Recurrence rate of intramucosal gastric cancer with positive vertical margin due to lesion damage during endoscopic submucosal dissection.

BACKGROUND AND STUDY AIM: In principle, additional surgery is performed after endoscopic submucosal dissection for early gastric cancer if the vertical margin is positive, regardless of lesion damage. The recurrence rate of vertical margin-positive lesions due to lesion damage after endoscopic submucosal dissection is unknown, and unnecessary surgeries may be performed. In this study, we investigated whether there was a difference in the recurrence rate between vertical margin-positive lesions due to lesion damage and vertical margin-negative lesions. PATIENTS AND METHODS: We included 1,294 intramucosal gastric cancer lesions that were resected by endoscopic submucosal dissection between January 2008 and December 2016, without additional surgery. The lesions were divided into the Damage and No damage groups based on vertical margin status. The Damage group had only one non-curative indication: a positive vertical margin due to lesion damage. The No damage group had no non curative indications. We compared the recurrence rate between the Damage and No damage groups. RESULTS: The recurrence rates of the Damage and No damage groups were 0% (0/23; 95% confidence interval: 0-14.8%) and 0% (0/1,271; 95% confidence interval: 0-0.003%), respectively, with no statistically significant difference. CONCLUSIONS: In intramucosal gastric cancer, the recurrence rate of vertical margin-positive lesions due to lesion damage was 0%, which did not differ from that of vertical margin-negative lesions with curative resection. Follow-up, instead of additional surgery, may be an option for patients with non-curative resection when the only non-curative indication is a positive vertical margin due to lesion damage.

Relativistic magnetic reconnection in laser laboratory for testing an emission mechanism of hard-state black hole system.

Magnetic reconnection in a relativistic electron magnetization regime was observed in a laboratory plasma produced by a high-intensity, large energy, picoseconds laser pulse. Magnetic reconnection conditions realized with a laser-driven several kilotesla magnetic field is comparable to that in the accretion disk corona of black hole systems, i.e., Cygnus X-1. We observed particle energy distributions of reconnection outflow jets, which possess a power-law component in a high-energy range. The hardness of the observed spectra could explain the hard-state x-ray emission from accreting black hole systems.

Quantitative Modeling and Simulation in PMDA: A Japanese Regulatory Perspective.

In Japan in October 2016, the Pharmaceuticals and Medical Devices Agency (PMDA) began to receive electronic data in new drug applications (NDAs). These electronic data are useful to conduct regulatory assessment of sponsors' submissions and contribute to the PMDA's research. In this article, we summarize the number of submissions of quantitative modeling and simulation (M&S) documents in NDAs in Japan, and we describe our current thinking and activities about quantitative M&S in PMDA.

Conductance fluctuations in high mobility monolayer graphene: Nonergodicity, lack of determinism and chaotic behavior.

We have fabricated a high mobility device, composed of a monolayer graphene flake sandwiched between two sheets of hexagonal boron nitride. Conductance fluctuations as functions of a back gate voltage and magnetic field were obtained to check for ergodicity. Non-linear dynamics concepts were used to study the nature of these fluctuations. The distribution of eigenvalues was estimated from the conductance fluctuations with Gaussian kernels and it indicates that the carrier motion is chaotic at low temperatures. We argue that a two-phase dynamical fluid model best describes the transport in this system and can be used to explain the violation of the so-called ergodic hypothesis found in graphene.

Probing weak localization in chemical vapor deposition graphene wide constriction using scanning gate microscopy.

Low-temperature scanning gate microscopy (LT-SGM) studies of graphene allow one to obtain important spatial information regarding coherent transport such as weak localization (WL) and universal conductance fluctuations. Although fascinating LT-SGM results on pristine graphene prepared by mechanical exfoliation have been reported in the literature, there appears to be a dearth of LT-SGM results on chemical vapor deposition (CVD)-grown graphene whose large scale and flexible substrate transferability make it an ideal candidate for coherent electronic applications. To this end, we have performed LT-SGM studies on CVD-grown graphene wide constriction (0.8 µm), which can be readily prepared by cost-effective optical lithography fully compatible with those in wafer foundry, in the WL regime. We find that the movable local gate can sensitively modulate the total conductance of the CVD graphene constriction possibly due to the intrinsic grain boundaries and merged domains, a great advantage for applications in coherent electronics. Moreover, such a conductance modulation by LT-SGM provides an additional, approximately magnetic-field-independent probe for studying coherent transport such as WL in graphene and spatial conductance variation.

Biological index of environmental lead pollution: accumulation of lead in liver and kidney in mice.

