Impact of the Economic Status of the Patient's Country of Residence on the Outcome of Oncology Clinical Trials.

BACKGROUND: Prolongation of overall survival (OS) is commonly evaluated as a primary endpoint in confirmative oncology clinical trials; however, it is potentially affected by subsequent treatments carried out in practice. To design and implement multi-regional clinical trials properly, we compared survival outcomes between Organisation for Economic Co-operation and Development (OECD) and non-OECD countries. MATERIALS AND METHODS: Individual patient data from industry-sponsored multi-regional phase III oncology trials were obtained from the Project Data Sphere. Patients of each arm were divided into several subgroups based on race and country where patients were enrolled. We defined the member countries of the OECD. Cox regression analysis was conducted to estimate the hazard ratio (HR) for progression-free survival (PFS) and OS between the different subgroups in each trial, followed by a meta-analysis to estimate the summary HR and its confidence interval with a random-effect model. RESULTS: Eleven arms from 10 clinical trials were eligible for the analysis. No statistically significant difference was observed in PFS and OS between Caucasian and Asian. A prolongation of OS was observed in patients enrolled in the OECD group compared with non-OECD group, while no statistically significant difference was observed in PFS. CONCLUSION: The economic status and healthcare environment of countries where patients reside have an impact on the outcome of OS. Clinical trial sponsors are recommended to consider carefully how to properly design oncology clinical trials including the selection of countries and data management of subsequent treatments.

A new protocol for the preparation of superconducting KBi2.

A superconducting KBi2 sample was successfully prepared using a liquid ammonia (NH3) technique. The temperature dependence of the magnetic susceptibility (M/H) showed a superconducting transition temperature (T c) as high as 3.6 K. In addition, the shielding fraction at 2.0 K was evaluated to be 87%, i.e., a bulk superconductor was realized using the above method. The T c value was the same as that reported for the KBi2 sample prepared using a high-temperature annealing method. An X-ray diffraction pattern measured based on the synchrotron X-ray radiation was analyzed using the Rietveld method, with a lattice constant, a, of 9.5010(1) Šunder the space group of Fd3̄m (face-centered cubic, no. 227). The lattice constant and space group found for the KBi2 sample using a liquid NH3 technique were the same as those reported for KBi2 through a high-temperature annealing method. Thus, the superconducting behavior and crystal structure of the KBi2 sample obtained in this study are almost the same as those for the KBi2 sample reported previously. Strictly speaking, the magnetic behavior of the superconductivity was different from that of a KBi2 sample reported previously, i.e., the KBi2 sample prepared using a liquid NH3 technique was a type-II like superconductor, contrary to that prepared using a high-temperature annealing method, the reason for which is fully discussed. These results indicate that the liquid NH3 technique is effective and simple for the preparation of a superconducting KBi2. In addition, the topological nature of the superconductivity for KBi2 was not confirmed.

Preparation and characterization of a new graphite superconductor: Ca0.5Sr0.5C6.

We have produced a superconducting binary-elements intercalated graphite, CaxSr1-xCy, with the intercalation of Sr and Ca in highly-oriented pyrolytic graphite; the superconducting transition temperature, T c, was ~3 K. The superconducting CaxSr1-xCy sample was fabricated with the nominal x value of 0.8, i.e., Ca0.8Sr0.2Cy. Energy dispersive X-ray (EDX) spectroscopy provided the stoichiometry of Ca0.5(2)Sr0.5(2)Cy for this sample, and the X-ray powder diffraction (XRD) pattern showed that Ca0.5(2)Sr0.5(2)Cy took the SrC6-type hexagonal-structure rather than CaC6-type rhombohedral-structure. Consequently, the chemical formula of CaxSr1-xCy sample could be expressed as 'Ca0.5(2)Sr0.5(2)C6'. The XRD pattern of Ca0.5(2)Sr0.5(2)C6 was measured at 0-31 GPa, showing that the lattice shrank monotonically with increasing pressure up to 8.6 GPa, with the structural phase transition occurring above 8.6 GPa. The pressure dependence of T c was determined from the DC magnetic susceptibility and resistance up to 15 GPa, which exhibited a positive pressure dependence of T c up to 8.3 GPa, as in YbC6, SrC6, KC8, CaC6 and Ca0.6K0.4C8. The further application of pressure caused the rapid decrease of T c. In this study, the fabrication and superconducting properties of new binary-elements intercalated graphite, CaxSr1-xCy, are fully investigated, and suitable combinations of elements are suggested for binary-elements intercalated graphite.

