a bending strength of over 1000 MPa initially, and little time‐dependent change in strength was found in both in vivo environments. x‐Ray analysis showed little change in the transformation rate, i.e., less than 5 mol % in vivo and in vitro over a period of 3 years. To estimate time‐dependent changes in zirconia over a longer period, zirconia pieces were placed in 95°C saline solution for over 3 years and their mechanical properties examined at chosen intervals. No serious decrease of bending strength was found over the 3‐year period under these conditions. It is concluded that zirconia can be used clinically because it retains a bending strength of over 700 MPa under any experimental conditions for over 3 years. © 1993 John Wiley &amp; Sons, Inc.

Breast cancer resistance protein (BCRP/ABCG2) of an ATP-binding cassette half-transporter confers resistance against mitoxantrone and camptothecin derivatives of topotecan and irinotecan. Novobiocin, a coumermycin antibiotic, is known to enhance anticancer drug sensitivity of cancer cells in vitro and in vivo, the mechanism of which remains undetermined. Here we focused on drug efflux pump and examined whether novobiocin reversed drug resistance in multidrug-resistant cells highly expressing BCRP. To explore the reversal mechanisms, intracellular drug accumulation was measured by flow cytometry, and a topotecan transport study using plasma membrane vesicles was performed. We used PC-6/SN2-5H2 small cell lung cancer and MCF-7/MX breast cancer cells selected with SN-38 of the active irinotecan metabolite and mitoxantrone, respectively, and the BCRP cDNA transfectant MCF-7/clone 8 cells. These cells expressed high levels of BCRP mRNA but not other known transporters. Compared to the parental PC-6 cells, PC-6/SN2-5H2 cells were 141-, 173- and 57.2-fold resistant to topotecan, SN-38 and mitoxantrone, respectively. Novobiocin at 60 microM decreased the degree of the above resistance by approximately 26-fold in PC-6/SN2-5H2 cells, and similarly reversed resistance in MCF-7/MX, MCF-7/clone 8 and un-selected NCI-H460 cells highly expressing BCRP. Furthermore, novobiocin increased the intracellular topotecan accumulation in these cells and inhibited the topotecan transport into the membrane vesicles of PC-6/SN2-5H2 cells. No effects of novobiocin in these assay were observed in the parental PC-6 and MCF-7 cells. The kinetic parameters in the transport study indicated that novobiocin was a inhibitor for BCRP, resulting in competitive inhibition of BCRP-mediated topotecan transport. These findings suggest that novobiocin effectively overcomes BCRP-mediated drug resistance at acceptable concentrations.

FEBS LettersVolume 105, Issue 2 p. 296-298 Full-length articleFree Access Muscarinic receptor-mediated increase in cyclic GMP level in isolated bovine adrenal medullary cells Nobuyuki Yanagihara, Nobuyuki Yanagihara Department of Pharmacology, Tokushima University School of Medicine, Kuramoto-3, Tokushima 770, JapanSearch for more papers by this authorMinoru Isosaki, Minoru Isosaki Department of Pharmacology, Tokushima University School of Medicine, Kuramoto-3, Tokushima 770, JapanSearch for more papers by this authorTakeshi Ohuchi, Takeshi Ohuchi Department of Pharmacology, Tokushima University School of Medicine, Kuramoto-3, Tokushima 770, JapanSearch for more papers by this authorMotoo Oka, Motoo Oka Department of Pharmacology, Tokushima University School of Medicine, Kuramoto-3, Tokushima 770, JapanSearch for more papers by this author Nobuyuki Yanagihara, Nobuyuki Yanagihara Department of Pharmacology, Tokushima University School of Medicine, Kuramoto-3, Tokushima 770, JapanSearch for more papers by this authorMinoru Isosaki, Minoru Isosaki Department of Pharmacology, Tokushima University School of Medicine, Kuramoto-3, Tokushima 770, JapanSearch for more papers by this authorTakeshi Ohuchi, Takeshi Ohuchi Department of Pharmacology, Tokushima University School of Medicine, Kuramoto-3, Tokushima 770, JapanSearch for more papers by this authorMotoo Oka, Motoo Oka Department of Pharmacology, Tokushima University School of Medicine, Kuramoto-3, Tokushima 770, JapanSearch for more papers by this author First published: September 15, 1979 https://doi.org/10.1016/0014-5793(79)80633-XCitations: 95AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat No abstract is available for this article. References 1 J. Hochman, R.L. Perlman, Biochim. Biophys. Acta, 421, (1976), 168– 175. 10.1016/0304-4165(76)90180-X CASPubMedWeb of Science®Google Scholar 2 A.S. Schneider, R. Herz, K. Rosenheck, Proc. Natl. Acad. Sci. USA, 74, (1977), 5036– 5040. 10.1073/pnas.74.11.5036 CASPubMedWeb of Science®Google Scholar 3 J.C. Brooks, Endocrinology, 101, (1977), 1369– 1378. 10.1210/endo-101-5-1369 CASPubMedWeb of Science®Google Scholar 4 E.M. Fenwick, P.B. Fajdiga, N.B.S. Howe, B.G. Livett, J. Cell. Biol., 76, (1978), 12– 30. 10.1083/jcb.76.1.12 CASPubMedWeb of Science®Google Scholar 5 M. Oka, M. Isozaki, N. Yanagihara, E. Usdin Catecholamines: Basic and Clinical Frontiers (1979), Pergamon Oxford in press Google Scholar 6 A.S. Schneider, H.T. Cline, S. Lemaire, Life Sci., 24, (1979), 1389– 1394. 10.1016/0024-3205(79)90009-2 CASPubMedWeb of Science®Google Scholar 7 M. Fujimoto, S. Mihara, T. Okabayashi, T. Sugase, S. Tarui, J. Biochem., 78, (1975), 131– 137. 10.1093/oxfordjournals.jbchem.a130996 CASPubMedWeb of Science®Google Scholar 8 H. Weil-Malherbe, A.D. Bone, Biochem. J., 51, (1952), 311– 318. 10.1042/bj0510311 CASPubMedWeb of Science®Google Scholar 9 S.P. Wilson, N. Kirshner, J. Neurochem., 28, (1977), 687– 695. 10.1111/j.1471-4159.1977.tb10615.x CASPubMedWeb of Science®Google Scholar Citing Literature Volume105, Issue2September 15, 1979Pages 296-298 ReferencesRelatedInformation

The usefulness of the tuberculin skin test (TST) and the QuantiFERON TB-2G (QFT-TB) test were compared in immunocompromised patients. The subjects consisted of 252 immunocompromised patients who were clinically suspected of tuberculosis (TB) infection between April 2005 and December 2006. Regarding the underlying diseases, 74 subjects had malignant diseases, 72 were undergoing immunosuppressive treatment, 52 had diabetes mellitus, 50 had chronic renal failure and four had HIV infection. While the positive rate of the QFT-TB test for the diagnosis of TB infection (TB disease or latent TB infection) was 78.1%, that of TST for TB infection was 50.0%. The QFT-TB test was significantly better than TST. However, 32 (13%) patients had an indeterminate QFT-TB result. Indeterminate findings were significantly more frequent in patients receiving immunosuppressive treatment (28%), especially with lymphocytopaenia in the peripheral blood, than in those who had other underlying diseases. While TST-positive and QFT-TB test-negative results were recognised in immunocompromised patients with bacille Calmette-Guérin vaccination or nontuberculous mycobacterial disease, TST-negative and QFT-TB test-positive results were recognised in immunocompromised patients with a past history of TB infection. It was concluded that the QuantiFERON TB-2G test is a more useful diagnostic method for tuberculosis infection than tuberculin skin test for immunocompromised patients suspected of tuberculosis disease. However, because the results of the QuantiFERON TB-2G test show an indeterminate response for patients receiving immunosuppressive treatment, especially for those with lymphocytopaenia due to severe underlying diseases, care must be taken in the interpretation of the QuantiFERON TB-2G test for these patients.

