Combination gemcitabine plus S-1 versus gemcitabine plus cisplatin for advanced/recurrent biliary tract cancer: the FUGA-BT (JCOG1113) randomized phase III clinical trial.

BACKGROUND: Gemcitabine plus cisplatin (GC) is the standard treatment of advanced biliary tract cancer (BTC); however, it causes nausea, vomiting, and anorexia, and requires hydration. Gemcitabine plus S-1 (GS) reportedly has equal to, or better, efficacy and an acceptable toxicity profile. We aimed to confirm the non-inferiority of GS to GC for patients with advanced/recurrent BTC in terms of overall survival (OS). PATIENTS AND METHODS: We undertook a phase III randomized trial in 33 institutions in Japan. Eligibility criteria included chemotherapy-naïve patients with recurrent or unresectable BTC, an Eastern Cooperative Oncology Group Performance Status of 0 - 1, and adequate organ function. The calculated sample size was 350 with a one-sided α of 5%, a power of 80%, and non-inferiority margin hazard ratio (HR) of 1.155. The primary end point was OS, while the secondary end points included progression-free survival (PFS), response rate (RR), adverse events (AEs), and clinically significant AEs defined as grade ≥2 fatigue, anorexia, nausea, vomiting, oral mucositis, or diarrhea. RESULTS: Between May 2013 and March 2016, 354 patients were enrolled. GS was found to be non-inferior to GC [median OS: 13.4 months with GC and 15.1 months with GS, HR, 0.945; 90% confidence interval (CI), 0.78-1.15; P = 0.046 for non-inferiority]. The median PFS was 5.8 months with GC and 6.8 months with GS (HR 0.86; 95% CI 0.70-1.07). The RR was 32.4% with GC and 29.8% with GS. Both treatments were generally well-tolerated. Clinically significant AEs were observed in 35.1% of patients in the GC arm and 29.9% in the GS arm. CONCLUSIONS: GS, which does not require hydration, should be considered a new, convenient standard of care option for patients with advanced/recurrent BTC. CLINICAL TRIAL NUMBER: This trial has been registered with the UMIN Clinical Trials Registry (http://www.umin.ac.jp/ctr/index.htm), number UMIN000010667.

High precision optical cavity length and width measurements using double modulation.

We use doubly phase modulated light to measure both the length and the linewidth of an optical resonator with high precision. The first modulation is at RF frequencies and is set near a multiple of the free spectral range, whereas the second modulation is at audio frequencies to eliminate offset errors at DC. The light in transmission or in reflection of the optical resonator is demodulated while sweeping the RF frequency over the optical resonance. We derive expressions for the demodulated power in transmission, and show that the zero crossings of the demodulated signal in transmission serve as a precise measure of the cavity linewidth at half maximum intensity. We demonstrate the technique on two resonant cavities, with lengths 16 m and a 4 km, and achieve an absolute length accuracy as low as 70 ppb. The cavity width for the 16 m cavity was determined with an accuracy of approximately 6000 ppm. Through an analysis of the systematic errors we show that this result could be substantially improved with the reduction of technical sources of uncertainty.

Genetic diversity and population structure in native chicken populations from myanmar, Thailand and laos by using 102 indels markers.

The genetic diversity of native chicken populations from Myanmar, Thailand, and Laos was examined by using 102 insertion and/or deletion (indels) markers. Most of the indels loci were polymorphic (71% to 96%), and the genetic variability was similar in all populations. The average observed heterozygosities (H O ) and expected heterozygosities (H E ) ranged from 0.205 to 0.263 and 0.239 to 0.381, respectively. The coefficients of genetic differentiation (Gst) for all cumulated populations was 0.125, and the Thai native chickens showed higher Gst (0.088) than Myanmar (0.041) and Laotian (0.024) populations. The pairwise Fst distances ranged from 0.144 to 0.308 among populations. A neighbor-joining (NJ) tree, using Nei's genetic distance, revealed that Thai and Laotian native chicken populations were genetically close, while Myanmar native chickens were distant from the others. The native chickens from these three countries were thought to be descended from three different origins (K = 3) from STRUCTURE analysis. Genetic admixture was observed in Thai and Laotian native chickens, while admixture was absent in Myanmar native chickens.

Genetic Diversity of mtDNA D-loop Polymorphisms in Laotian Native Fowl Populations.

