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K Sakai

Publications and source records attributed to K Sakai.

18 recordsLinked to original sources
PubMed2026

Eribulin versus taxane as first-line chemotherapy combined with dual HER2 blockade in patients with HER2-positive locally advanced or metastatic breast cancer: final survival outcomes of the JBCRG-M06/EMERALD study.

BACKGROUND: The phase III JBCRG-M06/EMERALD study was the first to show noninferior progression-free survival (PFS) of eribulin to taxane, combined with dual human epidermal growth factor receptor 2 (HER2) blockade (trastuzumab plus pertuzumab), as a first-line treatment for HER2-positive locally advanced breast cancer or metastatic breast cancer (LABC/MBC). We report final survival outcomes and biomarker analyses of the EMERALD trial. PATIENTS AND METHODS: Patients with HER2-positive LABC/MBC were randomly assigned 1:1 to either eribulin or physician-choice taxane (docetaxel or paclitaxel), both combined with trastuzumab plus pertuzumab, as first-line chemotherapy. PFS and overall survival (OS) were assessed through 30 June 2023 for PFS and 31 December 2024 for OS. Survival outcomes were compared between the eribulin and taxane groups and according to circulating tumor DNA (ctDNA) detection of PIK3CA mutations (PIK3CAm+; E542K, E545K, H1047R, and N345K single nucleotide variants) or HER2 amplification (HER2 amp+; ERBB2 copy number >2.5). RESULTS: Median OS was 78.5 months [95% confidence interval (CI) 64.3-not reached (NR)] for eribulin and was NR for taxane, with a hazard ratio of 1.25 (95% CI 0.92-1.71, log-rank P = 0.19). The 60-month OS rates were 59.7% and 65.2% for eribulin and taxane, respectively. Median OS and 60-month OS rates were numerically lower in ctDNA PIK3CAm+ patients, and greater in ctDNA HER2 amp+ patients for all patients and with stratification by treatment group. There were no statistical interactions between treatment group with either ctDNA PIK3CAm or ctDNA HER2 amp status. Similar patterns were observed for PFS. CONCLUSION: Final survival analysis revealed that median OS exceeded 6 years with eribulin or physician-choice taxane, combined with trastuzumab plus pertuzumab, as first-line chemotherapy for HER2-positive LABC/MBC, with no significant differences between the two groups. ctDNA PIK3CAm+ status was a poor prognostic factor. ctDNA HER2 amp+ was associated with longer survival.

Aged↗
PubMed1979

[Persistence of paradoxical sleep in the cat after destruction of the pontine gagantocellular tegmental field with kainic acid].

The pontine gigantocellular tegmental field (FTG) does not play any role in paradoxical sleep (PS) since the destruction of the cell bodies of the FTG with kaïnic acid does not alter PS in the Cat. Elimination of PS following electrolytic destruction of the ventrolateral pontine reticular formation can be explained by lesions of fibers connecting the region of the locus caeruleus and the bulbar reticular formation.

Animals↗
PubMed1979

Tegmentoreticular projections with special reference to the muscular atonia during paradoxical sleep in the cat: an HRP study.

Using the retrograde tracer technique with horseradish peroxidase (HRP), attempts were made to determine the cells of origin and the descending pathway of the tegmentoreticular projections in order to give an anatomical substrate for the physiological phenomenon of the postural atonia observed during paradoxical sleep (PS) in the cat. The HRP was injected into various parts of the pontomedullary reticular formation (RF) including the caudal raphe nuclei, nucleus (n.) reticularis gigantocellularis (Gc), n. reticularis magnocellularis (Mc), and other pontomedullary structures adjacent to the Mc. The results indicated that the HRP injection into the Mc, particularly its caudal and lateral two-thirds, resulted in specific labeling of cells located in an area just medial to the LCa together with those in the most medial part of the LCa. Bilateral lesions of these pontine structures have been reported to suppress the atonia otherwise observed during PS in the normal cat. In addition to the HRP labeled cells, we have also observed HRP filled fiber bundles directed to labeled cells in the medial part of the LCa and immediately adjacent tegmental RF area. The same course of HRP labeled fiber bundles was also observed together with HRP labeled cells in the Mc after HRP injections into the medial part of the LCa area, indicating the existence of an interconnection between the LCa area and the Mc. The location of the tegmentoreticular pathway corresponded to that of the lesions effective to suppress the muscular atonia during PS. HRP injections into the caudal medullar caudal to the Mc, on the other hand, resulted in no or almost no HRP labeled cells in the area medial to the LCa, in spite of the presence of HRP containing neurons in other parts of the pontomedullary RF areas, showing that the tegmentoreticular projections as described above terminate almost exclusively in the Mc.