We investigated whether one of the Wnt receptors, frizzled-7 (FZD7), functions in the canonical Wnt signaling pathway of colorectal cancer (CRC) cells harboring an APC or CTNNB1 mutation and may be a potential therapeutic target for sporadic CRCs. The expression level of FZD gene family members in colon cancer cells and primary CRC tissues were determined by real-time PCR. Activation of the Wnt signaling pathway was evaluated by TOPflash assay. The expression level of Wnt target genes was determined by real-time polymerase chain reaction and/or Western blot analysis. Cell growth and cell invasion were assessed by MTS and matrigel assays, respectively. Among 10 FZD gene family members, FZD7 mRNA was predominantly expressed in six colon cancer cell lines with APC or CTNNB1 mutation. These six cell lines were transfected with FZD7 cDNA together with a TOPflash reporter plasmid, resulting in a 1.5- to 24.3-fold increase of Tcf transcriptional activity. The mRNA expression levels of seven known Wnt target genes were also increased by 1.5- to 3.4-fold after transfection of FZD7 cDNA into HCT-116 cells. The six cell lines were then cotransfected with FZD7-siRNA and a TOPflash reporter plasmid, which reduced Tcf transcriptional activity to 20% to 80%. FZD7-siRNA was shown to significantly decrease cell viability and in vitro invasion activity after transfection into HCT-116 cells. Our present data demonstrated that FZD7 activates the canonical Wnt pathway in colon cancer cells despite the presence of APC or CTNNB1 mutation and that FZD7-siRNA may be used as a therapeutic reagent for CRCs.

The negative-parity baryons are studied by a novel approach in the QCD sum rule. It is found that the parity of the ground-state nucleon is determined by the sign of the quark condensate. We predict the mass of negative-parity nucleon.

Hepatocellular carcinoma (HCC) is a major cause of death in Japan. It has been suggested that hepatitis C virus (HCV) plays an important role in hepatocarcinogenesis, because of high incidence among the patients. To understand the mechanism of hepatocarcinogenesis after HCV infection, we performed a comparative study on the protein profiles between tumorous and nontumorous specimens from the patients infected with HCV by means of two-dimensional electrophoresis. Eleven spots were decreased in HCC tissues from over 50% of the patients. Eight proteins out of 11 spots were identified using peptide mass fingerprinting with matrix-assisted laser desorption/ionization-time of flight-mass spectrometry. These proteins were liver type aldolase, tropomyosin beta-chain, ketohexokinase, enoyl-CoA hydratase, albumin, smoothelin, ferritin light chain, and arginase 1. The intensity of enoyl-CoA hydratase, tropomyosin beta-chain, ketohexokinase, liver type aldolase, and arginase 1 was significantly different (p < 0.05). The decrease of 8 proteins was characteristic in HCC. We will discuss the implication of these proteins for the loss of function of hepatocytes and for the possibility of carcinogenesis of HCV-related HCC.

The canonical Wnt signalling pathway is activated in most sporadic colorectal cancers (CRCs). We previously reported that FZD7 functions as a receptor for the canonical Wnt signalling pathway in colon cancer cells.In this study, we examined the function of FZD7 in survival, invasion and metastatic capabilities of colon cancer cells. FZD7_siRNA transfection decreased cell viability of HT-29 and HCT-116 colon cancer cells. Expression of c-Jun, phosphorylation of JNK and c-Jun, and activation of RhoA were suppressed after FZD7_siRNA transfection into HCT-116 cells. In vitro invasion activity and Wnt target gene expression were also reduced in HCT-116 cells transfected with FZD7_siRNA. Liver metastasis of stable FZD7_siRNA HCT-116 cell transfectants in scid mice was decreased to 40-50% compared to controls. The mRNA levels of FZD7 in 135 primary CRC tissues were examined by real-time PCR. FZD7 mRNA levels were significantly higher in stage II, III or IV tumours than in non-tumour tissues (P<0.005), and overall survival was shorter in those patients with higher FZD7 expression (P<0.001).These data suggest that FZD7 may be involved in enhancement of survival, invasion and metastatic capabilities of colon cancer cells through non-canonical Wnt signalling pathways as well as the canonical pathway.

The di-hyperon state (DH) predicted by Jaffe in the MIT bag model is studied in the non-relativistic quark cluster model. The resonating group method is applied to the ΛΛ, NΞ and ΣΣ coupled channels problem. No stable bound state is found below the lowest ΛΛ threshold but a sharp resonance with spin-parity 0+ is predicted just below the NΞ threshold. The structure of the state is similar to that of the flavour SU3 singlet state and the attractive nature of the color magnetic interaction in this state is responsible for the appearance of the resonance. The difference between the present model and the bag model which predicted a strongly bound state is attributed to the difference in the mechanism of confinement for these two models.

To evaluate the response to the QuantiFERON-TB-2 Gold (QFT-2G) test (Cellestis Ltd; Carnegie, VIC, Australia) in elderly patients with active tuberculosis (TB) to determine whether the QFT-2G test might be a feasible method for diagnosing TB infection in this group of patients.The subjects were 30 elderly patients with active TB and 100 younger patients with active TB. The QFT-2G test results were analyzed in relation to combined and separate responses to early secretory antigenic target 6-kD (ESAT-6) protein and culture filtrate protein 10 (CFP-10) antigens.Of the 30 elderly patients with active TB, 27% had a positive tuberculin skin test (TST) result and 77% had a positive QFT-2G test result. Of the 100 younger patients with active TB, 70% had a positive TST result and 87% had a positive QFT-2G test result. Although there was no significant difference between the two patient groups in the positive rate for the QFT-2G test results (p = 0.185), there was a significant difference in the rates of positive TST results between the elderly and younger patients (p = 0.012). The positive test result rate for both ESAT-6 and CFP-10 antigens in the elderly patients (17%) was significantly lower than that in younger patients (37%; p = 0.038). There was an indeterminate result for the QFT-2G test in five elderly patients, and this might have been related to the presence of lymphocytopenia due to underlying disease. A negative result on the QFT-2G test was detected in two elderly patients, and this might have been related to the severity of the active TB.We confirmed that the QFT-2G test might be a more useful method of diagnosing TB infection than the TST for elderly patients if peripheral lymphocyte counts have been preserved.

Community-acquired pneumonia (CAP) due to Mycoplasma pneumoniae is usually mild, but some cases develop a severe life-threatening pneumonia. To investigate the clinical features of severe M. pneumoniae pneumonia in adults admitted to an intensive care unit, a multi-centre CAP surveillance study was performed. Among all hospitalized CAP cases between January 2000 and December 2004, there were 227 cases with M. pneumoniae pneumonia without the complication of other pathogens. A total of 13 of the cases required admission to an intensive care unit because of acute respiratory failure (ARF), and the remaining 214 cases (non-ARF) were low to moderately severe. The clinical features of ARF cases were compared with those of non-ARF cases. The underlying conditions in both types of case were identical, whereas clinical findings on admission clearly differed between the two groups. A regimen of an antibiotic effective against M. pneumoniae was begun on average at 9.3 days after the onset of symptoms in ARF cases, which was significantly later than for non-ARF cases ( P &lt;0.0001). However, two of the ARF cases progressed to respiratory failure despite the fact that adequate antibiotics were initially administered within 3 days after the onset of symptoms. All ARF cases received corticosteroids with adequate antibiotics, and their condition improved promptly. These results indicate that the clinical features, excluding underlying conditions, clearly differed between severe M. pneumoniae pneumonia and low to moderately severe pneumonia. The delayed administration of adequate antibiotics may contribute to the severity of M. pneumoniae pneumonia. Early corticosteroid therapy with adequate antibiotics should be considered.

The St Gallen International Expert Consensus 2011 has proposed a new classification system for breast cancer. The purpose of this study was to elucidate the relationship between the breast cancer subtypes determined by the new classification system and genomic characteristics.Invasive breast cancers (n = 363) were immunohistochemically classified as follows: 111 (30.6%) as luminal A, 95 (26.2%) as luminal B (HER2 negative), 69 (19.0%) as luminal B (HER2 positive), 41 (11.3%) as HER2, and 47 (12.9%) as basal-like subtypes.The high expression of Ki-67 antigen was detected in 236 tumors; no cases of luminal A subtype showed high expression of the Ki-67 antigen, but more than 85% of tumors of the other subtypes showed high expression. In addition, DNA ploidy and chromosomal instability (CIN) were assessed using imaging cytometry and FISH, respectively. In this series, 336 (92.6%) tumors consisted of 129 diploid/CIN- and 207 aneuploid/CIN + tumors. Diploid/CIN- and aneuploid/CIN+ features were detected in 64.9% and 27.9% of luminal A, 41.1% and 49.5% of luminal B (HER2-), 11.6% and 81.2% of luminal B (HER2+), 4.9% and 90.2% of HER2, and 17.0% and 76.6% of basal-like subtypes, respectively. Unlike the luminal B (HER2+), HER2 and basal-like subtypes, the luminal A and luminal B (HER2-) subtypes were heterogeneous in terms of DNA ploidy and CIN.It is reasonable to propose that the luminal A and luminal B (HER2-) subtypes should be further divided into two subgroups, diploid/CIN- and aneuploid/CIN+, based on their underlying genomic status.

