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Satoshi Igawa,1 Noriko Nishinarita,1 Akira Takakura,1 Takahiro Ozawa,1 Shinya Harada,1 Seiichiro Kusuhara,1 Hideyuki Niwa,2 Shinji Hosotani,1 Hideyuki Sone,1 Yoshiro Nakahara,1,3 Tomoya Fukui,1 Hisashi Mitsufuji,4 Masanori Yokoba,5 Masaru Kubota,1 Masato Katagiri,5 Jiichiro Sasaki,6 Katsuhiko Naoki1 1Department of Respiratory Medicine, Kitasato University School of Medicine, Sagamihara 252-0374, Kanagawa, Japan; 2Department of Respiratory Medicine, National Hospital Organization Nagoya Medical Center, Nagoya 460-0001, Aichi, Japan; 3Department of Thoracic Oncology, Kanagawa Cancer Center, Yokohama 241-8515, Kanagawa, Japan; 4Kitasato University School of Nursing, Sagamihara 252-0329, Kanagawa, Japan; 5School of Allied Health Sciences, Kitasato University, Sagamihara 252-0373, Kanagawa, Japan; 6Research and Development Center for New Medical Frontiers, Kitasato University School of Medicine, Sagamihara 252-0374, Kanagawa, Japan Background: The optimal chemotherapy regimen for non-small-cell lung cancer (NSCLC) patients with interstitial lung disease (ILD) remains unknown. Therefore, in this study, we investigated the real-world efficacy and safety of carboplatin (CBDCA) plus nab-paclitaxel (nab-PTX) as a first-line regimen for NSCLC patients with ILD. Patients and methods: We retrospectively reviewed advanced NSCLC patients with ILD who had received CBDCA plus nab-PTX as a first-line chemotherapy regimen between April 2013 and March 2018. Patients were diagnosed with ILD based on the findings of a pretreatment high-resolution computed tomography of the chest. Results: The 34 patients enrolled in this study were included in the efficacy and safety analysis. Collagen vascular disease or a history of exposure to dust or asbestos was not reported for any patients. The median age of patients was 71 years (range, 59–83 years), and 32 patients had a performance status of 0 or 1. The overall response rate was 38.2%. The median progression-free survival and overall survival were 5.8 months and 12.7 months, respectively. Chemotherapy-related acute exacerbation of ILD was observed in two patients (5.7%). Other toxicities were feasible, and no treatment-related deaths occurred. Conclusion: CBDCA plus nab-PTX, as a first-line chemotherapy regimen for NSCLC, showed favorable efficacy and safety in patients with preexisting ILD. Keywords: interstitial lung disease, non-small-cell lung cancer, carboplatin, nab-paclitaxel

Yoshika Kurokawa,1 Hideko Sone,1 Tin-Tin Win-Shwe,1 Yang Zeng,1 Hiroyuki Kimura,2 Yosuke Koyama,1 Yusuke Yagi,2 Yasuto Matsui,3 Masashi Yamazaki,4 Seishiro Hirano1 1Center for Health and Environmental Risk Research, National Institute for Environmental Studies, Tsukuba, Ibaraki, 2Department of Analytical and Bioinorganic Chemistry, Kyoto Pharmaceutical University, 3Department of Environmental Engineering, Kyoto University Graduate School of Engineering, Kyoto, 4TIA Center Office, National Institute of Advanced Industrial Science and Technology, Tsukuba, Ibaraki, Japan Abstract: Dendrimers have been expected as excellent nanodevices for brain medication. An amine-terminated polyamidoamine dendrimer (PD), an unmodified plain type of PD, has the obvious disadvantage of cytotoxicity, but still serves as an attractive molecule because it easily adheres to the cell surface, facilitating easy cellular uptake. Single-photon emission computed tomographic imaging of a mouse following intravenous injection of a radiolabeled PD failed to reveal any signal in the intracranial region. Furthermore, examination of the permeability of PD particles across the blood–brain barrier (BBB) in vitro using a commercially available kit revealed poor permeability of the nanoparticles, which was suppressed by an inhibitor of caveolae-mediated endocytosis, but not by an inhibitor of macropinocytosis. Physicochemical analysis of the PD revealed that cationic PDs are likely to aggregate promptly upon mixing with body fluids and that this prompt aggregation is probably driven by non-Derjaguin–Landau–Verwey–Overbeek attractive forces originating from the surrounding divalent ions. Atomic force microscopy observation of a freshly cleaved mica plate soaked in dendrimer suspension (culture media) confirmed prompt aggregation. Our study revealed poor transfer of intravenously administered cationic PDs into the intracranial nervous tissue, and the results of our analysis suggested that this was largely attributable to the reduced BBB permeability arising from the propensity of the particles to promptly aggregate upon mixing with body fluids. Keywords: PAMAM dendrimer, nanomaterial, aggregation, blood–brain barrier