Here, we studied the genetic diversity of native fowls in Laos by analyzing a mitochondrial DNA (mtDNA) sequence polymorphism. A 546-bp fragment of the mtDNA D-loop region was sequenced in 129 chickens from the areas of Vientiane, Luang Prabang and Pakse. In total, 29 haplotypes were identified and formed five clades. Haplotype diversity and nucleotide diversity of the native fowls in Laos were 0.85536±0.0172 and 0.010158±0.005555, respectively. Although the Laotian native fowls were distributed across five clades, most of them were clustered in two main clades (A and B), which were originated in China. The other haplotypes were contained in clades D, F, and I, which originated from continental southeast Asia. These results suggest that multiple maternal lineages were involved in the origin of domestic chicken in Laos. Moreover, there appear to be at least two maternal lineages, one from China and the other from the southeast Asian continent.

Squeezed quadrature fluctuations in a gravitational wave detector using squeezed light.

Squeezed states of light are an important tool for optical measurements below the shot noise limit and for optical realizations of quantum information systems. Recently, squeezed vacuum states were deployed to enhance the shot noise limited performance of gravitational wave detectors. In most practical implementations of squeezing enhancement, relative fluctuations between the squeezed quadrature angle and the measured quadrature (sometimes called squeezing angle jitter or phase noise) are one limit to the noise reduction that can be achieved. We present calculations of several effects that lead to quadrature fluctuations, and use these estimates to account for the observed quadrature fluctuations in a LIGO gravitational wave detector. We discuss the implications of this work for quantum enhanced advanced detectors and even more sensitive third generation detectors.

Relationship between abdominal fat content and avian uncoupling protein gene expression in skeletal muscle of Japanese quail Coturnix japonica.

1. The genetic architecture of the avian uncoupling protein (avUCP) was investigated and the relationship between avUCP gene expression and the amount of abdominal fat of Japanese quail was determined by quantitative real-time PCR. 2. The Japanese quail avUCP gene consists of six exons and five introns. Sequences of nucleotides and amino acids were 94·6% and 86·0% identical to those of the chicken avUCP gene, and phylogenetic analysis showed that the Japanese quail avUCP gene consists of the same clusters as the chicken and turkey avUCP. 3. Expression of the avUCP gene was significantly higher in the Pectoralis major (1·28 ± 0·24) than in the Biceps femoris (0·63 ± 0·14). 4. A positive correlation coefficient between the avUCP gene expression in the Pectoralis major and Biceps femoris was observed (r = 0·79, P = 0·02), whereas a negative correlation coefficient was observed between the abdominal fat percentage (AFP) and gene expression in both the Pectoralis major (r = -0·82, P = 0·01) and Biceps femoris (r = -0·61, P = 0·11). 5. The avUCP gene was associated with the accumulation of abdominal fat in Japanese quail and it was concluded that modulation of avUCP gene expression could be utilised to control abdominal fat accumulation in poultry.

Optimal alignment sensing of a readout mode cleaner cavity.

Critically coupled resonant optical cavities are often used as mode cleaners in optical systems to improve the signal-to-noise ratio (SNR) of a signal that is encoded as an amplitude modulation of a laser beam. Achieving the best SNR requires maintaining the alignment of the mode cleaner relative to the laser beam on which the signal is encoded. An automatic alignment system that is primarily sensitive to the carrier field component of the beam will not, in general, provide optimal SNR. We present an approach that modifies traditional dither alignment sensing by applying a large amplitude modulation on the signal field, thereby producing error signals that are sensitive to the signal sideband field alignment. When used in conjunction with alignment actuators, this approach can improve the detected SNR; we demonstrate a factor of 3 improvement in the SNR of a kilometer-scale detector of the Laser Interferometer Gravitational-Wave Observatory. This approach can be generalized to other types of alignment sensors.

Genetic diversity and population structure of Indonesian native chickens based on single nucleotide polymorphism markers.