To evaluate the safety of combination vaccine treatment of multiple peptides, phase I clinical trial was conducted for patients with advanced colorectal cancer using five novel HLA-A*2402-restricted peptides, three peptides derived from oncoantigens, ring finger protein 43 (RNF43), 34 kDa-translocase of the outer mitochondrial membrane (TOMM34), and insulin-like growth factor-II mRNA binding protein 3 (KOC1), and the remaining two from angiogenesis factors, vascular endothelial growth factor receptor 1 (VEGFR1) and VEGFR2.Eighteen HLA- A*2402-positive colorectal cancer patients who had failed to standard therapy were enrolled in this study. 0.5 mg, 1.0 mg or 3.0 mg each of the peptides was mixed with incomplete Freund's adjuvant and then subcutaneously injected at five separated sites once a week. We also examined possible effect of a single site injection of "the cocktail of 5 peptides" on the immunological responses. ELISPOT assay was performed before and after vaccinations in the schedule of every 4 weeks.The vaccine treatment using multiple peptides was well tolerated without any severe treatment-associated systemic adverse events. Dose-dependent induction of peptide-specific cytotoxic T lymphocytes was observed. The single injection of "peptides cocktail" did not diminish the immunological responses. Regarding the clinical outcome, one patient achieved complete response and 6 patients revealed stable disease for 4 to 7 months. The median overall survival time (MST) was 13.5 months. Patients, in which we detected induction of cytotoxic T lymphocytes specific to 3 or more peptides, revealed significantly better prognosis (MST; 27.8 months) than those with poorer immune responses (MST; 3.7 months) (p = 0.032).Our cancer vaccine treatment using multiple peptides is a promising approach for advanced colorectal cancer with the minimum risk of systemic adverse reactions.UMIN-CTR number UMIN000004948.

We previously conducted a phase I trial for advanced colorectal cancer (CRC) using five HLA-A*2402-restricted peptides, three derived from oncoantigens and two from vascular endothelial growth factor (VEGF) receptors, and confirmed safety and immunological responses. To evaluate clinical benefits of cancer vaccination treatment, we conducted a phase II trial using the same peptides in combination with oxaliplatin-based chemotherapy as a first-line therapy.The primary objective of the study was the response rates (RR). Progression free survival (PFS), overall survival (OS), and immunological parameters were evaluated as secondary objective. The planned sample size was more than 40 patients for both HLA2402-matched and -unmatched groups. All patients received a cocktail of five peptides (3 mg each) mixed with 1.5 ml of IFA which was subcutaneously administered weekly for the first 12 weeks followed by biweekly administration. Presence or absence of the HLA-A*2402 genotype were used for classification of patients into two groups.Between February 2009 and November 2012, ninety-six chemotherapy naïve CRC patients were enrolled under the masking of their HLA-A status. Ninety-three patients received mFOLFOX6 and three received XELOX. Bevacizumab was added in five patients. RR was 62.0% and 60.9% in the HLA-A*2402-matched and -unmatched groups, respectively (p=0.910). The median OS was 20.7 months in the HLA-A*2402-matched group and 24.0 months in the unmatched group (log-rank, p=0.489). In subgroup with a neutrophil/lymphocyte ratio (NLR) of <3.0, patients in the HLA-matched group did not survive significantly longer than those in the unmatched group (log-rank, p=0.289) but showed a delayed response.Although no significance was observed for planned statistical efficacy endpoints, a delayed response was observed in subgroup with a NLR of <3.0. Biomarkers such as NLR might be useful for selecting patients with a better treatment outcome by the vaccination.Trial registration: UMIN000001791.

Purpose: This study evaluated the influence of surgical site infections (SSIs) after abdominal or cardiac surgery on the post-operative duration of hospitalization and cost. Methods: A retrospective 1:1 matched case-control study of length of stay and healthcare expenditures for patients who were discharged from nine hospitals, between April 1, 2006 and March 31, 2008, after undergoing abdominal or cardiac surgery and who did and did not have a SSI. Results: Information was obtained from 246 pairs of patients who had undergone abdominal surgery and 27 pairs of patients who had undergone cardiac surgery. Overall, the mean post-operative hospitalization was 20.7 days longer and the mean post-operative healthcare expenditure was $8,791 higher in the SSI group than for the SSI-free group. Among the patients who had undergone abdominal surgery, development of SSI extended the average hospitalization by 17.6 days and increased the average healthcare expenditure by $6,624. Among the patients who had undergone cardiac surgery, SSI extended the post-operative hospitalization by an average of 48.9 days and increased the post-operative healthcare expenditure by an average of $28,534. Conclusions: Under the current healthcare system in Japan, the development of SSI after abdominal surgery necessitates extension of hospitalization two-fold and increases the post-operative healthcare expenditure 2.5-fold. Development of SSI after cardiac surgery necessitates extension of hospitalization fourfold and increases the healthcare expenditure six-fold.

Abstract We conducted a phase I clinical trial of a cancer vaccine using a 20‐mer NY‐ESO‐1f peptide (NY‐ESO‐1 91–110) that includes multiple epitopes recognized by antibodies, and CD4 and CD8 T cells. Ten patients were immunized with 600 μg of NY‐ESO‐1f peptide mixed with 0.2 KE Picibanil OK‐432 and 1.25 ml Montanide ISA‐51. Primary end points of the study were safety and immune response. Subcutaneous injection of the NY‐ESO‐1f peptide vaccine was well tolerated. Vaccine‐related adverse events observed were fever (Grade 1), injection‐site reaction (Grade 1 or 2) and induration (Grade 2). Vaccination with the NY‐ESO‐1f peptide resulted in an increase or induction of NY‐ESO‐1 antibody responses in nine of ten patients. The sera reacted with recombinant NY‐ESO‐1 whole protein as well as the NY‐ESO‐1f peptide. An increase in CD4 and CD8 T cell responses was observed in nine of ten patients. Vaccine‐induced CD4 and CD8 T cells responded to NY‐ESO‐1 91–108 in all patients with various HLA types with a less frequent response to neighboring peptides. The findings indicate that the 20‐mer NY‐ESO‐1f peptide includes multiple epitopes recognized by CD4 and CD8 T cells with distinct specificity. Of ten patients, two with lung cancer and one with esophageal cancer showed stable disease. Our study shows that the NY‐ESO‐1f peptide vaccine was well tolerated and elicited humoral, CD4 and CD8 T cell responses in immunized patients.

We investigate the decays of the charmed baryons aiming at the systematic understanding of hadron internal structures based on the quark model by paying attention to heavy quark symmetry. We evaluate the decay widths from the one pion emission for the known excited states, \Lambda_c^*(2595), \Lambda_c^*(2625), \Lambda_c^*(2765), \Lambda_c^*(2880) and \Lambda_c^*(2940), as well as for the ground states \Sigma_c(2455) and \Sigma_c^*(2520). The decay properties of the lower excited charmed baryons are well explained, and several important predictions for higher excited baryons are given. We find that the axial-vector type coupling of the pion to the light quarks is essential, which is expected from chiral symmetry, to reproduce the decay widths especially of the low lying \Lambda_c^* baryons. We emphasize the importance of the branching ratios of \Gamma(\Sigma_c^*\pi)/\Gamma(\Sigma_c\pi) for the study of the nature of higher excited \Lambda_c^* baryons.