Nobumasa Ohara,1 Hiroshi Suzuki,1 Akiko Suzuki,1 Masanori Kaneko,1 Masahiro Ishizawa,1 Kazuo Furukawa,1 Takahiro Abe,1 Yasuhiro Matsubayashi,1 Takaho Yamada,1 Osamu Hanyu,1 Takayoshi Shimohata,2 Hirohito Sone1 1Department of Hematology, Endocrinology and Metabolism, Faculty of Medicine, Niigata University, Niigata, Japan; 2Department of Neurology, Brain Research Institute, Niigata University, Niigata, Japan Abstract: Endogenous Cushing’s syndrome is an endocrine disease resulting from chronic exposure to excessive glucocorticoids produced in the adrenal cortex. Although the ultimate outcome remains uncertain, functional and morphological brain changes are not uncommon in patients with this syndrome, and generally persist even after resolution of hypercortisolemia. We present an adolescent patient with Cushing’s syndrome who exhibited cognitive impairment with brain atrophy. A 19-year-old Japanese male visited a local hospital following 5 days of behavioral abnormalities, such as money wasting or nighttime wandering. He had hypertension and a 1-year history of a rounded face. Magnetic resonance imaging (MRI) revealed apparently diffuse brain atrophy. Because of high random plasma cortisol levels (28.7 µg/dL) at 10 AM, he was referred to our hospital in August 2011. Endocrinological testing showed adrenocorticotropic hormone-independent hypercortisolemia, and abdominal computed tomography demonstrated a 2.7 cm tumor in the left adrenal gland. The patient underwent left adrenalectomy in September 2011, and the diagnosis of cortisol-secreting adenoma was confirmed histologically. His hypertension and Cushingoid features regressed. Behavioral abnormalities were no longer observed, and he was classified as cured of his cognitive disturbance caused by Cushing’s syndrome in February 2012. MRI performed 8 months after surgery revealed reversal of brain atrophy, and his subsequent course has been uneventful. In summary, the young age at onset and the short duration of Cushing’s syndrome probably contributed to the rapid recovery of both cognitive dysfunction and brain atrophy in our patient. Cushing’s syndrome should be considered as a possible etiological factor in patients with cognitive impairment and brain atrophy that is atypical for their age. Keywords: Cushing’s syndrome, brain atrophy, cognitive impairment, adrenalectomy, adolescent

In support of the U.S. DOE SubTER Crosscut initiative, we established a field test facility in a deep mine and designed and carried outin situ hydraulic fracturing experiments relevant to enhanced geothermal systems (EGS) in crystalline rock to characterize the stressfield, understand the effects of rock fabric on fracturing, and gain experience in monitoring using geophysical methods. The project alsoincluded pre- and post-fracturing simulation and analysis, and laboratory measurements and experiments. The kISMET (permeability(k) and Induced Seismicity Management for Energy Technologies) site was established in the West Access Drift of the SanfordUnderground Research Facility (SURF) 4757 ft (1450 m) below ground (on the 4850 ft level (4850L)) in phyllite of the PrecambrianPoorman Formation. We drilled and continuously cored five near-vertical boreholes in a line on 3 m (10 ft) spacing, deviating the twooutermost boreholes slightly to create a five-spot pattern around the test borehole centered in the test volume 40 m below the drift invert(floor) at a total depth of ~1490 m (4890 ft). Laboratory measurements of core from the center test borehole showed P-wave velocityheterogeneity along each core indicating strong, fine-scale (~1 cm or smaller) changes in the mechanical properties of the rock. Fieldmeasurements of the stress field by hydraulic fracturing showed that the minimum horizontal stress at the kISMET site averages 21.7MPa (3146 psi) trending approximately N-S (356 degrees azimuth) and plunging slightly NNW at 12°. The vertical and horizontalmaximum stresses are similar in magnitude at 42-44 MPa (6090-6380 psi) for the depths of testing, which averaged approximately 1530m (5030 ft). Hydraulic fractures were remarkably uniform suggesting core-scale and larger rock fabric did not play a role in controllingfracture orientation. Analytical solutions suggest that the fracture radius of the large fracture (stimulation test) was more than 6 m (20ft), depending on the unknown amount of leak-off.

