Phonon Lifetime Observation in Epitaxial ScN Film with Inelastic X-Ray Scattering Spectroscopy.

Phonon-phonon scattering dominates the thermal properties in nonmetallic materials, and it directly influences device performance in applications. The understanding of the scattering has been progressing using computational approaches, and the direct and systematic observation of phonon modes that include momentum dependences is desirable. We report experimental data on the phonon dispersion curves and lifetimes in an epitaxially grown ScN film using inelastic x-ray scattering measurements. The momentum dependence of the optical phonon lifetimes is estimated from the spectral width, and the highest-energy phonon mode around the zone center is found to possess a short lifetime of 0.21 ps. A comparison with first-principles calculations shows that our observed phonon lifetimes are quantitatively explained by three-body phonon-phonon interactions.

FOLFIRI plus bevacizumab as second-line therapy in patients with metastatic colorectal cancer after first-line bevacizumab plus oxaliplatin-based therapy: the randomized phase III EAGLE study.

BACKGROUND: A targeted agent combined with chemotherapy is the standard treatment in patients with metastatic colorectal cancer (mCRC). The present phase III study was conducted to compare two doses of bevacizumab combined with irinotecan, 5-fluorouracil/leucovorin (FOLFIRI) in the second-line setting after first-line therapy with bevacizumab plus oxaliplatin-based therapy. PATIENTS AND METHODS: Patients were randomly assigned to receive FOLFIRI plus bevacizumab 5 or 10 mg/kg in 2-week cycles until disease progression. The primary end point was progression-free survival (PFS), and secondary end points included overall survival (OS), time to treatment failure (TTF), and safety. RESULTS: Three hundred and eighty-seven patients were randomized between September 2009 and January 2012 from 100 institutions in Japan. Baseline patient characteristics were well balanced between the two groups. Efficacy was evaluated in 369 patients (5 mg/kg, n = 181 and 10 mg/kg, n = 188). Safety was evaluated in 365 patients (5 mg/kg, n = 180 and 10 mg/kg, n = 185). The median PFS was 6.1 versus 6.4 months (hazard ratio, 0.95; 95% confidence interval [CI] 0.75-1.21; P = 0.676), and median TTF was 5.2 versus 5.2 months (hazard ratio, 1.01; 95% CI 0.81-1.25; P = 0.967), respectively, for the bevacizumab 5 and 10 mg/kg groups. Follow-up of OS is currently ongoing. Adverse events, including hypertension and hemorrhage, occurred at similar rates in both groups. CONCLUSION: Bevacizumab 10 mg/kg plus FOLFIRI as the second-line treatment did not prolong PFS compared with bevacizumab 5 mg/kg plus FOLFIRI in patients with mCRC. If bevacizumab is continued after first-line therapy in mCRC, a dose of 5 mg/kg is appropriate for use as second-line treatment. CLINICAL TRIAL IDENTIFIER: UMIN000002557.

Does "conversion chemotherapy" really improve survival in metastatic colorectal cancer patients with liver-limited disease?

BACKGROUND: The clinical benefits of conversion chemotherapy followed by liver resection for initially unresectable colorectal liver metastases are still controversial. The criteria for unresectability vary from one team to another. To clarify this issue, we retrospectively assessed the survival and characteristics of metastatic colorectal cancer (mCRC) patients with liver-limited disease (LLD) who underwent conversion therapy. METHOD: Our criteria for resectability depended on the size of the remnant liver volume (>30 %) and expected function after removal of all metastases. Between December 2007 and September 2011, a total of 115 patients were diagnosed as having mCRC with LLD and received chemotherapy. Among them, 47 had tumors that were initially diagnosed as resectable. They underwent hepatic resection after chemotherapy (resected group). Of the 67 tumors were initially diagnosed as unresectable, 12 became resectable after chemotherapy (conversion group), leaving 55 tumors that remained unresectable after chemotherapy (unresected group). RESULTS: The median follow-up was 25.2 months. Hepatic resection was more invasive in the conversion group than in the resected group. Median disease-free survival was significantly higher in the resected group than in the conversion group (p = 0.013). Overall survival (OS) was also higher in the resected group, but the difference was not significant (p = 0.36). However, OS was significantly higher in the conversion group than in the unresected group (p = 0.034). Multivariate analysis of the resected and conversion groups showed that OS was significantly negatively influenced by abnormal carcinoembryonic antigen levels at surgery (p = 0.037) and a hospital stay >30 days (p = 0.009). CONCLUSIONS: Our results showed that conversion chemotherapy could contribute to longer OS in mCRC patients with LLD.