The purpose of this study was to retrospectively determine the risk factors and evaluate the management of bile leakage.Three hundred and thirty-four patients who underwent hepatectomy for Child classification grade A liver disease, without biliary reconstruction and laparoscopic procedures, between 2003 and 2013 were included. Risk factors were identified using multivariate analysis.Bile leakage was observed in 30 (9.0%) patients. Multivariate analysis demonstrated that type of hepatectomy (segmentectomy 1, medial sectionectomy, anterior sectionectomy, or central bisectionectomy) and operating time was independent risk factors for bile leakage. Among 30 patients with confirmed bile leakage, central type leakage that was in communication with the biliary tree occurred in 23 (76.7%) patients and peripheral type, which was not in communication with the biliary tree, in 7 (23.3%) patients. Ten patients were treated with only drainage. Endoscopic or percutaneous transhepatic procedures were performed in 15 cases with central type leakage. Ablation treatment using ethanol or minocycline was mainly performed for peripheral type leakage. Four cases with central type leakage had strictures of the right hepatic duct. Two of them were treated with ablation treatment, portal vein embolization, or fistulojejunostomy. Median duration from diagnosis to end of therapy was 77 days (11-323) in central type and 44 days (6-123) in peripheral type leakage, respectively.Complex hepatectomy and operating time are independent risk factors for postoperative bile leakage. Biliary exploration should be performed as soon as possible after diagnosis, because most bile leakage is the central type. Central type of bile leakage is sometimes refractory to therapy, needing various treatments and requiring a long time for recovery.

Using the axial-vector coupling and the electromagnetic form factors of the D and D⁎ mesons in 2+1 flavor lattice QCD, we compute the D⁎Dπ, DDρ and D⁎D⁎ρ coupling constants, which play an important role in describing the charm hadron interactions in terms of meson-exchange models. We also extract the charge radii of D and D⁎ mesons and determine the contributions of the light and charm quarks separately.

We investigate the mass spectra of open heavy flavor mesons in an external constant magnetic field within QCD sum rules. Spectral ans\"atze on the phenomenological side are proposed in order to properly take into account mixing effects between the pseudoscalar and vector channels, and the Landau levels of charged mesons. The operator product expansion is implemented up to dimension-5 operators. As a result, we find for neutral D mesons a significant positive mass shift that goes beyond simple mixing effects. In contrast, charged D mesons are further subject to Landau level effects, which together with the mixing effects almost completely saturate the mass shifts obtained in our sum rule analysis.

Cancer stem cells (CSCs) are thought to play important roles in therapy-resistance. In this study, we induced cancer stem-like cells from hepatocellular carcinoma (HCC) cell lines using a unique medium, and examined their potential for resistance to anti-cancer drugs.The human HCC cell lines SK-HEP-1 (SK), HLE, Hep 3B, and HuH-7 were used to induce cancer stem-like cells with our sphere induction medium supplemented with neural survival factor-1. NANOG and LIN28A were examined as stemness markers. Several surface markers for CSC such as CD24, CD44, CD44 variant, and CD90 were analyzed by flow-cytometry. To assess the resistance to anti-cancer drugs, the MTS assay, cell cycle analysis, and reactive oxygen species (ROS) activity assay were performed.Poorly differentiated HCC derived SK and undifferentiated HCC derived HLE cell lines efficiently formed spheres of cells (SK-sphere and HLE-sphere), but well-differentiated HCC-derived HuH-7 and Hep 3B cells did not. SK-spheres showed increased NANOG, LIN28A, and ALDH1A1 mRNA levels compared to parental cells. We observed more CD44 variant-positive cells in SK-spheres than in parental cells. The cell viability of SK-spheres was significantly higher than that of SK cells in the presence of several anti-cancer drugs except sorafenib (1.7- to 7.3-fold, each P < 0.05). The cell cycle of SK-spheres was arrested at the G0/G1 phase compared to SK cells. SK-spheres showed higher ABCG2 and HIF1A mRNA expression and lower ROS production compared to parental cells.Our novel method successfully induced cancer stem-like cells, which possessed chemoresistance that was related to the cell cycle, drug efflux, and ROS.

In the tumor microenvironment, factors inhibiting the targeting of cancer cells by activated T cells have recently been noted. B7-H3 belongs to the B7 superfamily of immune regulatory ligands and plays an important role in the adaptive immune response of co-inhibitory/stimulatory factors in regulating T cells. However, the degree to which B7-H3 directly affects tumor immune evasion mechanisms remains unclear, particularly in patients with breast cancer. Regulatory T cells (Tregs) are known as a key player in the inhibition of immune mechanisms. The present study demonstrated that expression of B7-H3 on tumor cells and the number of Tregs in the tumor microenvironment independently affected prognosis in breast cancer patients.We immunohistochemically investigated the presence of B7-H3 and forkhead box P3 (Foxp3)-positive Tregs in pathological specimens from 90 patients with breast cancer.Positive B7-H3 expression was associated with shorter recurrence-free survival (RFS) (p = 0.014). A higher percentage of Foxp3-positive cells also correlated with shorter RFS (p = 0.039). Multivariate analysis showed B7-H3 as an independent factor on RFS. Foxp3 expression in tumor-infiltrating lymphocytes (TILs) correlated significantly with larger tumor size (>2 cm), expression of human epidermal growth factor receptor 2 (HER2), and higher nuclear grade (p = 0.003, p < 0.001, p = 0.001, respectively). No correlation was identified between expression of B7-H3 and the percentage of Foxp3-positive TILs.B7-H3 and Foxp3 can be regarded as markers of poor prognosis in breast cancer. These expressions were not correlated, suggesting that B7-H3 expression plays an independent role in tumor immune evasion, regardless of Tregs.

Background Accumulating evidence shows an over-abundance of Fusobacterium nucleatum in colorectal tumour tissues. Although stool DNA testing of Fusobacterium nucleatum might be a potential marker for the detection of colorectal tumours, the difficulty in detecting Fusobacterium nucleatum in stool by conventional methods prevented further explorations. Therefore, we developed a droplet digital polymerase chain reaction (PCR) assay for detecting Fusobacterium nucleatum in stool and investigated its clinical utility in the management of colorectal tumours in a Japanese population. Methods Feces were collected from 60 healthy subjects (control group) and from 11 patients with colorectal non-advanced adenomas (non-advanced adenoma group), 19 patients with colorectal advanced adenoma/carcinoma in situ (advanced adenoma/carcinoma in situ (CIS) group) and 158 patients with colorectal cancer of stages I to IV (colorectal cancer group). Absolute copy numbers of Fusobacterium nucleatum were measured by droplet digital PCR. Results The median copy number of Fusobacterium nucleatum was 17.5 in the control group, 311 in the non-advanced adenoma group, 122 in the advanced adenoma/CIS group, and 317 in the colorectal cancer group. In comparison with that in the control group, the Fusobacterium nucleatum level was significantly higher in the non-advanced adenoma group, the advanced adenoma/CIS group and the colorectal cancer group. Conclusions This study illustrates the potential of stool DNA testing of Fusobacterium nucleatum by droplet digital PCR to detect individuals with colorectal tumours in a Japanese population.

KIF20A (RAB6KIFL) belongs to the kinesin superfamily of motor proteins, which play critical roles in the trafficking of molecules and organelles during the growth of pancreatic cancer. Immunotherapy using a previously identified epitope peptide for KIF20A is expected to improve clinical outcomes. A phase I clinical trial combining KIF20A-derived peptide with gemcitabine (GEM) was therefore conducted among patients with advanced pancreatic cancer who had received prior therapy such as chemotherapy and/or radiotherapy. GEM was administered at a dose of 1000 mg/m(2) on days 1, 8, and 15 in a 28-day cycle. The KIF20A-derived peptide was injected subcutaneously on a weekly basis in a dose-escalation manner (doses of 0.5, 1, and 3 mg/body; 3 patients/cohort). Safety and immunologic parameters were assessed. No severe adverse effects of grade 3 or higher related to KIF20A-derived peptide were observed. Of the 9 patients who completed at least one course of treatment, interferon-γ (IFN-γ)-producing cells were induced in 4 of 9 patients (P2, P3, P6, and P7), and IFN-γ-producing cells were increased in 4 of the 9 patients (P1, P5, P8, and P9). Four of the 9 patients achieved stable disease. The disease control rate was 44%. The median survival time after first vaccination was 173 days and 1-year survival rate was 11.1%. IFN-γ-producing cells were induced by the KIF20A-derived peptide vaccine at a high rate, even in combination with GEM. These results suggest that this combination therapy will be feasible and promising for the treatment of advanced pancreatic cancer.