Photoelectron Holographic Atomic Arrangement Imaging of Cleaved Bimetal-intercalated Graphite Superconductor Surface.

From the C 1s and K 2p photoelectron holograms, we directly reconstructed atomic images of the cleaved surface of a bimetal-intercalated graphite superconductor, (Ca, K)C8, which differed substantially from the expected bulk crystal structure based on x-ray diffraction (XRD) measurements. Graphene atomic images were collected in the in-plane cross sections of the layers 3.3 Å and 5.7 Å above the photoelectron emitter C atom and the stacking structures were determined as AB- and AA-type, respectively. The intercalant metal atom layer was found between two AA-stacked graphenes. The K atomic image revealing 2 × 2 periodicity, occupying every second centre site of C hexagonal columns, was reconstructed, and the Ca 2p peak intensity in the photoelectron spectra of (Ca, K)C8 from the cleaved surface was less than a few hundredths of the K 2p peak intensity. These observations indicated that cleavage preferentially occurs at the KC8 layers containing no Ca atoms.

Chemical analysis of superconducting phase in K-doped picene.

Potassium-doped picene (K3.0picene) with a superconducting transition temperature (T C) as high as 14 K at ambient pressure has been prepared using an annealing technique. The shielding fraction of this sample was 5.4% at 0 GPa. The T C showed a positive pressure-dependence and reached 19 K at 1.13 GPa. The shielding fraction also reached 18.5%. To investigate the chemical composition and the state of the picene skeleton in the superconducting sample, we used energy-dispersive x-ray (EDX) spectroscopy, MALDI-time-of-flight (MALDI-TOF) mass spectroscopy and x-ray diffraction (XRD). Both EDX and MALDI-TOF indicated no contamination with materials other than K-doped picene or K-doped picene fragments, and supported the preservation of the picene skeleton. However, it was also found that a magnetic K-doped picene sample consisted mainly of picene fragments or K-doped picene fragments. Thus, removal of the component contributing the magnetic quality to a superconducting sample should enhance the volume fraction.

Emergence of superconductivity in (NH3)yMxMoSe2 (M: Li, Na and K).

We report syntheses of new superconducting metal-doped MoSe2 materials (MxMoSe2). The superconducting MxMoSe2 samples were prepared using a liquid NH3 technique, and can be represented as '(NH3)yMxMoSe2'. The Tcs of these materials were approximately 5.0 K, independent of x and the specific metal atom. X-ray diffraction patterns of (NH3)yNaxMoSe2 were recorded using polycrystalline powders. An increase in lattice constant c showed that the Na atom was intercalated between MoSe2 layers. The x-independence of c was observed in (NH3)yNaxMoSe2, indicating the formation of a stoichiometric compound in the entire x range, which is consistent with the x-independence of Tc. A metallic edge of the Fermi level was observed in the photoemission spectrum at 30 K, demonstrating its metallic character in the normal state. Doping of MoSe2 with Li and K also yielded superconductivity. Thus, MoSe2 is a promising material for designing new superconductors, as are other transition metal dichalcogenides.

Recent progress on carbon-based superconductors.

This article reviews new superconducting phases of carbon-based materials. During the past decade, new carbon-based superconductors have been extensively developed through the use of intercalation chemistry, electrostatic carrier doping, and surface-proving techniques. The superconducting transition temperature T c of these materials has been rapidly elevated, and the variety of superconductors has been increased. This review fully introduces graphite, graphene, and hydrocarbon superconductors and future perspectives of high-T c superconductors based on these materials, including present problems. Carbon-based superconductors show various types of interesting behavior, such as a positive pressure dependence of T c. At present, experimental information on superconductors is still insufficient, and theoretical treatment is also incomplete. In particular, experimental results are still lacking for graphene and hydrocarbon superconductors. Therefore, it is very important to review experimental results in detail and introduce theoretical approaches, for the sake of advances in condensed matter physics. Furthermore, the recent experimental results on hydrocarbon superconductors obtained by our group are also included in this article. Consequently, this review article may provide a hint to designing new carbon-based superconductors exhibiting higher T c and interesting physical features.

