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Innate and adaptive resistance to cancer therapies, such as chemotherapies, molecularly targeted therapies, and immune-modulating therapies, is a major issue in clinical practice. Subpopulations of tumor cells expressing the receptor tyrosine kinase AXL become enriched after treatment with antimitotic drugs, causing tumor relapse. Elevated AXL expression is closely associated with drug resistance in clinical samples, suggesting that AXL plays a pivotal role in drug resistance. Although several molecules with AXL inhibitory activity have been developed, none have sufficient activity and selectivity to be clinically effective when administered in combination with a cancer therapy. Here, we report a novel small molecule, ER-851, which is a potent and highly selective AXL inhibitor. To investigate resistance mechanisms and identify driving molecules, we conducted a comprehensive gene expression analysis of chemoresistant tumor cells in mouse xenograft models of genetically engineered human lung cancer and human triple-negative breast cancer. Consistent with the effect of AXL knockdown, cotreatment of ER-851 and antimitotic drugs produced an antitumor effect and prolonged relapse-free survival in the mouse xenograft model of human triple-negative breast cancer. Importantly, when orally administered to BALB/c mice, this compound did not induce retinal toxicity, a known side effect of chronic MER inhibition. Together, these data strongly suggest that AXL is a therapeutic target for overcoming drug resistance and that ER-851 is a promising candidate therapeutic agent for use against AXL-expressing antimitotic-resistant tumors.

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Innate and adaptive resistance to cancer therapies, such as chemotherapies, molecularly targeted therapies, and immune-modulating therapies, is a major issue in clinical practice. Subpopulations of tumor cells expressing the receptor tyrosine kinase AXL become enriched after treatment with anti-mitotic drugs, causing tumor relapse. Elevated AXL expression is closely associated with drug resistance in clinical samples, suggesting that AXL plays a pivotal role in drug resistance. Although several molecules with AXL inhibitory activity have been developed, none have sufficient activity and selectivity to be clinically effective when administered in combination with a cancer therapy. Here, we report a novel small molecule, ER-001259851-000, which is a potent and highly selective AXL inhibitor. To investigate resistance mechanisms and identify driving molecules, we conducted a comprehensive gene expression analysis of chemo-resistant tumor cells in mouse xenograft models of genetically engineered human lung cancer and human triple-negative breast cancer. Consistent with the effect of AXL knockdown, co-treatment of ER-001259851-000 and antimitotic drugs produced an anti-tumor effect and prolonged relapse-free survival in the mouse xenograft model of human triple-negative breast cancer. Importantly, when orally administered to BALB/c mice, this compound did not induce retinal toxicity, a known side effect of chronic MER inhibition. Together, these data strongly suggest that AXL is a therapeutic target for overcoming drug resistance and that ER-001259851-000 is a promising candidate therapeutic agent for use against AXL-expressing anti-mitotic-resistant tumors.

Axl and Mer are members of the TAM (Tyro3-Axl-Mer) family of receptor tyrosine kinases. Previously, we reported that enzyme-mediated inhibition of Mer by an Axl/Mer dual inhibitor led to retinal toxicity in mice, whereas selective Axl inhibition by compound 1 did not. On the other hand, compound 1 showed low membrane permeability. Here, we designed and synthesized a novel series of 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine derivatives and evaluated their Axl and Mer inhibitory activities, leading to identification of ER-001259851-000 as a potent and selective Axl inhibitor with drug-likeness and a promising pharmacokinetic profile in mice.

Axl and Mer are a members of the TAM (Tyro3-Axl-Mer) family of receptor tyrosine kinases, which, when activated, can promote tumor cell survival, proliferation, migration, invasion, angiogenesis, and tumor-host interactions. Chronic inhibition of Mer leads to retinal toxicity in mice. Therefore, successful development of an Axl targeting agent requires ensuring that it is safe for prolonged treatment. Here, to clarify whether enzyme inhibition of Mer by a small molecule leads to retinal toxicity in mice, we designed and synthesized Axl/Mer inhibitors and Axl-selective inhibitors. We identified an Axl/Mer dual inhibitor 28a, which showed retinal toxicity at a dose of 100 mg/kg in mice. Subsequent derivatization of a pyridine derivative led to the discovery of a pyrimidine derivative, 33g, which selectively inhibited the activity of Axl over Mer without retinal toxicity at a dose of 100 mg/kg in mice. Additionally, the compound displayed in vivo anti-tumor effects without influencing body weight in a Ba/F3-Axl isogenic subcutaneous model.