Lead (Pb) is known to be highly poisonous, and the acute poisoning of Cd causes the abdominal pains, vomiting, and shock. The digestive and nervous symptom is observed in the chronic lead poisoning. It was also known that the defect in hemoglobin synthesis by Pb produce anemia. The release of Pb into the environment presents a source of exposure for wild animals. In this study, we examined the utility of a new Pb-monitoring index in mice administered Pb. A solution containing 0.02, 0.2, 2, or 4 ppm lead chloride (PbCl2) was administered intraperitoneally to mice, and the Pb contents of the kidney and liver were determined at designated time points. The mean Pb content of both organs increased depending on the administered Pb dosage. Although the results of control was near the detection limits, the administration of 4 ppm in 4 weeks resulted in Pb levels of 260 mg ppm/wet weight and 110 ppm wet weight in the kidney and liver, respectively. However, there were no significant relationships among administered dose, duration of Pb treatment, and liver or kidney Pb content. Then, values in all mice administered control or 0.02 mg Pb were located inside the ellipse, representing the confidence area of the new index, and values in all mice administered more than 2 mg Pb were located outside the ellipse. These results confirm that animals exposed to high concentrations of Pb would be detected by this new index.

Metal-insulator transition in the quasi-one-dimensional transport of fractional quantum Hall states.

We investigate edge state transmission in quantum point contacts (QPCs) in the fractional quantum-Hall regime, finding behavior reminiscent of a metal-insulator transition. The transition is suggested by an unusual behavior of the differential conductance in the fractional-quantum-Hall regime, and by the presence of a fixed point and universal scaling in the temperature dependence of the linear conductance. Noting that the 0.7 feature evolves continuously into a last fractional plateau at high magnetic fields, we suggest that this still unresolved feature may itself be viewed as a manifestation of a local, microscopic, metal-insulator transition.

Scanning gate imaging of a disordered quantum point contact.

Scanning gate microscopy (SGM) is a novel technique that has been used to image characteristic features related to the coherent electron flow in mesoscopic structures. For instance, SGM has successfully been applied to study peculiar electron transport properties that arise due to small levels of disorder in a system. The particular case of an InGaAs quantum well layer in a heterostructure, which is dominated by a quasi-ballistic regime, was analyzed. A quantum point contact fabricated onto this material exhibits conduction fluctuations that are not expected in typical high-mobility heterostructures such as AlGaAs/GaAs. SGM revealed not only interference patterns corresponding to specific conductance fluctuations but also mode-dependent resistance peaks corresponding to the first and second quantum levels of conductance (2e(2)/h) at zero magnetic field. On the other hand, clear conductance plateaus originating from the integer quantum Hall effect were observed at high magnetic fields. The physical size of incompressible edge channels was estimated from cross-sectional analysis of these images.

On the zero-bias anomaly and Kondo physics in quantum point contacts near pinch-off.

We investigate the linear and non-linear conductance of quantum point contacts (QPCs), in the region near pinch-off where Kondo physics has previously been connected to the appearance of the 0.7 feature. In studies of seven different QPCs, fabricated in the same high-mobility GaAs/AlGaAs heterojunction, the linear conductance is widely found to show the presence of the 0.7 feature. The differential conductance, on the other hand, does not generally exhibit the zero-bias anomaly (ZBA) that has been proposed to indicate the Kondo effect. Indeed, even in the small subset of QPCs found to exhibit such an anomaly, the linear conductance does not always follow the universal temperature-dependent scaling behavior expected for the Kondo effect. Taken collectively, our observations demonstrate that, unlike the 0.7 feature, the ZBA is not a generic feature of low-temperature QPC conduction. We furthermore conclude that the mere observation of the ZBA alone is insufficient evidence for concluding that Kondo physics is active. While we do not rule out the possibility that the Kondo effect may occur in QPCs, our results appear to indicate that its observation requires a very strict set of conditions to be satisfied. This should be contrasted with the case of the 0.7 feature, which has been apparent since the earliest experimental investigations of QPC transport.

Tuning the Fano resonance with an intruder continuum.

Through a combination of experiment and theory we establish the possibility of achieving strong tuning of Fano resonances (FRs), by allowing their usual two-path geometry to interfere with an additional, "intruder", continuum. As the coupling strength to this intruder is varied, we predict strong modulations of the resonance line shape that, in principle at least, may exceed the amplitude of the original FR itself. For a proof-of-concept demonstration of this phenomenon, we construct a nanoscale interferometer from nonlocally coupled quantum point contacts and utilize the unique features of their density of states to realize the intruder. External control of the intruder coupling is enabled by means of an applied magnetic field, in the presence of which we demonstrate the predicted distortions of the FR. This general scheme for resonant control should be broadly applicable to a variety of wave-based systems, opening up the possibility of new applications in areas such as chemical and biological sensing and secure communications.

Fast energy relaxation of hot carriers near the Dirac point of graphene.