Emergence of Multiple Superconducting Phases in (NH3)yMxFeSe (M: Na and Li).

We previously discovered multiple superconducting phases in the ammoniated Na-doped FeSe material, (NH3)yNaxFeSe. To clarify the origin of the multiple superconducting phases, the variation of Tc was fully investigated as a function of x in (NH3)yNaxFeSe. The 32 K superconducting phase is mainly produced in the low-x region below 0.4, while only a single phase is observed at x = 1.1, with Tc = 45 K, showing that the Tc depends significantly on x, but it changes discontinuously with x. The crystal structure of (NH3)yNaxFeSe does not change as x increases up to 1.1, i.e., the space group of I4/mmm. The lattice constants, a and c, of the low-Tc phase (Tc = 32.5 K) are 3.9120(9) and 14.145(8) Å, respectively, while a = 3.8266(7) Å and c = 17.565(9) Å for the high-Tc phase (~46 K). The c increases in the high Tc phase, implying that the Tc is directly related to c. In (NH3)yLixFeSe material, the Tc varies continuously within the range of 39 to 44 K with changing x. Thus, the behavior of Tc is different from that of (NH3)yNaxFeSe. The difference may be due to the difference in the sites that the Na and Li occupy.

The Female Encounter Test: A Novel Method for Evaluating Reward-Seeking Behavior or Motivation in Mice.

BACKGROUND: Reduced motivation is an important marker of psychiatric disorders, including depression. We describe the female encounter test, a novel method of evaluating reward-seeking behavior in mice. METHODS: The test apparatus consists of three open chambers, formed with partitions that allow the animal to move freely from one chamber to another. A test male mouse is habituated in the apparatus, and subsequently a female and male mouse are introduced into a wire-mesh box in the left and right chamber, respectively. The time the test male mouse spends in the female or male area is measured for 10 min. RESULTS: All six strains of mice tested showed a significant preference for female encounters. The preference was observed in 7-30-week-old mice. The preference was blocked by castration of the resident male test mouse, and was not affected by the phase of the menstrual cycle of the female intruder. The preference was impaired in mouse models of depression, including social isolation-reared, corticosterone-treated, and lipopolysaccharide-treated mice. The impairment was alleviated by fluvoxamine in isolation-reared and lipopolysaccharide-treated mice, and it was improved by the metabotropic glutamate 2/3 receptor antagonist LY341495 in corticosterone-treated mice. Encounter with a female, but not male, mouse increased c-Fos expression in the nucleus accumbens shell of test male mice. Furthermore, both the preference and encounter-induced increases in c-Fos expression were blocked by dopamine D1 and D2 receptor antagonists. CONCLUSIONS: These findings indicate that motivation in adult male mice can be easily evaluated by quantitating female encounters.

Pharmacological profile of encounter-induced hyperactivity in isolation-reared mice.

We have recently found that isolation-reared mice show hyperactivity during an encounter with an intruder. However, it is not known whether encounter-induced hyperactivity may model some aspects of psychiatric disorders. The present study examined the pharmacological profile of encounter-induced hyperactivity in isolation-reared mice. Encounter-induced hyperactivity was reduced by acute administration of various antidepressants including the tricyclic antidepressant desipramine (10 mg/kg), the selective serotonin (5-HT) reuptake inhibitors fluvoxamine (10 mg/kg) and paroxetine (10 mg/kg), the 5-HT/noradrenaline reuptake inhibitors venlafaxine (10 mg/kg) and duloxetine (10 mg/kg), the antipsychotic drug risperidone (0.01 mg/kg), the 5-HT2 antagonist ritanserin (1 mg/kg), and the glucocorticoid receptor antagonist RU-43044 (30 mg/kg). The α2 adrenoceptor agonist clonidine (0.03 mg/kg) and the 5-HT4 receptor agonist BIMU8 (30 mg/kg) also reduced encounter-induced hyperactivity. The effect of desipramine was blocked by the α2 adrenoceptor antagonist idazoxan (0.3 mg/kg). The effect of fluvoxamine was blocked by the 5-HT4 receptor antagonist GR125487 (3 mg/kg), but not the 5-HT1A receptor antagonist WAY100635 (1 mg/kg), the 5-HT3 receptor antagonist azasetron (3 mg/kg), or the 5-HT6 receptor antagonist SB399885 (3 mg/kg). The effect of venlafaxine was blocked by the simultaneous administration of idazoxan (0.3 mg/kg) and GR125487 (3 mg/kg), but not by either compound alone. These findings suggest that encounter-induced hyperactivity in isolation-reared mice is a robust model for testing the pharmacological profile of antidepressants, although the range of antidepressants tested is limited and some non-antidepressants are also effective. The present study also shows a key role of α2 and 5-HT4 receptors in the antidepressant effect in this model.