Indonesian native chickens are considered an important genetic resource, particularly with respect to their excellent traits for meat and egg production. However, few molecular genetic studies of these native chickens have been conducted. We analyzed the genetic diversity and differentiation of 4 populations of Indonesian native chickens: Black Kedu (BK), Kedu (KD), Kampung (LOC), and Arab (AR). Blood samples from 188 individuals were collected in central and western Java. Genomic DNA was genotyped using 98 autosomal SNP markers, of which 87 were found to be polymorphic. The proportion of polymorphic loci and the average heterozygosity of each population were in the range of 0.765 to 0.878 and 0.224 to 0.263, respectively. The 4 populations of Indonesian chickens appeared to be derived from 3 genetic populations (K = 3): maximum likelihood clustering showed that the BK variety and AR breed were each assigned to a distinct cluster, whereas the LOC ecotype and KD variety were admixed populations with similar proportions of membership. Principal components analysis revealed that eigenvector 1 separated BK and AR from the other 2 populations. Neighbor-joining trees constructed from pairwise distance matrix (F(ST)) estimates, for individuals and between populations, corroborated that the LOC ecotype and KD variety were related closely, whereas the BK variety and AR breed diverged at greater distances. These results also confirmed the usefulness of SNP markers for the study of genetic diversity.

Approaching the motional ground state of a 10-kg object.

The motion of a mechanical object, even a human-sized object, should be governed by the rules of quantum mechanics. Coaxing them into a quantum state is, however, difficult because the thermal environment masks any quantum signature of the object's motion. The thermal environment also masks the effects of proposed modifications of quantum mechanics at large mass scales. We prepared the center-of-mass motion of a 10-kilogram mechanical oscillator in a state with an average phonon occupation of 10.8. The reduction in temperature, from room temperature to 77 nanokelvin, is commensurate with an 11 orders-of-magnitude suppression of quantum back-action by feedback and a 13 orders-of-magnitude increase in the mass of an object prepared close to its motional ground state. Our approach will enable the possibility of probing gravity on massive quantum systems.

Indels within promoter and intron 1 of bovine prion protein gene modulate the gene expression levels in the medulla oblongata of two Japanese cattle breeds.

Genetic differences which exist in the prion protein gene (PRNP) have been reported to influence susceptibility of humans, sheep and goats to prion diseases. In cattle, however, none of the known coding polymorphisms has a direct effect on bovine spongiform encephalopathy (BSE). It has been reported that 23-bp insertion/deletion (indel) polymorphisms within the promoter region have a tentative association to BSE susceptibility in German cattle, and a lower number of 24-bp repeat units in the open reading frame (ORF) was reported to reduce BSE susceptibility in transgenic mice. In this study, because of the hypothesis that bovine PRNP promoter polymorphisms cause changes in PRNP expression, we genotyped PRNP polymorphisms in the promoter and intron 1 using 218 genomic DNA samples from two Japanese cattle breeds. We also analysed the expression levels of prion in 40 animals by quantification of real-time PCR using mRNAs extracted from the medulla oblongata to study the relationship between PRNP genotypes and PRNP expression. We found a significant correlation between promoter indel polymorphisms and PRNP-mRNA expression (P(0.0413)) and therefore hypothesize that differences in polymorphisms could be one of the causes of differences in PRNP expression levels. We also report a novel difference in PRNP expression (P < 0.0001) between Japanese Black and Japanese Brown cattle breeds. There was no significant difference based on age and sex of the animals.

Microinjections of melanin concentrating hormone into the nucleus tractus solitarius of the rat elicit depressor and bradycardic responses.

The presence of melanin-concentrating hormone (MCH) containing processes, projecting from the lateral hypothalamus to the medial nucleus tractus solitarius (mNTS), has been reported in the rat. It was hypothesized that MCH acting within the mNTS may modulate the central regulation of cardiovascular function. This hypothesis was tested in urethane-anesthetized, artificially ventilated, adult male Wistar rats. Microinjections (100 nl) of MCH (0.25, 0.5, 0.75, and 1 mM) into the mNTS of anesthetized rats elicited decreases in mean arterial pressure (20.4+/-1.6, 50.7+/-3.3, 35.7+/-2.8 and 30.0+/-2.6 mm Hg, respectively). The decreases in heart rate in response to these concentrations of MCH were 40.0+/-8.7, 90.0+/-13.0, 48.0+/-7.3 and 48.0+/-8.0 beats/min, respectively. Maximum cardiovascular responses were elicited by a 0.5 mM concentration of MCH. Cardiovascular responses to MCH were similar in unanesthetized mid-collicular decerebrate rats. Control microinjections of normal saline (100 nl) did not elicit any cardiovascular response. Ipsilateral or bilateral vagotomy significantly attenuated MCH-induced bradycardia. Prior microinjections of PMC-3881-PI (2 mM; MCH-1 receptor antagonist) into the mNTS blocked the cardiovascular responses to microinjections of MCH. Microinjection of MCH (0.5 mM) into the mNTS decreased efferent greater splanchnic nerve activity. Direct application of MCH (0.5 mM; 4 nl) to barosensitive nucleus tractus solitarius (NTS) neurons increased their firing rate. These results indicate that: 1) MCH microinjections into the mNTS activate MCH-1 receptors and excite barosensitive NTS neurons, causing a decrease in efferent sympathetic activity and blood pressure, and 2) MCH-induced bradycardia is mediated via the activation of the vagus nerves.

