Sensitivity of epidermal growth factor receptor with single or double uncommon mutations to afatinib confirmed by a visual assay.

Patients with non-small cell lung cancer (NSCLC) harboring common mutations of the epidermal growth factor receptor (EGFR) are sensitive to EGFR-tyrosine kinase inhibitors (TKI). Although forms of EGFR harboring single uncommon mutations such as G719X or L861Q are thought to be less sensitive to EGFR-TKI, the efficacy of these drugs in patients with double uncommon mutations has remained unclear. We here present an NSCLC patient found to be positive for double uncommon EGFR mutations (G719X and L861Q) by clinical genomic sequencing analysis of a pleural effusion specimen who showed a durable response to the EGFR-TKI afatinib. The sensitivity of EGFR with single or double uncommon mutations to afatinib and the EGFR-TKI erlotinib was also evaluated in vitro with a visual assay based on HEK293 cells transiently transfected with expression plasmids for yellow fluorescent protein (YFP)-tagged fragments of the EGFR intracellular domain (ICD). Whereas forms of EGFR with double uncommon mutations were more sensitive to erlotinib than were those with single uncommon mutations, those with single or double uncommon mutations were similarly sensitive to afatinib, consistent with the patient's clinical outcome. Our data support the notion that afatinib is the most suitable EGFR-TKI for NSCLC harboring uncommon mutations of EGFR. Furthermore, the YFP-EGFR-ICD assay is potentially applicable to prediction of EGFR-TKI efficacy in patients with such mutations.

Large-Gap Magnetic Topological Heterostructure Formed by Subsurface Incorporation of a Ferromagnetic Layer.

Inducing magnetism into topological insulators is intriguing for utilizing exotic phenomena such as the quantum anomalous Hall effect (QAHE) for technological applications. While most studies have focused on doping magnetic impurities to open a gap at the surface-state Dirac point, many undesirable effects have been reported to appear in some cases that makes it difficult to determine whether the gap opening is due to the time-reversal symmetry breaking or not. Furthermore, the realization of the QAHE has been limited to low temperatures. Here we have succeeded in generating a massive Dirac cone in a MnBi2Se4/Bi2Se3 heterostructure, which was fabricated by self-assembling a MnBi2Se4 layer on top of the Bi2Se3 surface as a result of the codeposition of Mn and Se. Our experimental results, supported by relativistic ab initio calculations, demonstrate that the fabricated MnBi2Se4/Bi2Se3 heterostructure shows ferromagnetism up to room temperature and a clear Dirac cone gap opening of ∼100 meV without any other significant changes in the rest of the band structure. It can be considered as a result of the direct interaction of the surface Dirac cone and the magnetic layer rather than a magnetic proximity effect. This spontaneously formed self-assembled heterostructure with a massive Dirac spectrum, characterized by a nontrivial Chern number C = -1, has a potential to realize the QAHE at significantly higher temperatures than reported up to now and can serve as a platform for developing future "topotronics" devices.

Modulation of hippocampus-prefrontal cortex synaptic transmission and disruption of executive cognitive functions by MK-801.

Noncompetitive N-methyl-d-aspartate receptor antagonists such as phencyclidine and MK-801 are known to impair cognitive function in rodents and humans, and serve as a useful tool to study the cellular basis for pathogenesis of schizophrenia cognitive symptoms. In the present study, we tested in rats the effect of MK-801 on ventral hippocampus (HPC)-medial prefrontal cortex (mPFC) synaptic transmission and the performance in 2 cognitive tasks. We found that single injection of MK-801 (0.1 mg/kg) induced gradual and long-lasting increases of the HPC-mPFC response, which shares the common expression mechanisms with long-term potentiation (LTP). But unlike LTP, its induction required no enhanced or synchronized synaptic inputs, suggesting aberrant characteristics. In parallel, rats injected with MK-801 showed impairments of mPFC-dependent cognitive flexibility and HPC-mPFC pathway-dependent spatial working memory. The effects of MK-801 on HPC-mPFC responses and spatial working memory decayed in parallel within 24 h. Moreover, the therapeutically important subtype 2/3 metabotropic glutamate receptor agonist LY379268, which blocked MK-801-induced potentiation, ameliorated the MK-801-induced impairment of spatial working memory. Our results show a novel form of use-independent long-lasting potentiation in HPC-mPFC pathway induced by MK-801, which is associated with impairment of HPC-mPFC projection-dependent cognitive function.