We investigate the influence of foliation orientation and fine-scale folding on the static and dynamic elastic properties and unconfined strength of the Poorman schist. Measurements from triaxial and uniaxial laboratory experiments reveal a significant amount of variability in the static and dynamic Young’s modulus depending on the sample orientation relative to the foliation plane. Dynamic P-wave modulus and S-wave modulus are stiffer in the direction parallel to the foliation plane as expected for transversely isotropic mediums with average Thomsen parameters values 0.133 and 0.119 for epsilon and gamma, respectively. Static Young’s modulus varies significantly between 21 and 117 GPa, and a peculiar trend is observed where some foliated sample groups show an anomalous decrease in the static Young’s modulus when the symmetry axis (x3-axis) is oriented obliquely to the direction of loading. Utilizing stress and strain relationships for transversely isotropic medium, we derive the analytical expression for Young’s modulus as a function of the elastic moduli E1, E3, ν31, and G13 and sample orientation to fit the static Young’s modulus measurements. Regression of the equation to the Young’s modulus data reveals that the decrease in static Young’s modulus at oblique symmetry axis orientations is directly influenced by a low shear modulus, G13, which we attribute to shear sliding along foliation planes during static deformation that occurs as soon as the foliation is subject to shear stress. We argue that such difference between dynamic and static anisotropy is a characteristic of near-zero porosity anisotropic rocks. The uniaxial compressive strength also shows significant variability ranging from 21.9 to 194.6 MPa across the five sample locations and is the lowest when the symmetry axis is oriented 45° or 60° from the direction of loading, also a result of shear sliding along foliation planes during static deformation.

In support of the U.S. DOE SubTER Crosscut initiative, we established a field test facility in a deep mine and designed and carried outin situ hydraulic fracturing experiments relevant to enhanced geothermal systems (EGS) in crystalline rock to characterize the stressfield, understand the effects of rock fabric on fracturing, and gain experience in monitoring using geophysical methods. The project alsoincluded pre- and post-fracturing simulation and analysis, and laboratory measurements and experiments. The kISMET (permeability(k) and Induced Seismicity Management for Energy Technologies) site was established in the West Access Drift of the SanfordUnderground Research Facility (SURF) 4757 ft (1450 m) below ground (on the 4850 ft level (4850L)) in phyllite of the PrecambrianPoorman Formation. We drilled and continuously cored five near-vertical boreholes in a line on 3 m (10 ft) spacing, deviating the twooutermost boreholes slightly to create a five-spot pattern around the test borehole centered in the test volume 40 m below the drift invert(floor) at a total depth of ~1490 m (4890 ft). Laboratory measurements of core from the center test borehole showed P-wave velocityheterogeneity along each core indicating strong, fine-scale (~1 cm or smaller) changes in the mechanical properties of the rock. Fieldmeasurements of the stress field by hydraulic fracturing showed that the minimum horizontal stress at the kISMET site averages 21.7MPa (3146 psi) trending approximately N-S (356 degrees azimuth) and plunging slightly NNW at 12°. The vertical and horizontalmaximum stresses are similar in magnitude at 42-44 MPa (6090-6380 psi) for the depths of testing, which averaged approximately 1530m (5030 ft). Hydraulic fractures were remarkably uniform suggesting core-scale and larger rock fabric did not play a role in controllingfracture orientation. Analytical solutions suggest that the fracture radius of the large fracture (stimulation test) was more than 6 m (20ft), depending on the unknown amount of leak-off.