A functional SNP upstream of the beta-2 adrenergic receptor gene (ADRB2) is associated with obesity in Oceanic populations.

OBJECTIVE: Obesity is a growing health concern in the Oceanic populations. To investigate the genetic factors associated with adult obesity in the Oceanic populations, the association of single nucleotide polymorphisms (SNPs) of the beta-2 adrenergic receptor (ADRB2) gene with obesity was examined in 694 adults living in Tonga and Solomon Islands. RESULTS: A screening for variation in 16 Oceanic subjects detected 17 SNPs in the entire region of ADRB2, of which nine SNPs including two non-synonymous ones, rs1042713 (Arg16Gly) and rs1042714 (Gln27Glu), were further genotyped for all subjects. The rs34623097-A allele, at a SNP located upstream of ADRB2, showed the strongest association with risk for obesity in a logistic regression analysis adjusted for age, sex, and population (P=5.6 × 10(-4), odds ratio [OR]=2.5, 95% confidence interval [CI]=1.5-4.2). The 27Glu was also significantly associated with obesity in the single-point association analysis (P=0.013, OR=2.0, 95%CI=1.2-3.4); however, this association was no longer significant after adjustment for rs34623097 since these SNPs were in linkage disequilibrium with each other. A copy of the obesity-risk allele, rs34623097-A, led to a 1.6 kg/m(2) increase in body mass index (BMI; defined as weight in kilograms divided by height in meters squared) (P=0.0019). A luciferase reporter assay indicated that rs34623097-A reduced the transcriptional activity of the luciferase reporter gene by approximately 10% compared with rs34623097-G. An electrophoretic mobility shift assay demonstrated that rs34623097 modulated the binding affinity with nuclear factors. An evolutionary analysis implies that a G>A mutation at rs34623097 occurred in the Neandertal genome and then the rs34623097-A allele flowed into the ancestors of present-day humans. CONCLUSION: The present results suggest that rs34623097-A, which would lead to lower expression of ADRB2, contributes to the onset of obesity in the Oceanic populations.

Efficacy of azithromycin in preventing lethal graft-versus-host disease.

Acute graft-versus-host disease (GVHD) following allogeneic bone marrow transplantation (BMT) is initiated by donor T lymphocytes that recognize histocompatibility antigens presented by recipient dendritic cells (DCs). Current approaches to reduce GVHD are focused on suppressing donor T lymphocyte responses to alloantigens. However, these strategies may be inadequate in the setting of allogeneic transplants (particularly histoincompatible transplants), may increase the risk of tumour relapse and are associated with high rates of opportunistic infections. We hypothesized that inhibition of recipient DCs might suppress GVHD. We recently demonstrated in vitro that azithromycin, a macrolide antibiotic, also acts as a nuclear factor (NF)-κB inhibitor of murine DCs and inhibits their maturation and functions, including allogeneic responses. We investigated whether azithromycin could prevent alloreactions in a murine histoincompatibility model. Oral administration of azithromycin to recipient mice for 5 days during major-histoincompatible BMT suppressed lethal GVHD significantly, whereas ex-vivo lymphocyte function was not affected by the drug. These data suggest that azithromycin has potential as a novel prophylactic drug for lethal GVHD.

Giant optical rotation in a three-dimensional semiconductor chiral photonic crystal.