Infected complex renal cysts during crizotinib therapy in a patient with non-small cell lung cancer positive for ALK rearrangement.

Crizotinib is the first clinically available tyrosine kinase inhibitor that targets anaplastic lymphoma kinase (ALK) and is associated with the development of complex renal cysts. We now describe a 39-year-old woman who developed infected complex renal cysts during crizotinib treatment. After 10 months of such treatment, she presented with a high fever and low back pain. Computed tomography findings were consistent with complex renal cysts and perilesional inflammation. Interventions including cyst drainage and antibiotic administration contributed to diagnosis and management of the infected cysts.

Surface Tomonaga-Luttinger-Liquid State on Bi/InSb(001).

A 1D metallic surface state was created on an anisotropic InSb(001) surface covered with Bi. Angle-resolved photoelectron spectroscopy (ARPES) showed a 1D Fermi contour with almost no 2D distortion. Close to the Fermi level (E_{F}), the angle-integrated photoelectron spectra showed power-law scaling with the binding energy and temperature. The ARPES plot above E_{F}, obtained thanks to a thermally broadened Fermi edge at room temperature, showed a 1D state with continuous metallic dispersion across E_{F} and power-law intensity suppression around E_{F}. These results strongly suggest a Tomonaga-Luttinger liquid on the Bi/InSb(001) surface.

Design and performance of a new VIS-VUV photoluminescence beamline at UVSOR-III.

A new bending-magnet beamline with a 2.5 m normal-incidence monochromator has been constructed to serve with a light source in the visible-vacuum-ultraviolet region for photoluminescence, transmission and reflection spectroscopies of solids at the UVSOR-III 750 MeV synchrotron radiation light source. The aim is to pave the way to establishing a beamline with high photon flux, high brilliance, high energy-resolution, high linear-polarization and low higher-order light. To obtain high photon flux and brilliance, the acceptance angle of the bending-magnet radiation was designed to be 40 mrad (H) × 14 mrad (V) and the post-mirror system employed Kirkpatrick-Baez optics. The incidence angle of the incoming light to the optical elements, except to the gratings, was set to a grazing angle in order to keep a degree of linear polarization. For achieving high energy-resolution, an off-plane Eagle-type monochromator was adopted. Higher-order unwanted light in the energy range below ∼11 eV was suppressed to be less than 0.1%.

Early life stress affects the serotonergic system underlying emotional regulation.

Traumatic events in early life are implicated in an increased risk of psychiatric diseases, such as depression and anxiety disorders. Serotonin is thought to play a central role in stress-induced psychiatric diseases. Serotonergic systems, including neural organization and receptor function, could dramatically change with each developmental stage. Here, we reviewed the persistent influence of early life stress on emotional regulation, focusing on the serotonergic system in rats. An aversive stimulus, foot shock (FS), during the early postnatal period (2-3 weeks after birth) produced behavioral, neuroanatomical and electrophysiological changes accompanied by serotonergic dysfunction, especially functional impairment of the serotonin (5-hydroxytryptamine; 5-HT)1A receptor in the cortico-limbic area. These findings suggest that normalization of the cortico-limbic serotonergic function has therapeutic potential for early stress-induced emotional disturbance.

Trauma-associated left renal vein thrombosis with nutcracker syndrome.

