Yukawa hierarchy from extra dimensions and infrared fixed points

We discuss the existence of hierarchy of Yukawa couplings in the models with extra spatial dimensions. The hierarchical structure is induced by the power behavior of the cutoff dependence of the evolution equations which yield large suppressions of couplings at the compactification scale. The values of coupling constants at this scale can be made stable almost independently of the initial input parameters by utilizing the infrared fixed point. We find that the Yukawa couplings converge to the fixed points very quickly because of the enhanced energy dependence of the suppression factor from extra dimensions as well as in the case of large gauge couplings at high-energy scale.Comment: 13 pages, 3 eps figure

Spatial Distributions of GABA Receptors and Local Inhibition of Ca2+ Transients Studied with GABA Uncaging in the Dendrites of CA1 Pyramidal Neurons

GABA(γ-amino-butylic acid)-mediated inhibition in the dendrites of CA1 pyramidal neurons was characterized by two-photon uncaging of a caged-GABA compound, BCMACM-GABA, and one-photon uncaging of RuBi-GABA in rat hippocampal slice preparations. Although we found that GABAA-mediated currents were diffusely distributed along the dendrites, currents elicited at the branch points of the apical dendritic trunk were approximately two times larger than those elsewhere in the dendrite. We examined the inhibitory action of the GABA-induced currents on Ca2+ transients evoked with a single back-propagating action potential (bAP) in oblique dendrites. We found that GABA uncaging selectively inhibited the Ca2+ transients in the region adjacent (<20 µm) to the uncaging site, and that GABA uncaging was effective only within a short period after bAP (<20 ms). The strength of inhibition was linearly related to the amplitudes of the GABA currents, suggesting that the currents inhibited a sustained, subthreshold after-depolarization without preventing propagation of bAP. GABA uncaging at the dendritic branch points inhibited Ca2+ transients farther into dendritic branches (>20 µm). Our data indicate that GABA inhibition results in spatially confined inhibition of Ca2+ transients shortly after bAP, and suggest that this effect is particularly potent at the dendritic branch points where GABA receptors cluster

Analysis of Differentially Expressed Genes in Neuroendocrine Carcinomas of the Lung

IntroductionLarge cell neuroendocrine carcinoma (LCNEC) and small cell lung carcinoma (SCLC) show considerable differences in their histology but share neuroendocrine (NE) characteristics and also genetic and/or expression patterns.MethodsWe used the subtractive expression method to identify differences in gene expression that would allow discrimination between these two types of NE lung carcinoma.ResultsEight cDNA fragments were transcribed at a higher level in LCNEC compared with SCLC, and these corresponded to five mitochondrial genes, two ribosomal genes, and one fetal regulation factor, neuronatin (NNAT). Immunohistochemically, NNAT protein was detected in 43% (6/14) of LCNECs but in only 8% (1/13) of SCLCs (p < 0.05). Positive staining for NNAT was observed in areas that did not show the NE morphology, such as palisading and rosettes.ConclusionsThe present results suggest that NNAT has the potential to be used as a differential maker between LCNEC and SCLC

Yukawa Hierarchy Transfer Based on Superconformal Dynamics and Geometrical Realization in String Models

We propose a scenario that leads to hierarchical Yukawa couplings and degenerate sfermion masses at the same time, in the context of extra-dimensional models, which can be naturally embedded in a wide class of string models. The hierarchy of Yukawa couplings and degeneracy of sfermion masses can be realized thanks to superconformal gauge dynamics. The sfermion mass degeneracy is guaranteed by taking the superconformal fixed point to be family independent. In our scenario, the origin of Yukawa hierarchy is attributed to geometry of compactified dimensions and the consequent volume dependence of gauge couplings in the superconformal sectors. The difference in these gauge couplings is dynamically transferred to the hierarchy of the Yukawa couplings. Thus, our scenario combines a new dynamical approach and the conventional geometrical approach to the supersymmetric flavor problem.Comment: 12 pages, latex, no figur