Analysis of polymorphisms in the insulin-like growth factor 1 receptor (IGF1R) gene from Japanese quail selected for body weight.

Insulin-like growth factor 1 receptor (IGF1R) is essential for the signalling of growth. In this study, we performed single nucleotide polymorphism (SNP) detection in the Japanese quail IGF1R coding region and an association study between SNPs and body weight in two lines (SS and LL) selected for large and small body weight. Of 21 SNPs obtained, a SNP at position AB292766:c.2293G>A led to the replacement of a valine with an isoleucine (V765I). The two lines were fixed for alternate alleles, with allele encoding valine fixed in the LL line. A significant effect of the SNP genotype was found on 10-week body weight (P < 0.01) and on 4- to 10-week and 6- to 10-week average daily gain (P < 0.05) in the F(2) family obtained from lines LL and SS. In six populations maintained in Japan or France, the frequency of allele encoding valine was higher than the allele encoding isoleucine.

Inhibition of rat prostate carcinogenesis by a 5alpha-reductase inhibitor, FK143.

BACKGROUND: Androgen levels in the prostate may influence carcinogenesis in this organ. Inhibitors of the enzyme 5alpha-reductase block conversion of testosterone to the more active androgen dihydrotestosterone. The use of a 5alpha-reductase inhibitor, finasteride, in the chemoprevention of prostate cancer is being evaluated in a clinical trial. PURPOSE: This study was conducted to determine if a 5alpha-reductase inhibitor, FK143, inhibits the development of prostate cancer in rats. METHODS: Male ACI/Seg rats, which spontaneously develop prostate cancer, were randomly assigned at 80 weeks of age to receive one of three diets (n = 35/group) containing 0 (i.e., control group), 20, or 200 ppm FK143. At 140 weeks of age, the animals were killed, and the prostates were removed and examined for histopathologic features in addition to being assayed for androgen concentrations. Two-sided statistical tests were used to calculate all P values. RESULTS: The incidence of prostate carcinoma in the control group was 62.9% (22 of 35 rats); in the group fed the 20 ppm FK143-containing diet, it was 45.7% (16 of 35); and in the group fed the 200 ppm FK143-containing diet, it was 67.6% (23 of 34) (overall, P = .153). The corresponding incidences of macroscopic lesions were 17.1% (six of 35 rats), 0% (none of 35), and 23.5% (eight of 34), respectively (overall, P = .004). The incidence of macroscopic lesions in the prostates of rats in the 20-ppm diet group was significantly lower than that in the control group (P = .029) or that in the 200-ppm diet group (P = .003). Intraprostatic dihydrotestosterone content was significantly lower in rats in the groups fed diets containing 20 or 200 ppm FK143 (mean values: 4.51 and 4.33 pg/mg wet weight of prostate tissue, respectively) than in the control group (6.10 pg/mg) (overall, P<.001); by contrast, testosterone was higher in the 200-ppm diet group (2.09 pg/mg) than in the control group (1.08 pg/mg) or the 20-ppm diet group (1.21 pg/mg) (overall, P<.001). CONCLUSIONS: FK143, when fed to rats at 20 or 200 ppm, significantly reduced the level of dihydrotestosterone in their prostate tissue. However, the incidence of macroscopic cancer in the prostate was suppressed in rats consuming the 20 ppm FK143-containing diet but not in those consuming the 200-ppm diet. The lack of dose dependence for the chemopreventive activity of FK143 may be explained by the reciprocal increase of tissue testosterone in the 200-ppm diet group. IMPLICATIONS: The 5alpha-reductase inhibitor FK143 may, at specific doses, reduce the incidence of spontaneously developing prostate cancer; however, whether these findings in rats will apply to humans remains to be determined.