Background: Nutcracker syndrome is a compression of the left renal vein between the superior mesenteric artery and aorta, resulting in thrombogenesis. While renal vein thrombosis caused by renal disease is more common, solitary left renal vein thrombosis with nutcracker syndrome is rare. Case Presentation: We present the case of a patient with trauma-associated left renal vein thrombosis with nutcracker syndrome. A 24-year-old woman with low body mass index taking oral contraceptives was admitted for trauma. She had multiple injuries, including thoracolumbar fractures, for which elective spinal fusion surgery was scheduled. As the D-dimer level elevated to 82.5 µg/dL preoperatively, enhanced computed tomography was performed, which revealed a solitary left renal vein thrombus. Conclusion: This is the report of solitary left renal vein thrombosis in a patient with nutcracker syndrome after trauma. Patients with low body mass index and coagulopathy might have solitary left renal vein thrombosis associated with nutcracker syndrome.

Two-dimensional heavy fermion in a monoatomic-layer Kondo lattice YbCu2.

The Kondo effect between localized f-electrons and conductive carriers leads to exotic physical phenomena. Among them, heavy-fermion (HF) systems, in which massive effective carriers appear due to the Kondo effect, have fascinated many researchers. Dimensionality is also an important characteristic of the HF system, especially because it is strongly related to quantum criticality. However, the realization of the perfect two-dimensional (2D) HF materials is still a challenging topic. Here, we report the surface electronic structure of the monoatomic-layer Kondo lattice YbCu2 on a Cu(111) surface observed by synchrotron-based angle-resolved photoemission spectroscopy. The 2D conducting band and the Yb 4f state, located very close to the Fermi level, are observed. These bands are hybridized at low-temperature, forming the 2D HF state, with an evaluated coherence temperature of about 30 K. The effective mass of the 2D state is enhanced by a factor of 100 by the development of the HF state. Furthermore, clear evidence of the hybridization gap formation in the temperature dependence of the Kondo-resonance peak has been observed below the coherence temperature. Our study provides a new candidate as an ideal 2D HF material for understanding the Kondo effect at low dimensions.

Impact of increased plasma levels of calreticulin on prognosis of patients with advanced lung cancer undergoing combination treatment of chemotherapy and immune checkpoint inhibitors.

BACKGROUND: Damage-associated molecular pattern (DAMP)-related immunogenic cell death triggers secondary adaptive immune responses. The relationship between DAMP levels and prognosis in patients with non-small cell lung cancer (NSCLC) who undergo a combination therapy of immune checkpoint inhibitors (ICI) and chemotherapy remains unclear. METHODS: Serial plasma samples were prospectively collected from 45 patients treated with ICI combination therapy for advanced NSCLC. Plasma concentrations of high-mobility group box 1 (HMGB1), calreticulin (CRT), annexin A1, and heat shock protein 70 were measured. Associations between increases in plasma DAMP levels and the efficacy of the ICI combination therapy were evaluated. RESULTS: The maximum fold changes in plasma levels differed across individuals but demonstrated a marked increase, especially for CRT (mean ± SEM, 11.61 ± 46.15). Increased plasma DAMP levels were not clearly associated with clinical responses. There was a significant correlation between the maximum fold change in CRT levels and progression-free survival (PFS; r = 0.49, P < 0.001). Median PFS and overall survival (OS) rates were higher in patients with a ≥ 2-fold increase in plasma CRT levels than in those with a < 2-fold increase (PFS, 14.9 versus 6.0 months, hazard ratio (HR), 0.58; P = 0.17; OS, not reached versus 21.6 months, HR, 0.31, P = 0.02). CONCLUSIONS: Plasma CRT level monitoring has the potential to predict the efficacy of ICI combination therapy and shed light on the mechanisms underlying DAMP-related immunogenic cell death.

Phase-dependent synaptic changes in the hippocampal CA1 field underlying extinction processes in freely moving rats.