The transcendental thinking of Heidegger has its roots in his study of the medieval theory of ‘transcendentals’ during his Habilitation. By displacing the Aristotelico-Scholastic concept of ‘transcendentals’ from the realm of metaphysical speculation and replacing it with the context of Kantian transcendental philosophy and Husserlian phenomenology, Heidegger formed a project called ‘the explication of the transcendental horizon of time for the question of being’ in Being and Time. This point of view led him to a positive confrontation with Kantian thought. In this paper, we will investigate the traces of this transcendental thinking in Heidegger’s work, mainly based on his interpretation of Kant, and then explore the self-referential structure of transcendental imagination (Ein-bildungs-kraft), which makes the philosophical reflection in general possible through the medium of image (Bild).

E1210 is a first-in-class, broad-spectrum antifungal with a novel mechanism of action—inhibition of fungal glycosylphosphatidylinositol biosynthesis. In this study, the efficacies of E1210 and reference antifungals were evaluated in murine models of oropharyngeal and disseminated candidiasis, pulmonary aspergillosis, and disseminated fusariosis. Oral E1210 demonstrated dose-dependent efficacy in infections caused by Candida species, Aspergillus spp., and Fusarium solani . In the treatment of oropharyngeal candidiasis, E1210 and fluconazole each caused a significantly greater reduction in the number of oral CFU than the control treatment ( P < 0.05). In the disseminated candidiasis model, mice treated with E1210, fluconazole, caspofungin, or liposomal amphotericin B showed significantly higher survival rates than the control mice ( P < 0.05). E1210 was also highly effective in treating disseminated candidiasis caused by azole-resistant Candida albicans or Candida tropicalis . A 24-h delay in treatment onset minimally affected the efficacy outcome of E1210 in the treatment of disseminated candidiasis. In the Aspergillus flavus pulmonary aspergillosis model, mice treated with E1210, voriconazole, or caspofungin showed significantly higher survival rates than the control mice ( P < 0.05). E1210 was also effective in the treatment of Aspergillus fumigatus pulmonary aspergillosis. In contrast to many antifungals, E1210 was also effective against disseminated fusariosis caused by F. solani . In conclusion, E1210 demonstrated consistent efficacy in murine models of oropharyngeal and disseminated candidiasis, pulmonary aspergillosis, and disseminated fusariosis. These data suggest that further studies to determine E1210's potential for the treatment of disseminated fungal infections are indicated.

We described a rare example of an effective isoxazole synthesis via a 1,3-dipolar cycloaddition using ZnCl2, which allowed us to synthesize novel (2-aminopyridin-3-yl)isoxazole derivatives effectiv...

Quinoline amide, azaindole amide and pyridine amides were synthesized and tested for in vitro antifungal activity against fungi. These synthesized amides have potent antifungal activity against Candida albicans and Aspergillus fumigatus. Our results suggest that hetero ring amides may be potent antifungal agents that operate by inhibiting the function of Gwt1 protein in the GPI biosynthetic pathway.

The present study was designed to investigate characteristics by 38 school-age children in Grades 2, 4, and 6 of perseverative errors using the Wisconsin Card Sorting Test. Children's performance was measured as number of categories completed and perseverative errors, which were classified into perseverative errors of types described by Milner in 1963 and Nelson in 1976. Analysis indicated that the number of completed categories increased and perseverative errors decreased across age groups. Perseverative errors (Milner) were very similar in these grades and perseverative errors (Nelson) were significantly different between children in Grades 2 and 4. The results suggested a pattern of development for shifting inhibiting set.

The changes in skin temperature under anxiety were investigated by noninvasive measurements. The nasal skin temperature of 20 subjects was assessed by thermography. The measurement of the skin temperature by thermistor causes stress in subjects. The primary advantages of a thermography over use of a thermistor are noninvasive and accurate. Each subject was made anxious under the 2 conditions of sudden darkness (Sudden darkness condition) or experienced darkness (Experienced darkness condition). Under former, after a baseline facial skin temperature was established, the room light was suddenly turned off. The subject remained seated in darkness for 2 min. The time-series changes were significant for women, but not for men. For women, skin temperature significantly declined in sudden darkness. Experiments on experienced darkness were performed a week later. After a baseline facial skin temperature was established, the subject was told; “The room light would be turned off from now on, but please remain seated without moving.” After the instruction, the room light was turned off. The subject remained seated in darkness for 2 min. The resultant time-series changes in skin temperatures were significant in neither men nor women.