The purpose of the present study was to establish an effective immunotherapy by skewing the cosignal balance to be on the positive side by using the combination of monoclonal antibody (mAb) against 4-1BB also known as Cluster of Differentiation (CD) 137 as a co-stimulatory effector and to programmed death-1 (PD-1) to blockade the immune checkpoint.Mice implanted with 1×10(5) CT26 cells were treated with anti 4-1BB mAb alone, anti PD-1 mAb alone, or both anti 4-1BB mAb and anti PD-1 mAb. Immune cell populations were analyzed by flow cytometry. Tumor-infiltrating T-cells were evaluated by immunohistochemistry.Mice treated with the combination therapy had the best antitumor response that resulted in complete tumor rejection. The numbers of CD4(+) interferon (IFN)-γ(+) and CD8(+) IFN-γ(+) T-cells were significantly higher in the combination group. The number of tumor-infiltrating T-cells was significantly increased in the combination therapy.The therapeutic strategy of targeting co-signal molecules has promising clinical applications in the future.

We previously conducted a phase I clinical trial combining the HLA ‐A*2402‐restricted KIF 20A‐derived peptide vaccine with gemcitabine for advanced pancreatic cancer ( PC ) and confirmed its safety and immunogenicity in cancer patients. In this study, we conducted a multicenter, single‐armed, phase II trial using two antiangiogenic cancer vaccines targeting VEGFR 1 and VEGFR 2 in addition to the KIF 20A peptide. We attempted to evaluate the clinical benefit of the cancer vaccination in combination with gemcitabine. Chemotherapy naïve PC patients were enrolled to evaluate primarily the 1‐year survival rate, and secondarily overall survival ( OS ), progression free survival ( PFS ), response rate ( RR ), disease control rate ( DCR ) and the peptide‐specific immune responses. All enrolled patients received therapy without the HLA ‐A information, and the HLA genotypes were used for classification of the patients. Between June 2012 and May 2013, a total of 68 patients were enrolled. No severe systemic adverse effects of Grade 3 or higher related to these three peptides were observed. The 1‐year survival rates between the HLA ‐A*2402‐matched and ‐unmatched groups were not significantly different. In the HLA ‐A*2402 matched group, patients showing peptide‐specific CTL induction for KIF 20A or VEGFR 1 showed a better prognosis compared to those without such induction ( P = 0.023, P = 0.009, respectively). In the HLA ‐A*2402‐matched group, the patients who showed a strong injection site reaction had a better survival rate ( P = 0.017) compared to those with a weak or no injection site reaction. This phase II study demonstrated that this therapeutic peptide cocktail might be effective in patients who demonstrate peptide‐specific immune reactions although predictive biomarkers are needed for patient selection in its further clinical application.

In this paper, a simulation method for predicting global and local hydroelastic response of a ship which couples CFD and FEA is developed and validated. By comparing the prediction with linear/nonlinear strip method, 3D panel method and towing tank test results under various wave conditions in terms of rigid body motions and slamming impact pressure, the effectiveness of the CFD-FEA coupling method is confirmed. The hydroelastic behavior, so-called the whipping moment, evaluated from the CFD-FEA coupling method is further validated by comparing with nonlinear strip method, 3D panel method and tank test results. Finally, the proposed method is applied to a realistic large container ship structure in severe waves. The structural response of the double bottom structure subjected to global and local bending moments is investigated.

We systematically study the mass spectrum and strong decays of the S-wave $\bar c\bar s q q$ states in the compact tetraquark scenario with the quark model. The key ingredients of the model are the Coulomb, the linear confinement, and the hyperfine interactions. The hyperfine potential leads to the mixing between different color configurations, as well as the large mass splitting between the two ground states with $I(J^P)=0(0^+)$ and $I(J^P)=1(0^+)$. We calculate their strong decay amplitudes into the $\bar D^{(*)}K^{(*)}$ channels with the wave functions from the mass spectrum calculation and the quark interchange method. We examine the interpretation of the recently observed $X_0(2900)$ as a tetraquark state. The mass and decay width of the $I(J^P)=1(0^+)$ state are $M=2941$ MeV and $\Gamma_X=26.6$ MeV, respectively, which indicates that it might be a good candidate for the $X_0(2900)$. Meanwhile, we also obtain an isospin partner state $I(J^P)=0(0^+)$ with $M=2649$ MeV and $\Gamma_{X\rightarrow \bar D K}=48.1$ MeV, respectively. Future experimental search for $X(2649)$ will be very helpful.

A novel framework is proposed to extract near-threshold resonant states from finite-volume energy levels of lattice QCD and is applied to elucidate structures of the positive parity D_{s}. The quark model, the quark-pair-creation mechanism and D^{(*)}K interaction are incorporated into the Hamiltonian effective field theory. The bare 1^{+} cs[over ¯] states are almost purely given by the states with heavy-quark spin bases. The physical D_{s0}^{*}(2317) and D_{s1}^{*}(2460) are the mixtures of bare cs[over ¯] core and D^{(*)}K component, while the D_{s1}^{*}(2536) and D_{s2}^{*}(2573) are almost dominated by bare cs[over ¯]. Furthermore, our model reproduces the clear level crossing of the D_{s1}^{*}(2536) with the scattering state at a finite volume.

Spectrum of the doubly heavy tetraquarks, bbq¯q¯, is studied in a constituent quark model. Four-body problem is solved in a variational method where the real scaling technique is used to identify resonant states above the fall-apart decay thresholds. In addition to the two bound states that were reported in the previous study we have found several narrow resonant states above the BB⁎ and B⁎B⁎ thresholds. Their structures are studied and are interpreted by the quark dynamics. A narrow resonance with spin-parity JP=1+ is found to be a mixed state of a compact tetraquark and a B⁎B⁎ scattering state. This is driven by a strong color Coulombic attraction between the bb quarks. Negative-parity excited resonances with JP=0−, 1− and 2− form a triplet under the heavy-quark spin symmetry. It turns out that they share a similar structure to the λ-mode of a singly heavy baryon as a result of the strongly attractive correlation for the doubly heavy diquark.

In this paper, a new wave spectra estimation method is proposed in which the frequency domain wave estimation method (FDWE) is extended into a probabilistic analytical framework in order to estimate the encountered sea states involving uncertainty in transfer functions of a ship. The proposed method, named the Stochastic Wave Spectra Estimation (SWSE), makes use of an Hermite polynomial chaos expansion (PCE) to represent the uncertainty in the transfer functions and the response surfaces. The method involves a mathematical formulation where an extension of the deterministic FDWE concept to the space of random variables is made. The proposed method can accurately and easily estimate the encountered wave spectra based on ship response measurements accounting for uncertainty in the transfer functions. In this paper, numerical and experimental investigations of the proposed SWSE are made, where the uncertainties in the transfer functions of heave and pitch motions of a containership are taken into account. The validity of the SWSE is demonstrated by comparison to results of uncertainty analyses through the Monte-Carlo simulations (MCS).

The authors determined whether the decrease in lymphocytes after surgery is related to apoptosis.Surgery induces a profound but transient depletion of circulating lymphocytes, However, the mechanism underlying this phenomenon is unclear.Peripheral blood mononuclear cells were obtained from 18 patients before and after elective surgery and studied for morphologic and biochemical markers of apoptosis, DNA fragmentation, and Fas expression.The DNA staining of peripheral blood mononuclear cells obtained after surgery, which had been cultured for 24 hours in vitro, showed chromatin condensation and fragmentation of cells into collapsed spheres. Moreover, DNA isolated from these peripheral blood mononuclear cells formed a ladder of oligonucleosomal fragments. However, peripheral blood mononuclear cells obtained before surgery showed neither of these changes. The observation that none of these apoptotic cells ingested latex suggested that they were of lymphocytic origin. Fas-positive lymphocytes increased significantly 2 hours after the start of surgery and returned to preoperative levels by postoperative day 7. Anti-Fas antibody augmented apoptosis, whereas ZB4, a Fas antagonist, inhibited apoptosis in lymphocytes after surgery.These results indicate that circulating lymphocytes in the early perioperative period are susceptible to Fas-mediated apoptosis, which may cause depletion of circulating lymphocytes after surgery.

Fifteen cases (16 concavities) of the so-called “Stafne's bone cavity” were investigated with the use of computed tomography. The sizes, bony outlines, and contents were analyzed on axial images. In all cases, computed tomography clearly demonstrated the concavities on the lingual surface of the mandible. There were no empty concavities. The bony outlines and contents were divided into three types. The concavities with a portion of submandibular gland as a content were larger than those with other contents. Four of six concavities not extending to the buccal cortical plate were filled solely with fat tissue, whereas all concavities with expansion of the buccal cortical plate contained submandibular gland.

