Path Integral over Reparametrizations: Levy Flights versus Random Walks

We investigate the properties of the path integral over reparametrizations (= the boundary value of the Liouville field in open string theory). Discretizing the path integral, we apply the Metropolis-Hastings algorithm to numerical simulations of a proper (subordinator) stochastic process and find that typical trajectories are not Brownian but rather have discontinuities of the type of Levy's flights. We study a fractal structure of these trajectories and show that their Hausdorff dimension is zero. We confirm thereby the discretization and heuristic consideration of QCD scattering amplitudes by analytical and numerical calculations. We also perform Monte Carlo simulations of the path integral over reparametrization in the effective-string ansatz for a circular Wilson loop and discuss their subtleties associated with the discretization of Douglas' functional.Comment: 22pp., RevTex, 9 figures; v2: sect.IV modified; v3: minor changes, to appear in Nucl. Phys.

Gel-Free 3D Tumoroids with Stem Cell Properties Modeling Drug Resistance to Cisplatin and Imatinib in Metastatic Colorectal Cancer

Researchers have developed several three-dimensional (3D) culture systems, including spheroids, organoids, and tumoroids with increased properties of cancer stem cells (CSCs), also called cancer-initiating cells (CICs). Drug resistance is a crucial issue involving recurrence in cancer patients. Many studies on anti-cancer drugs have been reported using 2D culture systems, whereas 3D cultured tumoroids have many advantages for assessing drug sensitivity and resistance. Here, we aimed to investigate whether Cisplatin (a DNA crosslinker), Imatinib (a multiple tyrosine kinase inhibitor), and 5-Fluorouracil (5-FU: an antimetabolite) alter the tumoroid growth of metastatic colorectal cancer (mCRC). Gene expression signatures of highly metastatic aggregative CRC (LuM1 cells) vs. low-metastatic, non-aggregative CRC (Colon26 and NM11 cells) were analyzed using microarray. To establish a 3D culture-based multiplexing reporter assay system, LuM1 was stably transfected with the Mmp9 promoter-driven ZsGreen fluorescence reporter gene, which was designated as LuM1/m9 cells and cultured in NanoCulture Plate®, a gel-free 3D culture device. LuM1 cells highly expressed mRNA encoding ABCG2 (a drug resistance pump, i.e., CSC/CIC marker), other CSC/CIC markers (DLL1, EpCAM, podoplanin, STAT3/5), pluripotent stem cell markers (Sox4/7, N-myc, GATA3, Nanog), and metastatic markers (MMPs, Integrins, EGFR), compared to the other two cell types. Hoechst efflux stem cell-like side population was increased in LuM1 (7.8%) compared with Colon26 (2.9%), both of which were markedly reduced by verapamil treatment, an ABCG2 inhibitor. Smaller cell aggregates of LuM1 were more sensitive to Cisplatin (at 10 μM), whereas larger tumoroids with increased ABCG2 expression were insensitive. Notably, Cisplatin (2 μM) and Imatinib (10 μM) at low concentrations significantly promoted tumoroid formation (cell aggregation) and increased Mmp9 promoter activity in mCRC LuM1/m9, while not cytotoxic to them. On the other hand, 5-FU significantly inhibited tumoroid growth, although not completely. Thus, drug resistance in cancer with increased stem cell properties was modeled using the gel-free 3D cultured tumoroid system. The tumoroid culture is useful and easily accessible for the assessment of drug sensitivity and resistance

A First View of the Effect of a Trial of Early Mobilization on the Muscle Strength and Activities of Daily Living in Mechanically Ventilated Patients With COVID-19

Objective: To retrospectively investigate the effect of early mobilization on the muscle strength and activities of daily living in patients with COVID-19 under mechanical ventilation. Design: This was a single-center, retrospective, observational study. Setting: Inpatient rehabilitation care in Japan. Participants: The study subjects were divided based on the onset of mobilization: under mechanical ventilation (n=17; aged 68.5±11.9, 13 male) and after extubation (n=11; aged 59.7±7.1, 6 male; N=28). Interventions: Mobilization, including dangle sitting, standing, walking, and muscle strengthening exercises. Main Outcome Measures: The outcome measures were Barthel Index, Medical Research Council Manual Muscle Test, and intensive care unit Mobility Scale. Results: The difference in the Barthel Index, Medical Research Council Manual Muscle Test, and intensive care unit Mobility Scale scores pre- and postintervention were not statistically significant between the 2 groups, but all significantly improved after the intervention. Conclusion: This small sample size study found no difference in the functional recovery of patients with severe COVID-19 who underwent early mobilization under mechanical ventilation relative to when it was begun after extubation