We identified and cloned a homolog of mammalian mitogen-activated protein kinase-activated protein kinase (MAPKAPK)-2 and -3 from sea urchin, Hemicentrotus pulcherrimus. The obtained cDNA clone was composed of 350 amino acid residues which contain MAPK phosphorylation sites and the bipartite nuclear localization signal sites in its C-terminal domain. The clone showed 65.4 and 66.7% amino acid residue identity to human MAPKAPK-2 and -3, respectively. Phylogenetic analysis revealed that the homolog can be classified into a distinct group of MAPKAPK and, therefore, the identified homolog was designated as MAPKAPK-4. Biochemical characterization was performed using recombinant glutathione S -transferase (GST)–MAPKAPK-4 fusion protein. The protein kinase activity of GST–MAPKAPK-4 was activated by MAPK and this enabled the kinase to phosphorylate both glycogen synthase N-terminal peptide and the regulatory light chain of myosin II in vitro. Northern blot analysis showed that MAPKAPK-4 was expressed throughout the development of sea urchin embryos. These observations suggest that MAPKAPK-4 may play an important role in the regulation of myosin II activity during the development of sea urchin.

A one-pot primary aminomethylation with substrate (I) leads to the corresponding amines and is followed by deamidination to afford the desired products.

The reaction of various aromatic, heteroaromatic and cycloalkenic chlorides with (II) proceeds best under conventional heating to afford the corresponding methanol products with moderate to high yields.

From a viewpoint of safety assessment of insecticides being released with an electric vaporizer into a room a model of fluid dynamics was used to simulate the behavior of the evaporated active ingredient (ai), air flow and the temperature distribution at a steady and unsteady state under various conditions. The model delivered the behavior of the evaporated ai due to the variations of the air exchange rate, locations of the air inlet and electric vaporizer and room temperature. A simulation experiment showed that the calculated aerial concentration at a steady and unsteady state agreed well with the measured one. Thus, the model will be very useful to describe the behavior of ai by utilizing known, calculated, or easily available data of the rooms, use patterns and physicochemical properties (ai) without realization of experiments.

E1210 is a new antifungal compound with a novel mechanism of action and broad spectrum of antifungal activity. We investigated the in vitro antifungal activities of E1210 compared to those of fluconazole, itraconazole, voriconazole, amphotericin B, and micafungin against clinical fungal isolates. E1210 showed potent activities against most Candida spp. (MIC 90 of ≤0.008 to 0.06 μg/ml), except for Candida krusei (MICs of 2 to >32 μg/ml). E1210 showed equally potent activities against fluconazole-resistant and fluconazole-susceptible Candida strains. E1210 also had potent activities against various filamentous fungi, including Aspergillus fumigatus (MIC 90 of 0.13 μg/ml). E1210 was also active against Fusarium solani and some black molds. Of note, E1210 showed the greatest activities against Pseudallescheria boydii (MICs of 0.03 to 0.13 μg/ml), Scedosporium prolificans (MIC of 0.03 μg/ml), and Paecilomyces lilacinus (MICs of 0.06 μg/ml) among the compounds tested. The antifungal action of E1210 was fungistatic, but E1210 showed no trailing growth of Candida albicans , which has often been observed with fluconazole. In a cytotoxicity assay using human HK-2 cells, E1210 showed toxicity as low as that of fluconazole. Based on these results, E1210 is likely to be a promising antifungal agent for the treatment of invasive fungal infections.

Catalytic enantioselective epoxidation of homoallylic alcohols using Zr(Ot-Bu)(4) and tartrate ester (or tartramide) has been developed. In the Zr(Ot-Bu)(4)/diisopropyl tartrate-catalyzed epoxidation, the reverse of the enantiofacial preference was observed, depending on the Zr/ligand ratios of 1:1 or 1:2. [reaction--see text]

We present here the nucleotide sequence for a cDNA clone encoding p34cdc2 from sea urchin, Hemicentrotus pulcherrimus. The obtained cDNA comprised 301 amino acid residues that contained the PSTAIRE domain to be important for binding to cyclins. Amino acid sequence similarity between this clone and other eukaryotic cdc2 sequences averaged approximately 72%. Using p13suc1-conjugated Sepharose 4B and a selective inhibitor of p34cdc2 kinase, butyrolactone I, it was first suggested that p34cdc2 kinase is involved in the phosphorylation of MRLC at both MLCK site and two PKC sites.

The gaits of 15 patients with senile dementia of the Alzheimer type and 15 with vascular dementia were compared with those of 15 healthy control subjects. Patients with senile dementia showed significantly slower velocity and shorter step length than the healthy controls, and those with vascular dementia exhibited a reduction on these two variables relative to patients with senile dementia of the Alzheimer type.