Abstract Glass plates of the chemical composition: CaO (29.0), SiO 2 (31.0), Fe 2 O 3 (40.0), B 2 O 3 (3.0), P 2 O 5 (3.0) in weight ratio were heated to 1050 °C at a rate of 5 °C/min and then cooled to laboratory temperature. The resulting glass–ceramic containing magnetite and wollastonite crystals showed high‐saturation magnetization. The bonding ability of this new glass–ceramic to bone tissue was evaluated using rabbit tibiae, and compared with glass of the same composition. This glass–ceramic formed a Ca, P‐rich layer on its surface and bonded tightly with bone within 8 weeks of implantation. However, the glass did not form this Ca, P‐rich layer, nor had it bonded with bone at 25 weeks. The bone‐heating ability of this glass–ceramic was investigated by applying a max. 300‐Oe, 100‐kHz magnetic field. The granules of the glass–ceramic filled in the rabbit tibiae heated the whole surrounding bone to more than 42 °C and maintained this temperature for 30 min. Bioactive ceramics reinforce the mechanical strength of bone tissue. Furthermore, this heat‐generating bioactive glass–ceramic can be used for hyperthermic treatment of bone tumors.

It has been proposed that the essential requirement for artificial materials to bond to living bone is the formation of bone-like apatite on their surfaces in the body. Recent studies have shown that titanium hydrogel and silica gel induce apatite formation on their surface in a simulated body fluid. In this study, the influence of titanium oxide and titanium silicate on the bonding of titanium alloys to bone was studied. Rectangular implants (15 × 10 × 2.2 mm) of titanium, Ti-6Al-4V, Ti-6Al-2Nb-Ta, Ti-6Al-4V coated with TiO2, and Ti-6Al-4V coated with Ti5Si3 were implanted into the tibial metaphyses of mature rabbits. At 8 and 24 weeks after implantation, the tibiae containing the implants were dissected out and subjected to a detaching testing. The failure load for titanium, Ti-6Al-4V, Ti-6Al-2Nb-Ta, Ti-6Al-4V coated with TiO2, and Ti-6Al-4V coated with Ti5Si3 were, respectively, 0.68 ± 0.48, 0.22 ± 0.46, 0.67 ± 0.59, 2.18 ± 0.71 and 2.03 ± 0.41 kgf at 8 weeks, and 2.7 ± 0.91, 2.58 ± 1.29, 2.38 ± 0.41, 3.79 ± 1.7, and 2.79 ± 0.87 kgf at 24 weeks after implantation. Histological examination by Giemsa surface staining, CMR, and SEM-EPMA revealed the coated titanium alloy implants directly bonded to bone tissue during early implantation. A Ca-P layer was observed at the interface of the coated implants and the bone. The results of this study indicated that TiO2 and Ti5Si3 can enhance the early bonding of titanium alloys to bone by inducing a Ca-P layer (chemical apatite) on the surface of titanium alloys. It also is suggested that the direct bone contact occurs in relation to the calcium and phosphorus adsorption onto the surface of the titanium passive layer formed during long-term implantation. © 1996 John Wiley & Sons, Inc.

The surface reactions of calcium phosphate ceramics have been thought to play an important role in bonding with living bone. Hydroxyapatite (HA), tricalcium phosphate (TCP), and two kinds of apatite-containing glass ceramics were immersed in three types of solutions with different chemical constituents. The first solution was a physiological saline, the second contained phosphate (PO4), and the third was a balanced salt solution consisting of calcium (Ca), magnesium (Mg), and PO4. After serial incubation periods, changes in the solutions were assessed by measurement of total Ca, Mg, and PO4. The ceramic surfaces were studied using scanning electron spectroscopy, infrared reflection spectroscopy, and thin-film x-ray diffraction. The surface reactions of the ceramics were greatly affected by the chemical compositions of the surrounding media. In the complete solution with both Ca and PO4, a carbonated apatite layer was formed on the surfaces of HA, TCP, and the glass ceramics. In comparison to HA and TCP, the glass ceramics were characterized as Ca-releasing materials, the dissolved Ca creating an apatite layer on the surfaces in a few days, in conjunction with PO4 stock in the surrounding media. The immersion test with various solutions proved to be a simple and effective method of assessing surface conditions of ceramic materials.

Exotic penta-quark baryon with strangeness +1, \Theta^+, is studied in the QCD sum rule approach. We derive sum rules for the positive and negative parity baryon states with J=1/2 and I=0. It is found that the standard values of the QCD condensates predict a negative parity \Theta^+ of mass \simeq 1.5 GeV, while no positive parity state is found. We stress the roles of chiral-odd condensates in determining the parity and mass of \Theta^+.

In this study the aetiology of community-acquired pneumonia (CAP) in Japan was investigated and the incidence of causative pathogens in ambulatory and hospitalized patients was compared. In addition, the roles of Chlamydophila felis and Chlamydophila pecorum as causes of CAP were investigated. Five hundred and six patients with CAP who visited an outpatient clinic or were admitted to one of three different hospitals were enrolled in this study; 106 of them were outpatients and 400 were hospitalized patients. Among the 506 CAP cases, Mycoplasma pneumoniae was the most common pathogen found in the outpatients and Streptococcus pneumoniae was the most common in the hospitalized patients. No cases of Chlamydophila pecorum pneumonia were observed and only one patient had an antibody titre suggestive of recent infection with the feline strain of Chlamydophila. The incidence of infection with M. pneumoniae and Chlamydophila pneumoniae was higher among the outpatients than among hospitalized patients, whereas the incidence of infection with S. pneumoniae and Haemophilus influenzae was higher among the hospitalized patients. Recognition of these results will allow prompt and appropriate antimicrobial therapy to be provided using Japanese CAP guidelines.

Serum levels of interleukin 6 (IL-6) are correlated with the disease status and prognosis in cancer patients. IL-6 is also an important mediator of experimental cancer cachexia. We investigated the production of IL-6 and IL-6 receptors and expression of IL-6 mRNA by esophageal squamous carcinoma cells using immunohistochemical staining and in situ reverse transcription-PCR. We also measured levels of serum IL-6 using an ELISA in 50 patients with esophageal squamous cell carcinoma (ESCC) to determine the correlation between serum levels of IL-6 and clinicopathological factors IL-6 mRNA was expressed in the primary tumor. Esophageal squamous carcinoma cells produced both IL-6 and IL-6 receptor. IL-6 concentrations were significantly higher in the primary tumor than in the normal epithelium. The incidences of weight loss, tumor invasion to adjacent organs, and noncurative resection were significantly higher in ESCC patients with serum levels of IL-6 > or = 7 pg/ml (n = 13, group C) compared with patients with serum levels <7 pg/ml and > or = 3 pg/ml (n = 14, group B) and <3 pg/ml (n = 23, group A). Tumor size and C-reactive protein levels were significantly higher and albumin levels were significantly lower in group C. Results suggest that IL-6, which is produced by tumor cells, may be related to various disease parameters as well as to the nutritional status in patients with ESCC.

We prospectively investigated the relationship between the clinical efficacy of treatment of pulmonary Mycobacterium avium complex (MAC) disease and drug-sensitivity testing of MAC isolates for antituberculous drugs, new quinolone antibiotics, and clarithromycin (CAM). Fifty-two patients who satisfied the diagnostic criteria of the American Thoracic Society (ATS) and who received treatment between April 1998 and December 2005, using combined therapy of rifampicin (RFP), ethambutol (EB), streptomycin (SM), and CAM, were enrolled in this study. The causative microorganisms isolated were Mycobacterium avium in 30 patients and M. intracellulare in 22 patients. Although separation of the two strains showed drug sensitivity testing to have slightly better minimal inhibitory concentrations (MIC) for M. intracellulare than for M. avium, there were no significant differences in the sputum eradication rate or clinical improvement between the two strains. The MICs of various antibiotics for the isolated MAC strains were as follows: RFP, 0.125-8 microg/ml; CAM, 0.25-16 microg/ml; SM, 2-128< or =microg/ml; EB, 128< or = microg/ml; levofloxacin (LVFX), 1-32 microg/ml; sparfloxacin (SPFX), 0.5-16 microg/ml; and gatifloxacin (GFLX), 0.25-8 microg/ml. The isolated MAC strains showed the same excellent drug sensitivity test results for RFP, new quinolones, and CAM, but they showed resistant drug-sensitivity results for EB and SM. Regarding the relationship between clinical efficacy and the MICs of RFP, EB, CAM, and SM, there was a good relationship only for CAM. Although the ATS has not yet recommended routine drug susceptibility testing of CAM, we believe that drug susceptibility testing of CAM should be performed before the initial treatment is undertaken for pulmonary MAC disease.