Recent studies focus on the functional significance of a novel form of synaptic plasticity, low-frequency stimulation (LFS)-induced synaptic potentiation in the hippocampal CA1 area. In the present study, we elucidated dynamic changes in synaptic function in the CA1 field during extinction processes associated with context-dependent fear memory in freely moving rats, with a focus on LFS-induced synaptic plasticity. Synaptic transmission in the CA1 field was transiently depressed during each extinction trial, but synaptic efficacy was gradually enhanced by repeated extinction trials, accompanied by decreases in freezing. On the day following the extinction training, synaptic transmission did not show further changes during extinction retrieval, suggesting that the hippocampal synaptic transmission that underlies extinction processes changes in a phase-dependent manner. The synaptic potentiation produced by extinction training was mimicked by synaptic changes induced by LFS (0.5 Hz) in the group that previously received footshock conditioning. Furthermore, the expression of freezing during re-exposure to footshock box was significantly reduced in the LFS application group in a manner similar to the extinction group. These results suggest that LFS-induced synaptic plasticity may be associated with the extinction processes that underlie context-dependent fear memory. This hypothesis was supported by the fact that synaptic potentiation induced by extinction training did not occur in a juvenile stress model that exhibited extinction deficits. Given the similarity between these electrophysiological and behavioral data, LFS-induced synaptic plasticity may be related to extinction learning, with some aspects of neuronal oscillations, during the acquisition and/or consolidation of extinction memory.

Breakdown of bulk-projected isotropy in surface electronic states of topological Kondo insulator SmB6(001).

The topology and spin-orbital polarization of two-dimensional (2D) surface electronic states have been extensively studied in this decade. One major interest in them is their close relationship with the parities of the bulk (3D) electronic states. In this context, the surface is often regarded as a simple truncation of the bulk crystal. Here we show breakdown of the bulk-related in-plane rotation symmetry in the topological surface states (TSSs) of the Kondo insulator SmB6. Angle-resolved photoelectron spectroscopy (ARPES) performed on the vicinal SmB6(001)-p(2 × 2) surface showed that TSSs are anisotropic and that the Fermi contour lacks the fourfold rotation symmetry maintained in the bulk. This result emphasizes the important role of the surface atomic structure even in TSSs. Moreover, it suggests that the engineering of surface atomic structure could provide a new pathway to tailor various properties among TSSs, such as anisotropic surface conductivity, nesting of surface Fermi contours, or the number and position of van Hove singularities in 2D reciprocal space.

Electronic-structure-driven magnetic ordering in a Kondo semiconductor CeOs2Al10.

We report the anisotropic changes in the electronic structure of a Kondo semiconductor CeOs(2)Al(10) across an anomalous antiferromagnetic ordering temperature (T(0)) of 29 K, using optical conductivity spectra. The spectra along the a and c axes indicate that an energy gap due to the hybridization between conduction bands and nearly local 4f states, namely the c-f hybridization gap, emerges from a higher temperature continuously across T(0). Along the b axis, on the other hand, another energy gap with a peak at 20 meV becomes visible at 39 K (>T(0)) and fully opens at T(0) because of a charge instability. This result implies that the appearance of the energy gap, as well as the change in the electronic structure along the b axis, induces the antiferromagnetic ordering below T(0).

Interfacing 2D and 3D topological insulators: Bi(111) bilayer on Bi2Te3.

We report the formation of a bilayer Bi(111) ultrathin film, which is theoretically predicted to be in a two-dimensional quantum spin Hall state, on a Bi(2)Te(3) substrate. From angle-resolved photoemission spectroscopy measurements and ab initio calculations, the electronic structure of the system can be understood as an overlap of the band dispersions of bilayer Bi and Bi(2)Te(3). Our results show that the Dirac cone is actually robust against nonmagnetic perturbations and imply a unique situation where the topologically protected one- and two-dimensional edge states are coexisting at the surface.

Serotonin(1A) receptor-mediated synaptic response in the rat medial prefrontal cortex is altered by early life stress: in vivo and in vitro electrophysiological studies.