Animals↗
PubMed1979

[Neuronal activity specific to paradoxical sleep in the bulbar reticular formation in the unrestrained cat].

Single units were recorded in the bulbar reticular formation (BRF) of unrestrained, freely behaving Cats. In the ventromedial part of the BRF (n. reticularis magnocellularis, Mc) corresponding to the "bulbar inhibitory center", we have found a cluster of cells showing tonic activation highly selective to paradoxical sleep (PS). Furthermore, we have confirmed the presence of the same type of cells in the dorsomedial part of the BRF which corresponds to the medial part of the n. reticularis parvocellularis (Pc). The functional significance of these two groups of cells is discussed in terms of the postural atonia and the atonia of jaw closer muscles observed during PS.

Animals↗
PubMed1979

Regulatory and functional compartment of three multifunctional protein kinase systems.

Cyclic AMP-dependent protein kinase has been well established to be composed of catalytic and regulatory subunits, and cyclic AMP acts to dissociate these subunits to exhibit full enzymatic activity. In contrast, cyclic GMP-dependent protein kinase does not possess such a subunit structure and is activated by cyclic GMP simply in an allosteric manner. In addition to cyclic AMP-dependent and cyclic GMP-dependent protein kinases, another species of multifunctional protein kinase has been found in many mammalian tissues. This protein kinase is entirely independent of cyclic nucleotides and activated by lower concentrations of Ca2+ in the presence of a membrane-associated factor. This factor has been identified as phospholipids; in fact, phosphatidylinositol and phosphatidylserine are active in this role, whereas lecithin and sphingomyelin are unable to activate the enzyme. Thus, the three species of protein kinases mentioned above are activated in different manners. Nevertheless, these enzymes show very similar substrate specificities and phosphorylate the same specific seryl residues of histone fractions. In addition, all enzymes have abilities to activate and inactivate muscle phosphorylase kinase and glycogen synthetase, respectively, although the relative rates of reactions towards various substrates are markedly different. The Ca2+-dependent protein kinase seems to be associated with membranous components, whereas cyclic GMP-dependent protein kinase appears to be related to certain subcellular organella such as nucleus. Suggestive evidence is available implying that the cyclic AMP-, cyclic GMP- and Ca2+-activated three sets of protein kinase systems may play each specific physiological roles presumably owing to their own subcellular compartments.

Calcium↗
PubMed1979

A pharmacological analysis of the contractile action of histamine upon the ileal region of the isolated, blood-perfused small intestine of the rat.

1. The mode of action of histamine was investigated on the rat isolated small intestine perfused at a fixed flow rate through the superior mesenteric artery with blood from the carotid artery of a heparinized donor rat. Compounds were closely injected into the superior mesenteric artery. 2. Increasing doses (1 to 100 micrograms) of histamine caused a monophasic fast contraction of the ileum. 3. The fast contraction was abolished by tetrodotoxin, hexamethonium, morphine or mepyramine, but was not prevented by atropine. 4. The present study indicates that histamine produces the fast contraction of the ileum by primarily acting on the myenteric nerve plexus involving cholinergic interneurones.

Animals↗
PubMed1979

The actions of 5-hydroxytryptamine and histamine on the isolated ileum of the tree shrew (Tupaia glis).

1. Contractions to 5-hydroxytryptamine (5-HT) and histamine of longitudinal muscle from the isolated ileum of the tree shrew (Tupaia), guinea-pig and rat were investigated by constructing dose-response curves and studying the effects of various antagonists. 2 In the Tupaia and rat ileum the contraction to 5-HT was reduced by methysergide but not affected by tetrodotoxin (TTX), morphine, hexamethonium (C6) or atropine. The response of guinea-pig ileum to 5-HT was not significantly inhibited by methysergide or C6, but was blocked by TTX, morphine and atropine. 3 Histamine-induced contraction of Tupaia and guinea-pig ileum was antagonized by diphenhydramine but not by TTX, morphine, C6 or atropine. Histamine was almost without effect on the rat ileum.