A nonsynonymous single nucleotide polymorphism (Asp299Gly) in the Toll-like receptor-4 (TLR-4) gene affects the responsiveness to lipopolysaccharide in humans. To analyze this important polymorphism more efficiently, we developed a simple polymerase chain reaction (PCR) restriction length fragment polymorphism (RFLP) assay and examined the Asp299Gly allele frequency in a Japanese population. The PCR primer was designed with 1- or 2-bp mismatches, creating the recognition sequence for restriction enzyme BsaBI or BstXI, allowing RFLP analysis of the digested products. Genotyping was carried out with this assay for 275 DNA specimens from 107 healthy volunteers and 168 patients with various diseases, including ulcerative colitis (n = 86). The Asp299Gly allele of the TLR-4 gene was not detected in any of the specimens, suggesting that it is very rare in Japanese.

The possibility of flavor-SU(3)-octet dibaryon resonances is studied in the quark model. Because the color-magnetic gluon-exchange interaction is attractive for the flavor octets as well as the singlet, bound and/or resonance states are expected. The importance of two-baryon channel couplings and quark antisymmetrization is stressed for low-lying bound/resonance states. The dibaryon spectrum is studied by applying the quark cluster model to the J${=1}^{+}$ and ${2}^{+}$ six-quark states. Several J${=2}^{+}$ dibaryon resonances are predicted.

In a previous study, we showed that levels of cell-free DNA (cfDNA) were significantly higher in sera of patients with hepatocellular carcinoma (HCC) associated with hepatitis C virus (HCV) than in sera of non-HCC patients with HCV. To confirm this finding, we analysed serum cfDNA levels in a cohort of 96 patients with HCV-related HCC and in 100 HCV carriers without known HCC. Again we found that serum cfDNA levels were significantly higher in HCC patients than in HCV carriers (115.9+/-98.3 vs 34.4+/-40.4 ng ml(-1) (mean+/-s.d.), P<0.0001). Of 87 eligible patients who underwent curative hepatectomy, those with a high cfDNA level had a significantly shorter overall survival (OS) time than those in whom the cfDNA level was not high. Cox proportional hazards model showed the cfDNA level to be an independent prognostic factor for OS and cancer recurrence in distant organs. Our results suggest that the serum cfDNA level reflects the metastatic potential of HCV-related HCC and that it can be a useful predictive biomarker for distant metastasis after curative surgery.

The present authors assessed risk factors that can promote indeterminate results of QuantiFERON TB-2G (QFT-2G; Cellestis Ltd, Carnegie, Australia) tests. The subjects were 704 patients with suspected tuberculosis (TB) and latent TB infection between January 2005 and December 2007. The QFT-2G test and the tuberculin skin test (TST) were performed for all subjects. If the results of the QFT-2G test were indeterminate, the test was repeated within 1 month. In total, 72 (10.2%) patients showed indeterminate results on the QFT-2G test. Indeterminate results were due to positive control failure in 68 (88.9%) patients and negative control failure in four patients. The results of the TST were negative for 64 patients showing indeterminate results, the remaining eight patients showed a positive response to the TST. Indeterminate results were significantly associated with elderly and immunocompromised patients. Lymphocytopaenia and hypoalbuminaemia were significantly associated with indeterminate laboratory findings. When the QFT-2G test was repeated for all patients showing indeterminate results, 12 (16.7%) patients demonstrated determinate results on the subsequent test. Indeterminate results of the QuantiFERON TB-2G test under routine clinical practice are not infrequent. When scoring QuantiFERON TB-2G test results for elderly and immunocompromised patients, one must be careful because the possibility of obtaining determinate results may be low even if the test is repeated.

The Japanese Respiratory Society guidelines propose a differential diagnosis for atypical pneumonia and bacterial pneumonia using a scoring system for the selection of appropriate antibiotic. In order to improve this scoring system, the guidelines are seeking new specific parameter. The purpose of this study was to clarify the pattern of abnormalities with Mycoplasma pneumoniae pneumonia on chest computed tomography (CT) and whether the radiographic findings could distinguish M. pneumoniae pneumonia from Streptococcus pneumoniae pneumonia.A retrospective review was performed of the CT findings of 64 cases and 68 cases where M. pneumoniae and S. pneumoniae, respectively, were the only pathogen identified by the panel of diagnostic tests used.Of the 64 patients with M. pneumoniae pneumonia, bronchial wall thickening was observed most frequently (81%), followed by centrilobular nodules (78%), ground-glass attenuation (78%), and consolidation (61%). Bronchial wall thickening and centrilobular nodules were observed more often in M. pneumoniae patients than in S. pneumoniae patients (p < 0.0001). The presence of bilateral bronchial wall thickening or centrilobular nodules was only seen in patients with M. pneumoniae pneumonia. Using the scoring system of the Japanese Respiratory Society guidelines and chest CT findings, 97% of M. pneumoniae patients were suspected to be M. pneumoniae pneumonia without serology. When comparing the CT findings between early stage and progressed stage in the same patients with severe pneumonia, the radiographic features of early stage M. pneumoniae pneumonia were not observed clearly in the progressed stage.The present results indicate that the diagnosis of M. pneumoniae pneumonia would appear to be reliable when found with a combination of bronchial wall thickening and centrilobular nodules in the CT findings. However, these CT findings are not observed in progressed severe M. pneumoniae pneumonia patients.

Abstract Analysis of cytokine and chemokine production by tumor cell lines including five lung cancers, a malignant mesothelioma, and a malignant melanoma recently established in our laboratory showed rather high production of IL-8 in all tumors and IL-6 in one lung cancer, the malignant mesothelioma, and the malignant melanoma. We investigated the migration of PBMCs to these tumor cells using Transwell plates and showed enrichment of Foxp3+ CD4 regulatory T cells (Tregs) in migrated T cells to both IL-6– and IL-8–producing tumors. Marked induction of CXCR1 expression on Foxp3+ CD4 Tregs by IL-6 followed by IL-8–mediated migration appeared to be responsible for enriched migration. Frequent production of IL-8 by the tumors and Treg migration to those tumors through induction of IL-8R expression by IL-6 is one of the mechanisms for tumor escape.

Charmonia spectral functions at finite temperature are studied using QCD sum rules in combination with the maximum entropy method. This approach enables us to directly obtain the spectral function from the sum rules, without having to introduce any specific assumption about its functional form. As a result, it is found that while J/psi and eta_c manifest themselves as significant peaks in the spectral function below the deconfinement temperature T_c, they quickly dissolve into the continuum and almost completely disappear at temperatures between 1.0 T_c and 1.1 T_c.

The electromagnetic form factors of the spin-3/2 $\Omega$ baryons, namely $\Omega$, $\Omega_c^\ast$, $\Omega_{cc}^\ast$ and $\Omega_{ccc}$, are calculated in full QCD on $32^3\times 64$ PACS-CS lattices with a pion mass of 156(9) MeV. The electric charge radii and magnetic moments from the $E0$ and $M1$ multipole form factors are extracted. Results for the electric quadrupole form factors, $E2$, are also given. Quark sector contributions are computed individually for each observable and then combined to obtain the baryon properties. We find that the charm quark contributions are systematically smaller than the strange-quark contributions in the case of the charge radii and magnetic moments. $E2$ moments of the $\Omega_{cc}^\ast$ and $\Omega_{ccc}$ provide a statistically significant data to conclude that their electric charge distributions are deformed to an oblate shape. Properties of the spin-1/2 $\Omega_c$ and $\Omega_{cc}$ baryons are also computed and a thorough comparison is given. This complete study gives valuable hints about the heavy-quark dynamics in charmed hadrons.