In support of the U.S. DOE SubTER Crosscut initiative, we established a field test facility in a deep mine and designed and carried out in situ hydraulic fracturing experiments in the crystalline rock at the site to characterize the stress field, understand the effects of rock fabric on fracturing, and gain experience in monitoring using geophysical methods. The project also included pre- and post-fracturing simulation and analysis, laboratory measurements and experiments, and we conducted an extended analysis of the local stress state using previously collected data. Some of these activities are still ongoing. The kISMET (permeability (k) and Induced Seismicity Management for Energy Technologies) experiments meet objectives in SubTER’s “stress” pillar and the “new subsurface signals” pillar. The kISMET site was established in the West Access Drift of SURF 4850 ft (1478 m) below ground (on the 4850L) in phyllite of the Precambrian Poorman Formation. We drilled and cored five near-vertical boreholes in a line on 3 m spacing, deviating the two outermost boreholes slightly to create a five-spot pattern around the test borehole centered in the test volume at ~1528 m (5013 ft). Laboratory measurements of core from the center test borehole showed P-wave velocity heterogeneity along each core indicating strong, fine-scale (~1 cm or smaller) changes in the mechanical properties of the rock. The load-displacement record on the core suggests that the elastic stiffness is anisotropic. Tensile strength ranges between 3‒7.5 MPa and 5‒12 MPa. Permeability measurements are planned, as are two types of laboratory miniature hydraulic fracturing experiments to investigate the importance of rock fabric (anisotropy and heterogeneity) on near-borehole hydraulic fracture generation. Pre-fracturing numerical simulations with INL’s FALCON discrete element code predicted a fracture radius of 1.2 m for a corresponding injection volume of 1.2 L for the planned fractures, and negligible microseismicity. Field measurements of the stress field by hydraulic fracturing showed that the minimum horizontal stress at the kISMET site averages 21.7 MPa (3146 psi) pointing approximately N-S (356 degrees azimuth) and plunging slightly NNW at 12°. The vertical and horizontal maximum stress are similar in magnitude at 42-44 MPa (6090-6380 psi) for the depths of testing which averaged approximately 1530 m (5030 ft). Hydraulic fractures were remarkably uniform suggesting core-scale and larger rock fabric did not play a role in controlling fracture orientation. Monitoring using ERT and CASSM in the four monitoring boreholes, and passive seismic accelerometer-based measurements in the West Access Drift, was carried out during the generation of a larger fracture (so-called stimulation test) at a depth of 40 m below the invert. ERT was not able to detect the fracture created, nor were the accelerometers in the drift, but microseismicity was detected for first (deepest) hydraulic-fracturing stress measurement. The CASSM data have not yet been analyzed. Analytical solutions suggest fracture radius of the large fracture (stimulation test) was more than 6 m, depending on the unknown amount of leak-off. The kISMET results for stress state are consistent with large-scale mid-continent estimates of stress. Currently we are using the orientation of the stress field we determined to interpret a large number of borehole breakouts recorded in nearby boreholes at SURF to generate a more complete picture of the stress field and its variations at SURF. The efforts on the project have prompted a host of additional follow-on studies that we recommend be carried out at the kISMET site.