Involvement of prefrontal AMPA receptors in encounter stimulation-induced hyperactivity in isolation-reared mice.

We recently showed that social encounter stimulation induces hyperactivity in mice reared in social isolation from early life and this is associated with the transient activation of prefrontal dopaminergic and serotonergic systems. In the present study, we examined the effect of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor antagonist 2, 3-dioxo-6-nitro-1, 2, 3, 4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide (NBQX) on encounter-induced behavioural and neurochemical changes to study the role of the receptor in abnormal behaviours in isolation-reared mice. The encounter to an intruder mouse induced hyperactivity with transient increases in prefrontal dopamine and serotonin levels in isolation-reared mice. NBQX attenuated the encounter-induced hyperactivity and the associated neurochemical changes in isolation-reared mice. In addition, NBQX reduced aggressive behaviour and cognitive impairment in isolation-reared mice, but did not affect depressive-like behaviour or spontaneous hyper-locomotion in these animals. The AMPA receptor agonist (S)-AMPA increased prefrontal dopamine and serotonin release, and this effect was higher in isolation-reared mice than in the group-reared mice, suggesting higher prefrontal AMPA receptor activity in isolation-reared mice. Furthermore, isolation rearing increased the expression of AMPA receptor subunits (GluR1, GluR2 and GluR3) and GluR1 Ser845 phosphorylation in the prefrontal cortex, but not in the hippocampus or nucleus accumbens. Taken together, these results suggest that an increase in AMPA receptor activity in the prefrontal cortex contributes to some, but not all, abnormal behaviours in isolation-reared mice.

Role of social encounter-induced activation of prefrontal serotonergic systems in the abnormal behaviors of isolation-reared mice.

Isolation-reared male rodents show abnormal behaviors such as hyperlocomotion, aggressive behaviors, deficits of prepulse inhibition, and depression- and anxiety-like behaviors, but the neurochemical mechanism for the effects of psychological stress in these animals is not fully understood. This study examined the effects of social interactions between isolation-reared mice and intruder mice on brain monoaminergic systems. A cage was divided into two compartments by a mesh partition to prevent direct physical interactions. The 20-min encounter with an intruder elicited a restless and hyperexcitable state (hyperactivity) in male, but not in female, isolation-reared mice, whereas encounters with a sleeping intruder or a novel object did not. Although the encounter did not affect prefrontal neuronal-activity-marker c-Fos expression, dopamine (DA) levels, or serotonin (5-HT) levels in male group-reared mice or female isolation-reared mice, it increased prefrontal c-Fos expression, DA levels, and 5-HT levels in male isolation-reared mice. Furthermore, encounter-induced increases in c-Fos expression in the dorsal raphe nucleus and ventral tegmental area, but not in the nucleus accumbens shell, were much greater in isolation-reared than group-reared male mice. A 5-HT1A receptor agonist, a metabotropic glutamate 2/3 receptor agonist, and a gamma-aminobutyric acid A receptor agonist attenuated isolation-induced aggressive behaviors and encounter-induced hyperactivity, c-Fos expression in the prefrontal cortex and dorsal raphe nucleus, and increases in prefrontal 5-HT levels. These findings suggest that the prefrontal DA and 5-HT systems are activated by encounter stimulation in male isolation-reared mice, and the encounter-induced activation of 5-HT system triggers the induction of some abnormal behaviors in male isolation-reared mice. Furthermore, this study implies that the encounter stimulation-induced signal has a pharmacological significance.