Serotonin (5-HT)(1A) receptors play a critical role in the 5-HTergic mechanism associated with fear memory. Previously we showed that adult rats exposed to early postnatal stress, i.e. footshock (FS) stress experienced during the second week (PND 14-18, 2W-FS), exhibited low levels of fear expression. The present study explored whether aversive stress exposure in the second and/or the third week (PND 21-25, 3W-FS) affects the function of cortical 5-HT(1A) receptors, using in vivo and in vitro experiments. A 5-HT(1A) receptor agonist, 8-OH-DPAT (0.5 mg/kg, i.p.), slightly decreased the evoked potential in the mPFC in Non-FS control and 3W-FS group. In contrast, the evoked potential increased after 8-OH-DPAT in the 2W-FS group. The in vitro experiment using patch-clamp recording showed that application of 8-OH-DPAT (10 microM) elicited membrane hyperpolarization of pyramidal neurons in the mPFC in the Non-FS and 3W-FS groups, whereas no changes in membrane potential were observed in the 2W-FS group. These results suggest that synaptic facilitation induced by 8-OH-DPAT resulted from functional changes in cortical 5-HT(1A) receptors. Thus, aversive stress exposure during the second postnatal period appears to cause persistent changes mediated via 5-HT(1A) receptors, presumably involving signal transduction regulating the development of synaptic connectivity underlying fear circuits.

Correlation of 4-meter gait speed with clinical indicators of chronic obstructive pulmonary disease.

BACKGROUND: Measuring daily physical activity and exercise capacity is recommended in the routine care of patients with chronic obstructive pulmonary disease (COPD). The 4-m gait speed (4mGS) is simple and effective in stratifying patients according to exercise performance, dyspnea, health status, and prognosis. We assessed the reliability of the 4mGS as a clinical marker by examining its association with established clinical indicators among hospitalized patients with COPD. METHODS: This retrospective study included 78 patients hospitalized with COPD (mean age: 76.3 ± 0.9 years; males, n = 69) between January 2016 and June 2018 who were assessed using the 4mGS and divided into slow (<0.8 m/s) and normal (≥0.8 m/s) 4mGS groups. Clinical characteristics were compared, including death during the observation period, time to first exacerbation, and long-term oxygen therapy requirement. RESULTS: There were strong relationships between 4mGS performance, the 6-min walk test (R = 0.70; p < 0.0001), and the modified Medical Research Council dyspnea scale (R = 0.68; p < 0.0001) among the 78 patients. The slow 4mGS group had a higher frequency of death during the observation period (p = 0.0095) and a greater requirement for long-term oxygen therapy (p = 0.0063). The 4mGS correlated with inspiratory capacity (IC) and IC/total lung capacity ratios, which are respiratory failure indicators. CONCLUSIONS: The 4mGS is a simple and easy method of assessing the physical condition as well as estimating the prognosis of patients with COPD, and may serve as a useful marker in home medical treatment or clinical settings.

Bulk-sensitive spin-resolved resonant electron energy-loss spectroscopy (SR-rEELS): Observation of element- and spin-selective bulk plasmons.

We have developed spin-resolved resonant electron energy-loss spectroscopy with the primary energy of 0.3-1.5 keV, which corresponds to the core excitations of 2p-3d absorption of transition metals and 3d-4f absorption of rare-earths, with the energy resolution of about 100 meV using a spin-polarized electron source as a GaAs/GaAsP strained superlattice photocathode. Element- and spin-selective carrier and valence plasmons can be observed using the resonance enhancement of core absorptions and electron spin polarization. Furthermore, bulk-sensitive electron energy-loss spectroscopy spectra can be obtained because the primary energy corresponds to the mean free path of 1-10 nm. The methodology is expected to provide us with novel information about elementary excitations by resonant inelastic x-ray scattering and resonant photoelectron spectroscopy.

Increased plasma levels of damage-associated molecular patterns during systemic anticancer therapy in patients with advanced lung cancer.