Optical rotation is experimentally demonstrated in a semiconductor-based three-dimensional chiral photonic crystal (PhC) at a telecommunication wavelength. We design a rotationally-stacked woodpile PhC structure, where neighboring layers are rotated by 45° and four layers construct a single helical unit. The mirror-asymmetric PhC made from GaAs with sub-micron periodicity is fabricated by a micro-manipulation technique. The linearly polarized light incident on the structure undergoes optical rotation during transmission. The obtained results show good agreement with numerical simulations. The measurement demonstrates the largest optical rotation angle as large as ∼ 23° at 1.3 µm wavelength for a single helical unit.

Middle-ear carcinoid tumour metastasising to the parapharyngeal space and the parotid gland.

Background. Middle-ear carcinoid tumour is a rare malignant tumour with an indolent course occasionally causing regional or distant metastasis. This paper presents a case of middle-ear carcinoid tumour metastasising to the parapharyngeal space and the parotid gland 20 years after the first surgery.Case report. A 35-year-old woman who underwent multiple tympanomastoidectomies for middle-ear carcinoid presented with tumours of both the parapharyngeal space and parotid gland, detected by regular imaging. Based on the clinical course, metastatic relapse of middle-ear carcinoid was suspected. This was treated with subtotal parotidectomy with elective neck dissection (levels II and III), leading to the pathological diagnosis of carcinoid tumour. A cervico-parotid approach was selected to avoid complications associated with parapharyngeal space tumour removal. Transient facial palsy (House-Brackmann grade III) occurred, which completely recovered two months after surgery.Conclusion. Awareness of parapharyngeal space tumours possibly caused by metastasis from a middle-ear tumour is necessary.

The effect of azithromycin on the maturation and function of murine bone marrow-derived dendritic cells.

Dendritic cells (DCs) are professional antigen-presenting cells capable of initiating primary/adaptive immune responses and tolerance. DC functions are regulated by their state of maturation. However, the molecular pathways leading to DC development and maturation remain poorly understood. We attempted to determine whether inhibition of nuclear factor kappa B (NF-κB), which is one of the pivotal pathways underlying these processes, could induce immunophenotypic and functional changes in lipopolysaccharide-induced mature DCs derived from murine bone marrow. A comparative in vitro study of five clinically used drugs that are known to inhibit NF-κB demonstrated that azithromycin, a macrolide antibiotic, significantly inhibited expression of co-stimulatory molecules (CD40 and CD86) and major histocompatibility complex (MHC) class II by DCs. It also reduced Toll-like receptor 4 expression, interleukin-12 production and the allostimulatory capacity of DCs. These data suggest that azithromycin, as not only an NF-κB inhibitor but also an antibiotic, has potential as a novel drug for manipulation of allogeneic responses.

Large scale replication analysis of loci associated with lipid concentrations in a Japanese population.

BACKGROUND: Recent genome wide association studies discovered seven novel loci that influence plasma concentrations of triglycerides, high density lipoprotein (HDL) and low density lipoprotein (LDL) cholesterol in Europeans. To date, large scale replication studies using populations with known differences in genome-wide linkage disequilibrium (LD) pattern have not been undertaken. METHODS: To address this issue, we tested associations between single nucleotide polymorphisms (SNPs) within the seven novel loci and plasma lipid profiles in 21 010 Japanese individuals. RESULTS: Multiple linear regression analyses showed that the rs3812316 in MLXIPL was strongly associated with triglyceride concentrations (p approximately 3.0x10(-11), 7.1 mg/dl decrease per minor C allele) and that rs599839 in CELSR2/PSRC1/SORT1 was strongly associated with LDL cholesterol concentrations (p approximately 3.1x10(-11), 4.7 mg/dl decrease per minor G allele) in the Japanese population. SNPs near ANGPTL3, TRIB1 and GALNT2 showed evidence for associations with triglyceride concentrations (3.6x10(-6)

Increase of Q-factor in photonic crystal H1-defect nanocavities after closing of photonic bandgap with optimal slab thickness.