Fermion Mass Hierarchies and Small Mixing Angles from Extra Dimensions

In this paper we study renormalization-group evolutions of Yukawa matrices enhanced by Kaluza-Klein excited modes and analyze their infrared fixed-point structure. We derive necessary conditions to obtain hierarchies between generations on the fixed point. These conditions restrict how the fields in the models can extend to higher dimension. Several specific mechanisms to realize the conditions are presented. We also take account of generation mixing effects and find a scenario where the mixing angles become small at low energy even with large initial values at high-energy scale. A toy model is shown to lead realistic quark mass matrices.Comment: 23 pages, 7 figures, LaTeX, a supplementary explanation and references adde

First-line pembrolizumab vs chemotherapy in metastatic non-small-cell lung cancer: KEYNOTE-024 Japan subset

This prespecified subanalysis of the global, randomized controlled phase Ill KEYNOTE-024 study of pembrolizumab vs chemotherapy in previously untreated metastatic non-small-cell lung cancer without EGFR/ALK alterations and a programmed death-ligand 1 (PD-L1) tumor proportion score of 50% or greater evaluated clinical outcomes among patients enrolled in Japan. Treatment consisted of pembrolizumab 200 mg every 3 weeks (35 cycles) or platinum-based chemotherapy (four to six cycles). The primary end-point was progression-free survival; secondary end-points included overall survival and safety. Of 305 patients randomized in KEYNOTE-024 overall, 40 patients were enrolled in Japan (all received treatment: pembrolizumab, n = 21; chemotherapy, n = 19). The hazard ratio (HR) for progression-free survival by independent central review (data cut-off date, 10 July 2017) was 0.25 (95% confidence interval [CI], 0.10-0.64; one-sided, nominal P = .001). The HR for overall survival (data cut-off date, 15 February 2019) was 0.39 (95% CI, 0.17-0.91; one-sided, nominal P = .012). Treatment-related adverse events occurred in 21/21 (100%) pembrolizumab-treated and 18/19 (95%) chemotherapy-treated patients; eight patients (38%) and nine patients (47%), respectively, had grade 3-5 events. Immune-mediated adverse events and infusion reactions occurred in 11 patients (52%) and four patients (21%), respectively; four patients (19%) and one patient (5%), respectively, had grade 3-5 events. Consistent with results from KEYNOTE-024 overall, first-line pembrolizumab improved progression-free survival and overall survival vs chemotherapy with manageable safety among Japanese patients with metastatic non-small-cell lung cancer without EGFRIALK alterations and a PD-L1 tumor proportion score of 50% or greater

First-line pembrolizumab vs chemotherapy in metastatic non-small-cell lung cancer: KEYNOTE-024 Japan subset

This prespecified subanalysis of the global, randomized controlled phase III KEYNOTE‐024 study of pembrolizumab vs chemotherapy in previously untreated metastatic non‐small‐cell lung cancer without EGFR/ALK alterations and a programmed death ligand 1 (PD‐L1) tumor proportion score of 50% or higher evaluated clinical outcomes among patients enrolled in Japan. Treatment consisted of pembrolizumab 200 mg every 3 weeks (35 cycles) or platinum‐based chemotherapy (four to six cycles). The primary end‐point was progression‐free survival; secondary end‐points included overall survival and safety. Of 305 patients randomized in KEYNOTE‐024 overall, 40 patients were enrolled in Japan (all received treatment: pembrolizumab, n = 21; chemotherapy, n = 19). Median progression‐free survival was 41.4 (95% confidence interval [CI], 4.2‐42.5) months with pembrolizumab and 4.1 (95% CI, 2.8‐8.3) months with chemotherapy (hazard ratio [HR], 0.27 [95% CI, 0.11‐0.65]; one‐sided, nominal P = .001). Median overall survival was not reached (NR) (95% CI, 22.9‒NR) and 21.5 (95% CI, 5.2‐35.0) months, respectively (HR, 0.39 [95% CI, 0.17‐0.91]; one‐sided, nominal P = .012). Treatment‐related adverse events occurred in 21/21 (100%) pembrolizumab‐treated and 18/19 (95%) chemotherapy‐treated patients; eight patients (38%) and nine patients (47%), respectively, had grade 3‐5 events. Immune‐mediated adverse events and infusion reactions occurred in 11 pembrolizumab‐treated patients (52%) and four chemotherapy‐treated patients (21%), respectively; four patients (19%) and one patient (5%), respectively, had grade 3‐5 events. Consistent with results from KEYNOTE‐024 overall, first‐line pembrolizumab improved progression‐free survival and overall survival vs chemotherapy with manageable safety among Japanese patients with metastatic non‐small‐cell lung cancer without EGFR/ALK alterations and a PD‐L1 tumor proportion score of 50% or higher. The trial is registered with Clinicaltrials.gov: NCT02142738