Animals↗
PubMed1979

[Effects of diethyldithiocarbamate on ejaculatory inhibition and change in monoamine levels of accessory glands (author's transl)].

Effects of diethyldithiocarbamate(DDC) on erection and ejaculation were investigated and monoamine levels in central nervous system, gonad and accessory glands were determined in dogs. Intraperitoneal administration of 50, 75 and 100 mg/kg of DDC suppressed ejaculation 1 hour after administration, although penial erection did occur. This suppression of ejaculation was recovered to some extent 3 hours after DDC and completely recovered 24 hours after DDC. One hour after the administration of 100 mg/kg of DDC, noradrenaline (NA) level in the caudate and serotonin (5-HT) level in the posterior hypothalamus decreased significantly, as compared with the control. However, there were no significant changes in the regions of anterior hypothalamus and hippocampus which are known to play an important role in sexual behavior. In the epididymis, NA and adrenaline levels decreased significantly, though 5-HT levels increased, as compared with those of the control. In the prostate and posterior urethra, NA levels decreased significantly, as compared with the control. The seminal emission induced by hypogastric nerve stimulation induced a gradual rise in the posterior urethral pressure. When the pressure reached the maximum level, rhythmic alterations of the pressure considered to be a phenomenon associated with ejaculation occurred. DDC (100 mg/kg) abolished both seminal emission and rhythmic alterations of the posterior urethral pressure. These findings indicate that the sperm transport may be inhibited by decrease of NA level in accessory glands.

Amines↗
PubMed1979

Effects of intra-arterial bradykinin and substance P on isolated, blood-perfused small intestine of the rat.

Experiments were conducted on rat isolated, small intestine perfused at a fixed flow rate through the superior mesenteric artery with arterial blood from a donor rat, to determine the responses of the ileum to different peptides. Drugs were closely injected into the superior mesenteric artery. Single injections of bradykinin produced monophasic fast contractions of the ileum preceded by an initial fall and a subsequent rise of tone. The fast contraction was abolished by tetrodotoxin (TTX), morphine and hexamethonium (C6), but was resistant to blockade by atropine or mepyramine. Changes in ileal tone induced by bradykinin remained evident even in the presence of these blocking agents, thereby suggesting a direct action on smooth muscle fibers of the ileum. The fast contraction in response to substance P was not influenced by either TTX, morphine, C6, atropine or mepyramine. The present results indicate that bradykinin induces the fast contraction of the ileum by excitation of myenteric neuronal elements involving cholinergic interneurons, while substance P produces the contraction by a direct stimulation of smooth muscle fibers of the ileal region.

Animals↗
PubMed1976

Evidence for the presence of eye movement potentials during paradoxical sleep in cats.

1. Phasic activities related to eye movements in the dark in abducens nucleus (N.VI), lateral geniculate body (LGB), visual cortex, and lateral rectus muscle were analyzed in 18 cats with chronically implanted electrodes during waking and sleeping. 2. N.VI waves, both during waking and sleeping, were multiphasic, and two distinct wave forms were noticed on either side of the pons. The N.VI waves preceded each ocular movement by 10--20 msec. 3. Both during waking and paradoxical sleep (PS), N.VI waves always preceded those occurring in the LGB. During waking, eye movement potentials (EMPs) in LGB followed the onset of the N.VI wave with a long (greater than 60 msec) and variable latency, but followed the end of the same wave with a rather constant delay (about 20 msec). During PS, two distinct populations of latency were observed between onset of the pontine waves and that of LGB waves. The latency of one population was less than 35 msec, and of the other more than 66 msec. 4. Since the LGB waves following N.VI waves with a long latency were similar in a number of respects to EMPs during wakefulness (EMPw), they were judged to be EMPs (EMPps), and were distinguished from LGB PGO waves, which followed N.VI waves with a short latency. Cortical EMPps were observed as well, but occurred about 8--10 times less frequently than the PGO wave. 5. In the light of the present results, the mechanisms responsible for EMP and PGO wave activities are discussed.

Abducens Nerve↗
PubMed1976

Effects of ponto-mesencephalic lesions and electrical stimulation upon PGO waves and EMPs in unanesthetized cats.