We investigate energy relaxation of hot carriers in monolayer and bilayer graphene devices, demonstrating that the relaxation rate increases significantly as the Dirac point is approached from either the conduction or valence band. This counterintuitive behavior appears consistent with ideas of charge puddling under disorder, suggesting that it becomes very difficult to excite carriers out of these localized regions. These results therefore demonstrate how the peculiar properties of graphene extend also to the behavior of its nonequilibrium carriers.

Direct imaging of electron states in open quantum dots.

We use scanning gate microscopy to probe the ballistic motion of electrons within an open GaAs/AlGaAs quantum dot. Conductance maps are recorded by scanning a biased tip over the open quantum dot while a magnetic field is applied. We show that, for specific magnetic fields, the measured conductance images resemble the classical transmitted and backscattered trajectories and their quantum mechanical analogue. In addition, we prove experimentally, with this direct measurement technique, the existence of pointer states. The demonstrated direct imaging technique is essential for the fundamental understanding of wave function scarring and quantum decoherence theory.

Activation of the AKT/cyclin D1/Cdk4 survival signaling pathway in radioresistant cancer stem cells.

Radioresistance, which is a major cause of failure of radiotherapy (RT), is proposed as one of the intrinsic characteristics of cancer stem cells (CSCs) whose unique DNA damage response (DDR), efficient DNA repair and resistance to apoptosis are thought to confer the phenotype. We have isolated surviving CSCs by exposure to long-term fractionated radiation for 82 days from HepG2 and A172 cells (82FR-31NR cells). 82FR-31NR cells exhibited CSC properties, such as high expression of CSC marker CD133 and the ABC transporters (MDR1 and BCRP1), and high tumorigenic potential after transplantation into nude mice. The advantage of our isolated CSCs is that they can proliferate in as the same growth medium as that of parental cells without loss of CSC properties. Therefore, we can analyze DDR of non-stem cells and CSCs without any influences caused by different culture conditions. 82FR-31NR cells showed efficient DNA repair of radiation-induced DNA damage and radioresistance with activation of the AKT/cyclin D1 survival signaling pathway. In contrast, DNA damage persisted for a long time after irradiation in parental cells compared with isolated CSCs. Persisted DNA damage induced apoptosis in parental cells without activation of the AKT/cyclin D1 pathway. Therefore, inhibition of the AKT/cyclin D1 pathway by an AKT inhibitor, API-2, or cyclin D1 siRNA resulted in a loss of efficient DNA repair and radiosensitization of 82FR-31NR cells. Furthermore, knockdown of Cdk4 by its siRNA or a Cdk4 inhibitor was sufficient to suppress radioresistance of CSCs. In this study, we present a newly discovered DDR regarding the AKT/cyclin D1/Cdk4 pathway in response to radiation in CSCs. Combination of fractionated RT and reagents targeting the AKT/cyclin D1/Cdk4 pathway to eradicate CSCs would be effective therapeutic modality.

Enhancement of autophagy is a potential modality for tumors refractory to radiotherapy.

Radiotherapy is a well-established treatment for cancer. However, the existence of radioresistant cells is one of the major obstacles in radiotherapy. In order to understand the mechanism of cellular radioresistance and develop more effective radiotherapy, we have established clinically relevant radioresistant (CRR) cell lines, which continue to proliferate under daily exposure to 2 Gray (Gy) of X-rays for >30 days. X-ray irradiation significantly induced autophagic cells in parental cells, which was exiguous in CRR cells, suggesting that autophagic cell death is involved in cellular radiosensitivity. An autophagy inducer, rapamycin sensitized CRR cells to the level of parental cells and suppressed cell growth. An autophagy inhibitor, 3-methyladenine induced radioresistance of parental cells. Furthermore, inhibition of autophagy by knockdown of Beclin-1 made parental cells radioresistant to acute radiation. These suggest that the suppression of autophagic cell death but not apoptosis is mainly involved in cellular radioresistance. Therefore, the enhancement of autophagy may have a considerable impact on the treatment of radioresistant tumor.

Feasibility of endoscopic submucosal dissection: a new technique for en bloc resection of a large superficial tumor in the colon and rectum.

Endoscopic submucosal dissection (ESD) is a promising procedure that enables en bloc resection of large superficial tumors in the upper gastrointestinal tract. On the other hand, ESD in the colon and rectum is technically difficult to perform because of its anatomical features. At our institution, 137 consecutive superficial colorectal tumors larger than 20 mm in diameter in 137 patients were treated by ESD between April 2007 and October 2010, and 132 lesions were successfully resected. The average procedure time was 79.2 minutes, and the rate of en bloc resection was 89.1% (122/137). The rate of complete resection, defined as en bloc resection with tumor-free lateral and vertical margins, was 85.4% (117/137). The rate of perforation was 3.6% (5/137). Colorectal ESD achieved a high rate of en bloc resection and complete resection and is applicable in the colorectum.