Sfermion Mass Degeneracy, Superconformal Dynamics and Supersymmetric Grand Unified Theories

We discuss issues in a scenario that hierarchical Yukawa couplings are generated through strong dynamics of superconformal field theories (SCFTs). Independently of mediation mechanism of supersymmetry breaking, infrared convergence property of SCFTs can provide an interesting solution to supersymmetric flavor problem; sfermion masses are suppressed around the decoupling scale of SCFTs and eventually become degenerate to some degree, thanks to family-independent radiative corrections governed by the SM gaugino masses. We discuss under what conditions the degeneracy of sfermion mass can be estimated in a simple manner. We also discuss the constraints from lepton flavor violations. We then study explicitly sfermion mass degeneracy within the framework of grand unified theories coupled to SCFTs. It is found that the degeneracy for right-handed sleptons becomes worse in the conventional SU(5) model than in the MSSM. On the other hand, in the flipped SU(5) \times U(1) model, each right-handed lepton is still an SU(5)-singlet, whereas the bino mass M_1 is determined by two independent gaugino masses of SU(5) \times U(1). These two properties enable us to have an improved degeneracy for the right-handed sleptons. We also speculate how further improvement can be obtained in the SCFT approach.Comment: 24 pages, latex, 4 figure

Carcinogen‐induced tumors in SFN‐transgenic mice harbor a characteristic mutation spectrum of human lung adenocarcinoma

The landscape of genetic alterations in disease models such as transgenic mice or mice with carcinogen‐induced tumors has provided a huge amount of information that has shed light on the process of tumorigenesis in human non‐small‐cell lung cancer (NSCLC). We have previously identified stratifin (SFN) as a potent oncogene, and generated SFN‐transgenic (Tg‐SPC‐SFN+/−) mice, which express human SFN (hSFN) only in the lung. Here, we have found that carcinogen nicotine‐derived nitrosaminoketone (NNK)‐induced tumors developing in Tg‐SPC‐SFN+/− mice show a similar histology to human lung adenocarcinoma and exhibit high hSFN expression. In order to compare the genetic characteristics of Tg‐SPC‐SFN+/− tumors and human lung adenocarcinoma, the former were subjected to whole‐exome sequencing. Interestingly, Tg‐SPC‐SFN+/− tumors showed the distinct distribution of exonic mutations and high number of mutated genes and transversion. Moreover, Tg‐SPC‐SFN+/− tumors showed 73 genes that were commonly detected in more than 2 tumors, mutations of which were also found in human lung adenocarcinoma. The expression levels of some of these genes were significantly associated with the clinical outcome of lung adenocarcinoma patients. Additionally, mutated genes in Tg‐SPC‐SFN+/− tumors were closely associated with key canonical pathways such as PI3K/AKT signaling and apoptosis signaling. These results suggest that SFN overexpression is a universal abnormality in human lung adenocarcinogenesis and Tg‐SPC‐SFN+/− tumors recapitulate key features of major human lung adenocarcinoma. Therefore, Tg‐SPC‐SFN+/− mice provide a useful model for clarifying the molecular mechanism underlying lung adenocarcinogenesis