Influence of steric factors on oxygen binding. I. Studies on 2,4-diisopropyldeuteroheme-myoglobin.

Sperm whale apomyoglobin was recombined with 2,4-diisopropyldeuterohemin to form 2,4-diisopropyldeuteroheme-myoglobin and its various physico-chemical properties were investigated to get an insight into the structural and functional role of the peripheral vinyl groups. 2,4-Diisopropyldeuteroheme-myoglobin showed a four times lower oxygen affinity at 25 degrees C and larger enthalpy and entropy changes of oxygenation than the corresponding values of native myoglobin. 2,4-Diisopropyldeuteroheme-metmyoglobin shows a pKa value of 9.68 which is higher than those of native metmyoglobin and mesoheme-metmyoglobin. The rate of autooxidation of oxy-form was about seven times larger in 2,4-diisopropyldeuteroheme-myoglobin than in native myoglobin. The electron-donating effect of isopropyl groups does not give straightforward explanation for these anomalous properties of 2,4-diisopropyldeuteroheme-myoglobin. It is proposed that site and stereospecific van der Waals' interaction between the polypeptide side chains and the peripheral 2,4-diisopropyl groups may weaken the interaction between the bound oxygen molecule and the distal His, resulting in the decrease in the stability of oxyform.

Dax-1 as one of the target genes of Ad4BP/SF-1.

The DAX-1 (also known as AHC) gene encodes an unusual member of the nuclear hormone receptor superfamily. DAX-1 plays a critical role during gonadal and adrenal differentiation since mutations of the human DAX-1 gene cause X-linked adrenal hypoplasia congenita associated with hypogonadotropic hypogonadism. In recent studies, DAX-1 was reported to function as a transcriptional suppressor of Ad4BP/SF-1, a critical transcription factor in gonadal and adrenal differentiation. With respect to implication of Ad4BP/SF-1 in the transcriptional regulation of the DAX-1 gene, inconsistent findings have been previously reported. We investigated the upstream region of the mouse Dax-1 (also known as Ahch) gene and identified a novel Ad4/SF-1 site by transient transfection and electrophoretic mobility shift assays. In addition, immunohistochemical analyses with a specific antibody to Dax-1 indicated the presence of immunoreactive cells in steroidogenic tissues, pituitary gland, and hypothalamus. Although the distributions of Dax-1 and Ad4BP/SF-1 were very similar, they were not completely identical. The expression of Dax-1 was significantly impaired in knock-out mice of the Ftz-f1 gene, which encodes Ad4BP/ SF-1. Taken together, our findings indicate that Ad4BP/SF-1 controls the transcription of the Dax-1 gene.

Inhibition of plasminogen activator inhibitor-1 by angiotensin II receptor blockers on cyclosporine-treated renal allograft recipients.

INTRODUCTION: We previously showed that proteinuria from a renal graft was significantly decreased by administration of losartan potassium, an angiotensin II receptor blockers (ARB). To further evaluate the mechanism, we performed another clinical study focusing on the change in plasma plasminogen activator inhibitor-1 (PAI-1) levels among cyclosporine (CyA)-treated renal allograft recipients. METHODS: Among 12 hypertensive CyA-treated kidney transplant patients, four received 25 to 50 mg/day of losartan; four, 4 to 8 mg/day of candesartan cilexetil; and another four, 20 to 40 mg/day of nifedipine. Four CyA-treated kidney-transplanted patients without hypertension were selected as a control group. Informed consent was obtained from all participants. PAI-1 and serum creatinine (S-Cr) levels were monitored every 3 months for 1 year. RESULTS: Considering the pretreatment of PAI-1 as 100%, the mean percent of PAI-1 at 1 year after the onset of study for losartan, candesartan, nifedipine, and control groups were 78.6 +/- 6.7%, 81.4 +/- 8.0%, 96.7 +/- 7.6%, and 110.4 +/- 9.2%, respectively. The ARB groups demonstrated significant differences from the control group (P < .01), while the nifedipine group did not. S-Cr levels among ARB-administered groups were increased slightly but temporarily. As for S-Cr levels, no significant differences were seen among the four groups. CONCLUSIONS: Control of hypertension itself is important for all renal graft recipients; however, PAI-1 reduction by ARBs was thought to be a key for renal preservation. We expect that ARBs will contribute to prolonged renal allograft survival.