We investigate the dependence of quality factor Q of dipole modes in photonic crystal H1-defect nanocavity on the slab thickness and observe an increase of Q even after closing of the photonic bandgap both in numerical simulation and experimentation. This counter intuitive behavior results from the weak coupling between the cavity mode and the 2nd-guided mode in the photonic crystal slab. This is confirmed by computing the overlap between them in the momentum space.

Design of high-Q photonic crystal microcavities with a graded square lattice for application to quantum cascade lasers.

A high-Q photonic crystal (PC) microcavity for TM-like modes, which can be applied to quantum cascade lasers (QCLs), was successfully designed in an air-hole based PC slab with semiconductor cladding layers. In spite of no photonic badgaps for TM-like modes in air-hole based PC slabs, cavity Q reached up to 2,200 by utilizing a graded square lattice PC structure. This is approximately 18 times higher than those previously reported for PC defect-mode microcavities for QCLs. This large improvement is attributed to a suppression of the coupling between the cavity mode and the leaky modes thanks to the dielectric perturbation in the graded structure. We also predicted a dramatic reduction of the threshold current in the designed cavity down to one-fifteenth of that of a conventional QCL, due to a decreased optical volume.

The RHD gene is highly detectable in RhD-negative Japanese donors.

Recent molecular studies on the Rh blood group system have shown that the Rh locus of each haploid RhD-positive chromosome is composed of two structural genes: RHD and RHCE, whereas the locus is made of a single gene (RHCE) on each haploid RhD-negative chromosome. We analyzed the presence or absence of the RHD gene in 130 Japanese RhD-negative donors using the PCR method. The RhD-negative phenotypes consisted of 34 ccEe, 27 ccee, 17 ccEE, 26 Ccee, 19 CcEe, 1 CcEE, and 6 CCee. Among them, 36 (27.7%) donors demonstrated the presence of the RHD gene. Others showed gross or partial deletions of the RHD gene. These results were confirmed by Southern blot analysis. Additionally, the RHD gene detected in the RhD-negative donors seemed to be intact through sequencing of the RhD polypeptide cDNA and the promoter region of RHD gene. The phenotypes of these donors with the RHD gene were CC or Cc, but not cc. It suggested that there is some relationship between the RHD gene and the RhC phenotypes in RhD-negative individuals. In Caucasian RhD-negative individuals, the RHD gene has not been found outside of the report of Hyland et al. (Hyland, C.A., L.C. Wolter, and A. Saul. 1994. Blood. 84:321-324). The discrepant data on the RHD gene in RhD-negative donors between Japanese and Caucasians appear to be derived from the difference of the frequency of RhD-negative and RhC-positive phenotypes. Careful attention is necessary for clinicians in applying RhD genotyping to clinical medicine.

Leptin resistance conferred by a combination of single nucleotide polymorphism and the adoption of a Western lifestyle in urban areas of Thailand.

OBJECTIVES: An increasing number of lifestyle disorders have emerged in response to the rapid urbanization that has occurred in Thailand. Recently, leptin resistance has been nominated as a possible marker for the onset of metabolic disorders in Asian countries. The research aimed to assess the relationship between leptin-resistance and environmental and/or genetic factors by comparing urban and rural inhabitants in Thailand. METHODS: A total of 212 age- and sex-matched subjects from an urban area (Bangkok) and from rural areas (Sai Noi) participated in the study. Anthropometric measurements, blood biochemistry, single nucleotide polymorphism analyses, and interviews concerning lifestyles and dietary habits were conducted individually. Backward elimination multiple regression analyses and least trimmed sum of square methods were used to estimate the effects of possible factors. RESULTS: A transition of staple food from rice to bread (decreased rice intake; p < 0.01 and increased bread intake; p < 0.05) was significant in urban areas. Leptin levels were higher in urban groups, with a significant difference in women (p < 0.001 in women and p = 0.06 in men), but not in men. Predictors selected for leptin-resistance in women were genotypes of UCP2, PPARg2, bread intake, living area, and smoking habit (r = 0.510); in men, genotypes of UCP2 and UCP3p, smoking habit, and rice intake (r = 0.315). CONCLUSIONS: Urban women with del/del type of UCP2 exhibited significant leptin resistance. A combination of urbanization and UCP2 genotype were considered to be responsible.