BACKGROUND: Immunogenic cell death (ICD) characterized by the release of damage-associated molecular patterns (DAMPs) from dying cancer cells may contribute to the synergistic antitumor effect of cytotoxic chemotherapy combined with an immune checkpoint inhibitor. The kinetics of circulating DAMP levels in cancer patients have remained largely uncharacterized, however. METHODS: We evaluated the possible effects of various systemic anticancer therapy modalities on the kinetics of plasma DAMP concentrations in a prospective observational study of patients with advanced lung cancer. The plasma concentrations of high-mobility group box 1 (HMGB1), calreticulin (CRT), heat shock protein 70 (HSP70), annexin A1, and histone H3 were thus determined in 121 such patients at four time points during the first cycle of treatment. RESULTS: The mean of the maximum fold change in HMGB1, HSP70, or annexin A1 concentration observed during treatment was significantly greater than the corresponding baseline value (P<0.005). The maximum fold changes in HMGB1 and CRT concentrations tended to be associated with clinical response as evaluated by RECIST criteria, although the changes in the levels of these two DAMPs were not correlated, suggestive of differential induction mechanisms. Among the various treatment modalities administered, platinum-based combination or single-agent chemotherapy tended to elicit robust increases in the concentrations of HMGB1 and CRT. CONCLUSIONS: Serial monitoring of plasma revealed that systemic anticancer therapy increased the circulating levels of HMGB1 and CRT and that these changes tended to be associated with clinical response, suggesting that agents capable of releasing these DAMPs into plasma might induce ICD in advanced lung cancer patients.

Evidence for a preformed Cooper pair model in the pseudogap spectra of a Ca10(Pt4As8)(Fe2As2)5 single crystal with a nodal superconducting gap.

For high-Tc superconductors, clarifying the role and origin of the pseudogap is essential for understanding the pairing mechanism. Among the various models describing the pseudogap, the preformed Cooper pair model is a potential candidate. Therefore, we present experimental evidence for the preformed Cooper pair model by studying the pseudogap spectrum observed in the optical conductivity of a Ca10(Pt4As8)(Fe2As2)5 (Tc = 34.6 K) single crystal. We observed a clear pseudogap structure in the optical conductivity and observed its temperature dependence. In the superconducting (SC) state, one SC gap with a gap size of Δ = 26 cm-1, a scattering rate of 1/τ = 360 cm-1 and a low-frequency extra Drude component were observed. Spectral weight analysis revealed that the SC gap and pseudogap are formed from the same Drude band. This means that the pseudogap is a gap structure observed as a result of a continuous temperature evolution of the SC gap observed below Tc. This provides clear experimental evidence for the preformed Cooper pair model.

Relaxation dynamics of [Re(CO)2(bpy){P(OEt)3}2](PF6) in TEOA solvent measured by time-resolved attenuated total reflection terahertz spectroscopy.

To reveal highly efficient photocatalytic properties of an artificial photosynthesis material [Re(CO)2(bpy){P(OEt)3}2](PF6), we have directly observed the photo-induced relaxation dynamics and reductive quenching process of the photo-excited state on a photosynthesis material in Triethanolamine (TEOA) solvent as an electron donor by time-resolved attenuated total reflection spectroscopy in the terahertz (THz) region. The spectrum of the complex in TEOA has an intermolecular vibrational mode between the complex and TEOA molecules, which reflects the precursor of the reductive quenching process. The intermolecular vibrational mode has three-step relaxation process in a picosecond timescale after photo-excitation, where firstly the triplet metal-to-ligand charge transfer excited state is vibrationally cooled down, secondly the distance between Re and TEOA is reduced by the rotation of TEOA molecules due to dipole-dipole interaction accelerated by heat transfer, and finally electrons transfer from TEOA to Re. These observations provide us the detailed information of the electron transfer process of photocatalytic properties of [Re(CO)2(bpy){P(OEt)3}2](PF6) in TEOA solvent.