1. Phasic waves similar to those observed in the visual system of the awake and sleeping cat ("EMP" and "PGO waves" respectively) were recorded in an area surrounding brachium conjunctivum of the mesencephalic reticular formation (MRF). 2. MRF waves during paradoxical sleep (PS) (MRF PGO wave) occurred 1--2 msec after the waves recorded in the abducens nucleus (N.VI PGO waves), while MRF waves in the alert cat (MRF EMPs) occurred 35--70 msec or more after EMPs in N.VI. 3. Both MRF EMPs in the dark and MRF PGO waves preceded EMPs and PGO waves recorded in the lateral geniculate body (LGB) by 20 msec. 4. There was a time lag of about 40 msec between right and left MRF PGO waves. 5. MRF stimulation elicited short latency responses (5--9 msec) in LGB during waking and sleeping states. During PS, the same stimuli further elicited PGO waves (latency greater than or equal to 40 msec) in the same structure. 6. Stimulation of LGB elicited short latency responses (5--9msec) in MRF. 7. Unilateral MRF lesions reduced by about 50% the number of LGB PGO waves without modifying other characteristics of the PGO wave activity. 8. Following unilateral MRF lesion, LGB EMPs were observed with each eye movement in the dark. However, LGB EMPs ipsilateral to the lesion were greatly reduced in amplitude and followed the EMPs in the opposite LGB by a time lag similar to that observed between bilateral LGB PGO waves. 9. Bilateral MRF lesions completely abolished PGO waves and EMPs observed with the animal in the dark. However, EMPs observed in the light remained unmodified. 10. From the present study it was concluded that LGB and visual cortex gross potential changes related to eye movements in the alert cat have both retinal and non-retinal components. Further, the significance of the MRF area in the mechanisms of EMP and PGO wave activities was discussed.

Abducens Nerve↗
PubMed1976

[Afferent projections to the locus coeruleus nucleus in the cat. Study by the horseradish peroxidase technic].

Using a retrograde tracer technique with horseradish peroxidase, we have revealed some afferent projections to the locus coeruleus complex from the contralateral pontine tegmentum, raphe nuclei, substantia nigra, nucleus of the solitory tract, dorsal motor nucleus of the vagus and other regions of the ponto-bulbar reticular formation as well as from hypothalamic and preoptic areas.

Afferent Pathways↗
PubMed1975

[Hypersomnia by isthmic lesion in cat. II. Neurophysiological and pharmacological study].

(1) The bilateral destruction of the region of the dorsal norepinephrine bundle in the isthmus or in the mesencephalon induces a significant increase of both paradoxical sleep (PS) (up to 400%) and of slow-wave sleep (SWS). The increase of PS lasts for 4-5 days while the increase of SWS lasts at least 8-10 days. The same phenomenon is observed after total hypophysectomy. (2) control lesions effectuated in the isthmus outside the area of the dorsal norepinephrine bundle do not affect significantly the slee-walking cycle. (3) pretreatment with p-chlorophenylalanine suppresses the increase of sleep if the lesion is effectuated at the time of maximum insomnia, while a significant increase of PS is still observed if the lesion is made at the time of the recovery of sleep. (4) the mechanisms of this hypersomnia are discussed in light of the biochemical results showing an increase of the biosynthesis of serotonin in the rostral raphe system. It is postulated that some neurons of the dorsal norepinephrine bundle might tonically control the activity of the raphe system.

Animals↗
PubMed1975

Potentation of the cardiac response to aminophylline by oxyfedrine.

The influence of oxyfedrine on the cardiostimulatory effects of aminophylline was studied in the isolated perfused guinea-pig heart. It was found that oxyfedrine potentiated the stimulatory effects of aminophylline on isometric contraction, dF/dt, coronary flow and heart rate. This potentation was abolished after pretreatment with propranolol. Histamine, though to a lesser extent, also potentiated the effects of aminophylline. When oxyfedrine and histamine were infused simultaneously in the presence of propranolol, the response of the heart to aminophylline was also potentiated; the magnitude of this potentiation was comparable to that obtained with histamine alone, indicating that propranolol abolished only the action of oxyfedrine but not that of histamine. The mechanical effects of aminophylline were accompanied by a slight (15 per cent) but significant inhibition of phosphodiesterase, which was not further augmented by oxyfedrine. The results suggest that the potentiating effects of oxyfedrine or histamine on the cardiostimulatory actions of aminophylline are elicited by their stimulatory actions on adenylate cyclase activity.

Aminophylline↗