Age-related changes in the relation between natural and fast walking were investigated for 69 healthy women aged 21 to 88 years. The ratio (fast/natural) of both walking velocity and cadence declined significantly across age groups.

The conformational changes of poly-Ne-glutaryl-L-lysine (PGL) and poly-Ne-succinyl-L-lysine (PSL) in various salt solutions were studied by use of ORD and potentiometric titration measurements. The addition of alkali metal salts to the fully ionized PGL or PSL solution caused helix formation. The helical content of the polymers increases in the following sequences: at salt concentration 0–2 M, CsCl < KCl < LiCl < NaCl; and at 2–3 M, LiCl < CsCl < KCl ∼ NaCl. The preferential binding of the solvent components with various alkali metal salts of PGL or PSL was measured in LiCl, NaCl, and KCl solutions by means of equilibrium dialysis and differential refractometry. It was found that with increasing salt concentration, the polymers were preferentially hydrated in NaCl and KCl soultions; however the salt was preferentially bound to the polymers in LiCl solution. Such preferential binding was suggested to be closely related to conformational change. The addition of CaCl2 to polymer solutions led to the stabilization of the helical structure of PGL or PSL.

Metal analyses and the studies of the effects of EDTA on unfolding reactions have shown that α-lactalbumin is a calcium metalloprotein. The role of the calcium binding in its biological activity is considered. A plausible site of binding is presented on the basis of the metal-binding site of lysozyme and of the structural models of the protein based on the lysozyme structure.

In order to study the effect of side-chain length on the conformation of polypeptides, conformational changes of various ionic polypeptides with various lengths of side chain, poly-Ne-glutaryl-L-lysine (PGL), poly-Nδ-glutaryl-L-ornithine (PGO), poly-Ne-succinyl-L-lysine (PSL), and poly-Nδ-succinyl-L-ornithine (PGO), were investigated by ORD, potentiometric titration, and dilatometric measurements in aqueous solution. The results of optical rotation and potentiometric titration measurements indicate strongly that the α-helix stability increases in the sequence PSO < PSL ∼ PGO < PGL, which corresponds to increased side-chain length. The volume change associated with the helix–coil transition also increased in the above sequence. This series of polymers seems to be more hydrophobic compared with poly-L-glutamic acid or poly-L-lysine, as suggested from the values of enthalpy and entropy changes for coil–helix transitions.

The interactions between sodium dodecyl sulfate (SDS) and nonionizable water-soluble polypeptides, i.e., poly- N 5 -2-(2′-hydroxyethoxy)-ethyl- l -glutamine (PEEG), poly- N 5 -(3-hydroxypropyl)- l -glutamine (PHPG), poly- N 5 -(2-hydroxyethyl)- l -glutamine (PHEG) and poly- dl -alanine (PDLA), were studied in terms of sodium ion activity, conductivity, viscosity and dye solubilization measurements in polymer-surfactant mixed solutions. The experiments suggest the formation of complexes between polymers and SDS. The interaction of polymer with SDS depends on the hydrophobic character of polymer. At the constant concentration of polymer, the amount of SDS bound to the polymer increases in the following sequence; PDLA > PEEG > PHPG > PHEG. The degrees of dissociation of the polymer-SDS complexes calculated from activity data are in the order of PEEG ≈ PDLA > PHPG > PHEG. In polymer-tetramethylammonium dodecyl sulfate (TDS) systems, PEEG and PDLA interact more strongly with TDS than PHPG and PHEG.

The dependence of the dielectric constant and dielectric loss of aqueous solutions of poly-e, N-succinyl-L-lysine on its degree of polymerization, degree of neutralization, concentration of the polymer, and counterion type was studied in a frequency range from 300 Hz to 5 MHz. Regardless of the conformation, a low-frequency dispersion in a frequency range lower than 10 kHz and a high-frequency dispersion in a range higher than 100 kHz were found. The large value of the dielectric increment, its nonlinear dependence on concentration, its remarkable dependence on counterion type, and its dependence on the degree of polymerization suggest that the low-frequency dispersion is mainly due to the polarization of loosely bound counterions. These data were found for both the helical and coiled forms. The rotational motion of the electric dipole on the molecule could not have been primarily responsible for these results. On the other hand, the high-frequency dispersions may be attributable to the Maxwell–Wagner-type effect. The results were compared with the dispersions of poly(L-glutamic acid), poly(L-lysine), and their salts reported previously.