Alterations of the p53 gene in human primary cervical carcinoma with and without human papillomavirus infection.

A previous report using cervical carcinoma cell lines suggests that the inactivation of two tumor suppressor gene products, p53 and pRB, either by complex formation with the E6 and E7 proteins of oncogenic human papillomaviruses (HPVs) or by mutation, may be an important step in cervical carcinogenesis (M. Scheffner et al., Proc. Natl. Acad. Sci. USA, 88: 5523-5527, 1991). The present study was designed to clarify the association between p53 inactivation and infection with oncogenic HPVs in primary carcinomas of human uterine cervix. We examined 36 primary cervical carcinomas for the presence of HPV DNAs by Southern blot analysis with probes specific for HPV-16, -18, -31, -33, -52, -56, and -58. HPV DNA sequences were detected in 19 of 36 tumors: 10 cases with HPV-16; 3 cases with -18; 3 cases with -58; 2 cases with -56; and one case with -52. The presence of HPV-16 and -18 in cervical carcinomas was further reexamined using polymerase chain reaction. HPV DNA sequences were detected in an additional 10 cases: 9 cases with -16 and one case with -18. The inactivation of the p53 gene by allelic loss or by point mutation was also examined. No allelic loss at the polymorphic site in codon 72 of the p53 gene was detected in any of 10 informative cases. Missense point mutations in the highly conserved regions of the p53 gene were demonstrable as single-stranded conformational polymorphisms of polymerase chain reaction-amplified DNA fragments and subsequently identified by direct DNA sequencing. Point mutations were detected in only two cases: one with an ATG----CTG transversion in codon 133 of exon 5, resulting in a Met----Leu substitution, and another with a CGG----TGG transition in codon 248 of exon 7, resulting in an Arg----Trp substitution. Both tumors with point mutations in p53 genes were among 10 tumors which contained a small copy number of HPV-16 DNA sequences (1 copy of HPV/10(1) to 10(5) cells) detectable by polymerase chain reaction amplification but not by Southern blot analysis of genomic DNAs derived from the tumors. None of 19 tumors with a large copy number of HPV DNA sequences detectable by Southern blot analysis (more than 1 copy of HPV/2 to 10 cells) nor any of 7 tumors with undetectable HPV DNA sequences contained p53 gene mutations in the regions examined.(ABSTRACT TRUNCATED AT 400 WORDS)

Hydroxylforms of p-boronophenylalanine as potential boron carriers on boron neutron capture therapy for malignant brain tumors.

Hydroxylforms of boronophenylalanine (BPA) were synthesized by conjugation with a cascade of polyols to decrease the BPA uptake of normal parenchyma without affecting uptake into the tumor. We determined their tumor cell killing effect on boron neutron capture therapy (BNCT) against BPA using the human glioma cell line T98G. The thermal neutron doses yielding the D37 (dose used to inhibit 63% colony formation) values of dl-p-BPA(OH)n were 1.45 x 10(12)nvt (n = 1), 1.33 x 10(12)nvt (n = 2), 3.37 x 10(12)nvt (n = 4), and 1.72 x 10(12)nvt (n = 0). The relative tumor cell killing effect on BNCT of dl-p-BPA(OH)n against dl-p-BPA, which was defined as the ratio of D37-BPA to D37-BPA(OH)n, was 1.18 (n = 1) 1.29 (n = 2), and 0.51 (n = 4). The tumor:normal brain ratio of dl-p-BPA(OH)n in 9L rat brain tumor models was improved 1.2- (n = 1) and 1.4-fold (n = 2) against that of dl-p-BPA without a decrease of its uptake into the tumor. The water solubility of BPA(OH)n increased against BPA, and the toxicity represented as the IC50 value of dl-p-BPA(OH)2 was nearly one half that of dl-p-BPA, being established in our previous works. Hydroxylforms of BPA, especially dl-p-BPA(OH)2, might be more suitable boron carriers of BNCT to malignant brain tumors since the radiation injury to the normal parenchyma surrounding the tumor is reduced.