As a continuation of our recent work on the electromagnetic properties of the doubly charmed $\Xi_{cc}$ baryon, we compute the charge radii and the magnetic moments of the singly charmed $\Sigma_c$, $\Omega_c$ and the doubly charmed $\Omega_{cc}$ baryons in 2+1 flavor Lattice QCD. In general, the charmed baryons are found to be compact as compared to the proton. The charm quark acts to decrease the size of the baryons to smaller values. We discuss the mechanism behind the dependence of the charge radii on the light valence- and sea-quark masses. The magnetic moments are found to be almost stable with respect to changing quark mass. We investigate the individual quark sector contributions to the charge radii and the magnetic moments. The magnetic moments of the singly charmed baryons are found to be dominantly determined by the light quark and the role of the charm quark is significantly enhanced for the doubly charmed baryons.

We previously reported the clinical efficacy of adoptive immunotherapy (AIT) with dendritic cells (DCs) pulsed with mucin 1 (MUC1) peptide and cytotoxic T lymphocytes (CTLs). We also reported that gemcitabine (GEM) enhances anti-tumor immunity by suppressing regulatory T cells. Therefore, in the present study, we performed combination therapy with AIT and GEM for patients with unresectable or recurrent pancreatic cancer.Forty-two patients with unresectable or recurrent pancreatic cancer were treated. DCs were generated by culture with granulocyte macrophage colony-stimulating factor and interleukin-4 and then exposed to tumor necrosis factor-α. Mature DCs were transfected with MUC1-mRNA by electroporation (MUC1-DCs). MUC1-CTLs were induced by co-culture with YPK-1, a human pancreatic cancer cell line, and then with interleukin-2. Patients were treated with GEM, while MUC1-DCs were intradermally injected, and MUC1-CTLs were intravenously administered.Median survival time (MST) was 13.9 months, and the 1-year survival rate was 51.1%. Of 42 patients, one patient had complete response (2.4%), three patients had partial response (7.1%) and 22 patients had stable disease (52.4%). The disease control ratio was 61.9%. The MST and 1-year survival rate of 35 patients who received more than 1 × 10(7) MUC1-DCs per injection was 16.1 months and 60.3%, respectively. Liver metastasis occurred in only 5 patients among 35 patients without liver metastasis before treatment. There were no severe toxicities associated with AIT.AIT with MUC1-DCs and MUC1-CTLs plus GEM may be a feasible and effective treatment for pancreatic cancer.

Scattering lengths for two pseudoscalar meson systems, $\ensuremath{\pi}\ensuremath{\pi}(I=2)$, $KK(I=1)$ and $\ensuremath{\pi}K(I=3/2,1/2)$, are calculated from lattice QCD by using the finite size formula. We perform the calculation with ${N}_{f}=2+1$ gauge configurations generated on $3{2}^{3}\ifmmode\times\else\texttimes\fi{}64$ lattice using the Iwasaki gauge action and a nonperturbatively $\mathcal{O}(a)$-improved Wilson action at ${a}^{\ensuremath{-}1}=2.19\text{ }\text{ }\mathrm{GeV}$. The quark masses correspond to ${m}_{\ensuremath{\pi}}=0.17--0.71\text{ }\text{ }\mathrm{GeV}$. For the $\ensuremath{\pi}K(I=1/2)$ system, we use the variational method with the two operators, $\overline{s}u$ and $\ensuremath{\pi}K$, to separate the contamination from the higher states. In order to obtain the scattering length at the physical quark mass, we fit our results at several quark masses with the formula of the $\mathcal{O}({p}^{4})$ chiral perturbation theory and that includes the effects of the discretization error from the Wilson fermion, Wilson chiral perturbation theory. We found that the mass dependence of our results near ${m}_{\ensuremath{\pi}}=0.17\text{ }\text{ }\mathrm{GeV}$ are described well by Wilson chiral perturbation theory but not by chiral perturbation theory. The scattering lengths at the physical point are given as ${a}_{0}^{(2)}{m}_{\ensuremath{\pi}}=\ensuremath{-}0.04263(22)(41)$, ${a}_{0}^{(1)}{m}_{K}=\ensuremath{-}0.310(17)(32)$, ${a}_{0}^{(3/2)}{\ensuremath{\mu}}_{\ensuremath{\pi}K}=\ensuremath{-}0.0469(24)(20)$, and ${a}_{0}^{(1/2)}{\ensuremath{\mu}}_{\ensuremath{\pi}K}=0.142(14)(27)$. Possible systematic errors are also discussed.

Structure and production of doubly charmed tetraquarks Tcc (ccu¯d¯) are studied from the viewpoint of color configurations. Based on the diquark correlation, the tetraquark Tcc with I(JP)=0(1+) is considered to be stable against strong decay. We discuss that the mixing probability of color antitriplet and sextet cc components in Tcc is suppressed by 1/mc2, so the two configurations are separately realized in the heavy quark limit. Utilizing the nonrelativistic QCD framework, we evaluate the production cross sections of Tcc in electron–positron collisions. The momentum dependence of the cross section of color antitriplet is found to be different from that of sextet, which can be used to discriminate the color structure of the Tcc states in experimental measurements.

<h3>Introduction</h3> Tregs infiltrate tumors and inhibit immune responses against them. <h3>Methods</h3> We investigated subpopulations of Foxp3⁺ CD4 T cells previously defined by Miyara et al. (<i>Immunity</i> 30, 899–911, 2009) in peripheral blood mononuclear cells (PBMCs) and tumor infiltrating lymphocytes (TILs) in lung cancer. We also showed that Tregs in healthy donors that express CCR4 could be efficiently eliminated in vitro by cotreatment with antihuman (h) CCR4 mAb (KM2760) and NK cells. <h3>Results</h3> In lung cancer, the number of activated/effector Tregs and non-Tregs, but not resting/naive Tregs, was increased in TILs compared with the number of those cells in PBMCs. The non-Treg population contained Th2 and Th17. CCR4 expression on activated/effector Tregs and non-Tregs in TILs was down-regulated compared with that on those cells in PBMCs. Chemokinetic migration of CD25⁺ CD4 T cells containing the Treg population sorted from the PBMCs of healthy donors to CCL22/MDC was abrogated by pretreatment with anti-hCCR4 mAb (KM2760). The inhibitory activity of CD25⁺ CD127^dim/− CD4 Tregs on the proliferative response of CD4 and CD8 T cells stimulated with anti-CD3/CD28 coated beads was abrogated by adding an anti-hCCR4 mAb (KM2760) and CD56⁺ NK cells to the culture. <h3>Conclusions</h3> The findings suggested the CCR4 on activated/effector Tregs and non-Tregs was functionally involved in the chemokinetic migration and accumulation of those cells to the tumor site. In vitro findings of efficient elimination of Tregs may give the basis for implementation of a clinical trial to investigate Treg depletion by administration of an anti-hCCR4 mAb to solid cancer patients.

A quark model, which reproduces the ground-state mesons and baryons, i.e., the threshold energies, is applied to the $qqqc\bar c$ configurations, where $q$ is a light quark and~$c$ the charmed quark. In the calculation, several open channels are explicitly included such as $\Jpsi +N$, $\eta_c+N$, $\Lambda_c +D$, etc. To distinguish genuine resonances and estimate their width, we employ Gaussian Expansion Method supplemented by the real scaling method (stabilization). No resonance is found at the energies of the $P_c(4380)$ and $P_c(4450)$ pentaquarks. On the other hand, there is a sharp resonant state at 4690\,MeV with $J=1/2^-$ state and another one at 4920\,MeV with $J=3/2^-$ state, which have a compact structure.

A laser-Compton backscattering beam, which we call a ‘Laser-Electron Photon’ beam, was upgraded at the LEPS beamline of SPring-8. We accomplished the gains in backscattered photon beam intensities by factors of 1.5–1.8 with the injection of two adjacent laser beams or a higher power laser beam into the storage ring. The maximum energy of the photon beam was also extended from 2.4 GeV to 2.9 GeV with deep-ultraviolet lasers. The upgraded beams have been utilized for hadron photoproduction experiments at the LEPS beamline. Based on the developed methods, we plan the simultaneous injection of four high power laser beams at the LEPS2 beamline, which has been newly constructed at SPring-8. As a simulation result, we expect an order of magnitude higher intensities close to 107 s−1 and 106 s−1 for tagged photons up to 2.4 GeV and 2.9 GeV, respectively.