Our previous work demonstrated that the prenatally irradiated ultrasound of even a low-intensity might affect the functional development of the brain of offspring in rats. In the present study, in order to investigate the emotional and cognitive behaviour of offspring of rats that received the irradiation of a diagnostic ultrasound on the 9th day of gestation, the following three experiments were carried out: 1) The emotional reactivity of the offspring was measured by the open-field technique. 2) The same reactivity was further evaluated in terms of the excape response from electroshock. 3) The cognitive function of the offspring was assessed through the discrimination learning and the discrimination reversal learning. The offspring of irradiated rats showed significantly more distinct vocalization response to handling in the open-field test and significantly more distinct escape response from the electroshock, when compared with the two control rats (untreated control and sham-irradiated control). From these findings it may be suggested that the emotional behaviour in rats can be influenced by a low-intensity ultrasound irradiated during foetal stage. On the other hand, as for the cognitive behaviour, the results of the present study suggest no adverse effect on it.

The physical growth, the development of orienting behavior and neuromotor reflexes of offspring of rats that received an irradiation of a diagnostic level of ultrasound on the 9th day of gestation were estimated and compared with those of two control groups (untreated control and sham-irradiated or immobilized control). Results showed no significant group differences in terms of either physical development or development of orienting behavior. In the reflexological tests, however, a number of those reflexes that developed after 6 days of postnatal life of the offspring of irradiated rats showed significant delays in maturation when compared with those of the untreated control rats, but showed no difference from those of the sham-irradiated group. From these findings it is suggested that under certain circumstances such as in stress, the prenatally irradiated ultrasound of even a low-intensity may affect the development of the brain of offspring.

The effects of the prenatal and perinatal factors on the behavioral traits of infants were studied by the use of a maternal questionnaire. The factor analysis on the questionnaire data of 183 newborn and 264 l-month-old infants produced 6 and 7 factors (behavioral dimensions) for the newborn and the l-month-olds, respectively. The correlations between the obstetrical factors and the behavioral dimensions were examined by Hayashi's quantification method I which can be considered as a multiple regression analysis. The results suggested that even those minor prenatal and perinatal complications whose effects had scarcely been noticed clinically on neo-natal states may have an adverse influence on behaviors. In general, the influence of the perinatal factors seems to be manifested on behaviors of the newborn, and also that the influence of the prenatal factors seems to be manifested on behaviors of the l-month-olds as the influence of the perinatal factors diminishes., Les données de cette recherche ont été recueillies au moyen d'un questionnaire rempli par les mères. Les analyses factorielles concernant 183 nouveau-nés et 264 enfants de 1 mois, dégagent respectivement 7 facteurs (ou dimensions de comportements). Les corrélations entre les facteurs obstétricaux et les dimensions de comportements sont traitées par la Méthode de Quantification de Hayashi, laquelle peut être considérée comme une analyse de régression multiple. Les résultats suggèrent que même les complications mineures, prénatales et périnatales, dont les effets sur les états néo-natals n'ont guère été observés d'une façon clinique, peuvent avoir une influence néfaste sur les comportements., Murai Norio, Nihei Yoshiaki. Relations des facteurs prénatals et périnatals avec les caractéristiques de comportement des nouveau-nés. In: Enfance, tome 36, n°1-2, 1983. La première année de la vie. pp. 153-167.

The present study was designed to investigate the effects of four centrally acting drugs (chlorpromazine 6.0mg/kg, reserpine 0.1mg/kg, meprobamate 60.0mg/kg and phenobarbital 8.0mg/kg) upon the behavioral development, especially development of intelligence, of the offspring of rats, to which these drugs were administered during four days of the early and late periods, from the 5th to 8th and from the 17th to 20th days, of pregnancy. When the offsprings were 90 days old, the level of their general activity was measured by the revolving drum technique. In both the administration periods the activity level was significantly lower only in the meprobamate -treated group than that in the control group. Intelligence of 120-day-old animals was tested by Hebb-Williams' enclosed field test. When the administration was done in the early period of gestation, the intelligence of the chlorpromazine-, meprobamate- or phenobarbital-treated groups was each significantly lower than that of the control group. But when the administration was done in the late period of pregnancy, only the meprobamatetreated group showed a significantly lower intelligence than the control group. Theyse findings were also supported by the results of the brain activity test by a Woodbury's electroshock apparatus. From these results it is suggested that some of the centrally acting drugs have possibility of causing a retardation of mental development of offspring, and that the prenatal medication in the early period of gestation has a profounder effect than that in the late period.