Depletion of Lipid Efflux Pump ABCG1 Triggers the Intracellular Accumulation of Extracellular Vesicles and Reduces Aggregation and Tumorigenesis of Metastatic Cancer Cells

The ATP-binding cassette transporter G1 (ABCG1) is a cholesterol lipid efflux pump whose role in tumor growth has been largely unknown. Our transcriptomics revealed that ABCG1 was powerfully expressed in rapidly metastatic, aggregative colon cancer cells, in all the ABC transporter family members. Coincidently, genetic amplification of ABCG1 is found in 10–35% of clinical samples of metastatic cancer cases. Expression of ABCG1 was further elevated in three-dimensional tumoroids (tumor organoids) within stemness-enhancing tumor milieu, whereas depletion of ABCG1 lowered cellular aggregation and tumoroid growth in vitro as well as hypoxia-inducible factor 1α in cancer cells around the central necrotic areas in tumors in vivo. Notably, depletion of ABCG1 triggered the intracellular accumulation of extracellular vesicles (EVs) and regression of tumoroids. Collectively, these data suggest that ABCG1 plays a crucial role in tumorigenesis in metastatic cancer and that depletion of ABCG1 triggers tumor regression with the accumulation of EVs and their derivatives and cargos, implicating a novel ABCG1-targeting therapeutic strategy by which redundant and toxic substances may be accumulated in tumors leading to their regression

Basic Study to Review Whether Dietary Modifications for the Repression of the Body-fat Accumulation, Muscle-mass Loss and Bone Mineral Density （BMD） Loss in Postmenopausal Women: Effects of Dietary Amino Acid Supplements to the Diet on Muscle-mass, Femoral Bone Mineral Density and Running Activity of the Ovariectomized Adult Rats under Food-restriction

The present study aims to review whether dietary modifications will prevent body fat accumulation, muscle mass wasting and bone mineral density loss in postmenopausal women who incorporate physical exercise into daily life. 9-week-old ovariectomized Wistar strain female rats were divided into four groups: CA-Ex, Gln-Ex, Leu-Ex and CitD-Ex. Depending on which group they were in, the rats were given a 20％ casein protein based experimental diet supplemented with nothing （control diet, CA-Ex）; 5％ of L-glutamine （Gln-Ex）; 5％ of L-leucine （Leu-Ex）; or 2.5％ of L-citrulline＋2.5％ of D-serine （CitD-Ex）, each 11 g per day for 10 weeks. All of these rats were housed in individual cage with a running wheel for 10 weeks. A sham operation was carried out on another group of rats （Sham） and were given the same diet as CA-Ex, the control diet. Results were as follows: 1） Uterus weights of the ovariectomized rats, that is group CA-Ex, Gln-Ex, Leu-Ex and CitD-Ex, appeared to show lower values than that of the group Sham. 2） No significant differences were observed in a）changes in body weight, b）blood analyses, c）liver, kidney, uterus and muscle weights, and d）femoral-bone mineral density in groups Gln-Ex, Leu-Ex, and CitD-Ex as compared to the group CA-Ex. 3） Relatively higher running activity was observed in group CitD-Ex than that of group CA-Ex. This observation suggests that increasing dietary L-citrulline plus D-serine in postmenopausal rats may lead to an increase in physical activity. Further research is needed to understand the physiological and nutritional significance of the unexpected results that dietary amino acid may accelerate the physical activity.departmental bulletin pape

The Combination of ATM and Chk1 Inhibitors Induces Synthetic Lethality in Colorectal Cancer Cells

Genetic abnormalities induce the DNA damage response (DDR), which enables DNA repair at cell cycle checkpoints. Although the DDR is thought to function in preventing the onset and progression of cancer, DDR-related proteins are also thought to contribute to tumorigenesis, tumor progression, and drug resistance by preventing irreparable genomic abnormalities from inducing cell death. In the present study, the combination of ataxia telangiectasia-mutated serine/threonine kinase (ATM) and checkpoint kinase 1 (Chk1) inhibition exhibited synergistic antitumor effects and induced synergistic lethality in colorectal cancer cells at a low dose. The ATM and Chk1 inhibitors synergistically promoted the activation of cyclin-dependent kinase 1 by decreasing the phosphorylation levels of T14 and Y15. Furthermore, the combined treatment increased the number of sub-G1-stage cells, phospho-histone H2A.X-positive cells, and TdT-mediated dUTP nick-end labeling-positive cells among colon cancer cells, suggesting that the therapy induces apoptosis. Finally, the combined treatment exhibited a robust antitumor activity in syngeneic tumor model mice. These findings should contribute to the development of new treatments for colorectal cancer that directly exploit the genomic instability of cancer cells