Acquired radioresistance of human tumor cells by DNA-PK/AKT/GSK3beta-mediated cyclin D1 overexpression.

Recurrence is frequently associated with the acquisition of radioresistance by tumors and resulting failures in radiotherapy. We report, in this study, that long-term fractionated radiation (FR) exposures conferred radioresistance to the human tumor cells, HepG2 and HeLa with cyclin D1 overexpression. A positive feedback loop was responsible for the cyclin D1 overexpression in which constitutively active AKT was involved. AKT is known to inactivate glycogen synthase kinase-3beta (GSK3beta), which is essential for the proteasomal degradation of cyclin D1. The resulting cyclin D1 overexpression led to the forced progression of S-phase with the induction of DNA double strand breaks. Cyclin D1-dependent DNA damage activated DNA-dependent protein kinase (DNA-PK), which in turn activated AKT and inactivated GSK3beta, thus completing a positive feedback loop of cyclin D1 overproduction. Cyclin D1 overexpression led to the activation of DNA damage response (DDR) consisted of ataxia telangiectasia mutated (ATM)- and Chk1-dependent DNA damage checkpoint and homologous recombination repair (HRR). Long-term FR cells repaired radiation-induced DNA damage faster than non-FR cells. Thus, acquired radioresistance of long-term FR cells was the result of alterations in DDR mediated by cyclin D1 overexpression. Inhibition of the AKT/GSK3beta/cyclin D1/Cdk4 pathway by the AKT inhibitor, Cdk4 inhibitor or cyclin D1 targeting small interfering RNA (siRNA) suppressed the radioresistance. Present observations give a mechanistic insight for acquired radioresistance of tumor cells by cyclin D1 overexpression, and provide novel therapeutic targets for recurrent radioresistant tumors.

Regular conductance fluctuations indicative of quasi-ballistic transport in bilayer graphene.

Quasi-periodic conductance fluctuations are observed in the low-temperature magneto-conductance of a bilayer graphene sample. The quasi-periodic nature of the fluctuations is confirmed by their Fourier power spectrum, which consists of just a small number of dominant frequency components. From an experimental study of these features, which are highly reminiscent of those reported previously for ballistic semiconductor quantum dots, we suggest that they are associated with the formation of an open quantum dot in the submicron graphene sample.

A Zn(II)-glycine complex suppresses UVB-induced melanin production by stimulating metallothionein expression.

Oxidative stress caused by ultraviolet (UV) radiation generates reactive oxygen species (ROS) in the skin, induces the secretion of melanocyte growth and activating factors from keratinocytes, which results in the formation of cutaneous hyper-pigmentation. Thus, increasing the anti-oxidative ability of skin cells is expected to be a good strategy for skin-lightening cosmetics. Metallothionein (MT) is one of the stress-induced proteins and is known to exhibit a strong anti-oxidative property. We previously reported that a zinc(II) complex with glycine (Zn(II)(Gly)(2)) effectively induces MT expression in cultured human keratinocytes. To determine its potential as a new skin lightening active, we examined whether Zn(II)(Gly)(2) regulates the release of melanocyte-activating factors from UVB-irradiated keratinocytes and affects melanin production in a reconstructed human epidermal equivalent. Conditioned medium from UVB-irradiated keratinocytes accelerated melanocyte proliferation to 110%, and that increase could be prevented by pre-treatment with Zn(II)(Gly)(2). In addition, Zn(II)(Gly)(2) significantly reduced both the production of prostaglandin E(2) and proopiomelanocortin expression in UVB-irradiated keratinocytes. Zn(II)(Gly)(2) also decreased melanin production in a reconstructed human epidermal equivalent. These results indicate that MT-induction in the epidermis effectively up-regulates tolerance against oxidative stress and inhibits the secretion of melanocyte growth and activating factors from keratinocytes. Thus, Zn(II)(Gly)(2) is a good candidate as a new skin-lightening active.

Prevalence of herpes B virus genome in the trigeminal ganglia of seropositive cynomolgus macaques.

Herpes B virus infection is almost asymptomatic in macaques (Macaca spp.), which are the natural hosts of this pathogen, but is the cause of high mortality in humans. Reactivation of the latent virus in the trigeminal ganglia (TG) results in the shedding of infectious particles into the oral mucosal membrane. Saliva contaminated with the reactivated virus from the ganglia of the natural host is considered to be important for viral transmission to humans and other monkeys. In the present study, we investigated the prevalence of the herpes B virus genome in the left and right TG of seropositive asymptomatic cynomolgus macaques. The latent virus genome was detected using a polymerase chain reaction and microplate hybridization assay. We found that the virus DNA was present in one or both TG of 12 of the 30 macaques (40%) tested, with the virus being detected from both TG in five of the 12 macaques and from a single TG in the remaining seven.