Cloning and expression of the gene of hemocytin, an insect humoral lectin which is homologous with the mammalian von Willebrand factor.

Invertebrate lectins play an important role in a non-specific self-defense mechanism, as invertebrates do not synthesize specific antibodies. We report the cloning of several overlapping cDNAs encoding the entire silkworm (Bombyx mori) lectin, which we propose to call hemocytin. The sequence (10477 bp) encoded 3133 amino acids. The characteristics features of the carbohydrate-recognition domain of C-type animal lectin were revealed at C-terminal sequence of hemocytin. When cDNA encoding this region was introduced into baculovirus vector, hemagglutinating activities were detected in the culture fluid of a recombinant virus-infected cells. These activities were inhibited by D-mannose, N-acetyl-D-galactosamine, and D-maltose which are haptenic saccharides of authentic hemocytin. Analysis of dot and Northern blot hybridization revealed that hemocytin gene was transcribed in hemocytes of the silkworm at larval-pupal metamorphosis and/or after the injection of Escherichia coli and lipopolysaccharide. After silkworm larvae were injected with C-terminal portion of hemocytin, aggregation of hemocytes was observed in the hemolymph. Hemocytin has significant homology with mammalian von Willebrand factor which involves in platelet adhesion to subendothelium. Also, hemocytin has a homologous region with coagulation factor V and VIII. These results suggest that hemocytin molecule is an adhesive protein and relates to hemostasis or encapsulation of foreign substances for self-defense.

Expression of survivin and its relationship to loss of apoptosis in breast carcinomas.

Aberrant inhibition of programmed cell death (apoptosis) prevents normal homeostasis and promotes tissue tumorigenesis, but whether it also influences the outcome of common cancers has remained arguable. The expression of a novel IAP apoptosis inhibitor, survivin, in breast cancer and its association with tumor cell apoptosis and overall prognosis were examined in this study. Immunohistochemical analysis showed that survivin expression was positive in 118 of 167 cases (70.7%) of breast carcinomas of histological stages I to IH. In contrast, no expression of survivin in adjacent normal tissue was detected. Although survivin expression was not correlated with p53 mutations, survivin-positive cases were strongly associated with bcl-2 expression (78.0% versus 47.5%; P = 0.0005) and reduced apoptotic index (0.62% +/- 0.51% versus 1.27% +/- 1.37%; P < 0.0001). In addition, patients with low apoptotic index (<0.52%) had worse survival rates than the group with high apoptotic index (> or =0.52%; P = 0.028), and multivariate Cox proportional hazard model analysis identified apoptotic index as an independent prognostic factor (P = 0.024). The results suggest that apoptosis inhibition by survivin, alone or in cooperation with bcl-2, is a significant prognostic parameter of worse outcome in breast carcinoma.

Synthesis and biological properties of water-soluble p-boronophenylalanine derivatives. Relationship between water solubility, cytotoxicity, and cellular uptake.

Water-soluble p-boronophenylalanine (BPA) derivatives having cascade polyols, the monohydroxy derivative BPA(OH) (4), the dihydroxy analogue BPA(OH)2 (5), and the tetrahydroxy analogue BPA(OH)4 (6), were synthesized in order to elucidate a relationship between the molecular structures and the cellular uptake. Biological properties of these compounds in addition to BPA (1) itself were investigated. Water solubility increased in the order of BPA < BPA(OH) < or = BPA(OH)2 > BPA(OH)4. Cytotoxicity to B-16 melanoma and TIG hybrobrast cells decreased in the order of BPA >> BPA(OH) > or = BPA(OH)2 > BPA(OH)4. The cellular uptake by both B-16 and TIG cells decreased in the order of BPA > BPA(OH) > or = BPA(OH)2 > BPA(OH)4, whereas the uptake ratio of B-16/TIG increased in the order of BPA < BPA(OH) < or = BPA(OH)2 < BPA(OH)4. The latter ratio indicates the selectivity on the uptake by a cancer to normal cell.