Midkine promoter-based conditionally replicative adenovirus therapy for midkine-expressing human pancreatic cancer

<p>Abstract</p> <p>Background</p> <p>To develop a novel therapeutic strategy for human pancreatic cancer using a midkine promoter-based conditionally replicating adenovirus.</p> <p>Methods</p> <p>We examined midkine mRNA expression and midkine protein expression by seven human pancreatic cancer cell lines (AsPC-1, BxPC-3, CFPAC-1, HPAC, MIAPaCa-2, PANC-1, and Suit-2), as well as by non-cancerous pancreatic tissue and pancreatic cancers. Midkine promoter activity was measured in cancer cell lines by the dual luciferase reporter assay. Adenoviral transduction efficiency was assessed by fluorescent staining of cancer cell lines using adenovirus type 5 containing the green fluorescent protein gene (Ad5GFP). Replication of adenovirus type 5 containing the 0.6 kb midkne promoter (Ad5MK) was assessed by the detection of E1 protein in cancer cell lines. The cytotoxicity of Ad5MK for cancer cells was evaluated from the extent of growth inhibition after viral infection. Infection and replication were also assessed in nude mice with subcutaneous Suit-2 tumors by intratumoral injection of Ad5MK, Ad5GFP, or vehicle. E1a mRNA expression in the treated tumors and expression of the replication-specific adenoviral hexon protein were evaluated. Finally, the anti-tumor activity of Ad5MK against intraperitoneal xenografts of Suit-2 pancreatic cancer cells was examined after intraperitoneal injection of the virus.</p> <p>Results</p> <p>Both midkine mRNA expression and midkine protein expression were strong in AsPC-1 and CFPAC-1 cell liens, moderate in BxPC-3, HPAC, and Suit-2 cell lines, and weak in PANC-1 and MIAPaCa-2 cell lines. Expression of midkine mRNA was significantly stronger in pancreatic cancers than in non-cancerous pancreatic tissues. The relative luciferase activity mediated by the 0.6 kb midkne fragment in AsPC-1, PANC-1, and Suit-2 cell lines was approximately 6 to 20 times greater than that in midkne-negative MIAPaCa-2 cell lines. Pancreatic cancer cell lines exhibited a heterogeneous adenoviral transduction profile. E1A expression was higher in cell lines with strong midkine expression than in cell lines with weak midkine expression. Ad5MK showed much greater cytotoxicity for midkine-expressing Suit-2 and PANC-1 cell lines than for midkine-negative MIAPaCa-2 cell lines. In the Suit-2 subcutaneous xenograft model, expression of E1A was detected in Ad5MK-treated tumors, but not in untreated and Ad5GFP-treated tumors. In the Suit-2 intraperitoneal xenograft model, the Ad5MK group survived for significantly longer than the Ad5GFP, PBS, and untreated groups.</p> <p>Conclusion</p> <p>Ad5MK has an anti-tumor effect against human pancreatic cancer cell lines that express midkine mRNA. Midkine promoter-based conditionally replicative adenovirus might be a promising new gene therapy for pancreatic cancer.</p

Spectral evolution of GRB 060904A observed with Swift and Suzaku -- Possibility of Inefficient Electron Acceleration

We observed an X-ray afterglow of GRB 060904A with the Swift and Suzaku satellites. We found rapid spectral softening during both the prompt tail phase and the decline phase of an X-ray flare in the BAT and XRT data. The observed spectra were fit by power-law photon indices which rapidly changed from $\Gamma = 1.51^{+0.04}_{-0.03}$ to $\Gamma = 5.30^{+0.69}_{-0.59}$ within a few hundred seconds in the prompt tail. This is one of the steepest X-ray spectra ever observed, making it quite difficult to explain by simple electron acceleration and synchrotron radiation. Then, we applied an alternative spectral fitting using a broken power-law with exponential cutoff (BPEC) model. It is valid to consider the situation that the cutoff energy is equivalent to the synchrotron frequency of the maximum energy electrons in their energy distribution. Since the spectral cutoff appears in the soft X-ray band, we conclude the electron acceleration has been inefficient in the internal shocks of GRB 060904A. These cutoff spectra suddenly disappeared at the transition time from the prompt tail phase to the shallow decay one. After that, typical afterglow spectra with the photon indices of 2.0 are continuously and preciously monitored by both XRT and Suzaku/XIS up to 1 day since the burst trigger time. We could successfully trace the temporal history of two characteristic break energies (peak energy and cutoff energy) and they show the time dependence of $\propto t^{-3} \sim t^{-4}$ while the following afterglow spectra are quite stable. This fact indicates that the emitting material of prompt tail is due to completely different dynamics from the shallow decay component. Therefore we conclude the emission sites of two distinct phenomena obviously differ from each other.Comment: 19 pages, 9 figures, accepted for publication in PASJ (Suzaku 2nd Special Issue

Squamous cell carcinoma initially occurring on the tongue dorsum: a case series report with molecular analysis

Ono Sawako, Hirose Katsutoshi, Sukegawa Shintaro, et al. Squamous cell carcinoma initially occurring on the tongue dorsum: a case series report with molecular analysis. Diagnostic Pathology 19, 63 (2024); https://doi.org/10.1186/s13000-024-01487-0.Background: Squamous cell carcinoma (SCC) of the dorsum of the tongue is extremely rare, and it clinically resembles various benign lesions. Somatic mutations in TP53 and some driver genes were implicated in the development of SCC; however, the somatic genetic characteristics of dorsal tongue SCC remain unknown. With a detailed analysis of gene mutations in dorsal tongue SCC, we aimed to better understand its biology. Methods: Four cases of SCC initially occurring on the tongue dorsum were evaluated for clinical and histological findings and immunohistochemical expression of p53 and p16. Gene mutations were analyzed using next-generation sequencing with a custom panel of driver genes.Results: We retrospectively investigated 557 cases of tongue SCC, and only four cases of SCC initially occurred on the tongue dorsum. The four patients (cases 1–4) were one woman and three men with a mean age of 53.75 years (range: 15–74 years). Histological analysis revealed well-differentiated SCC. Through molecular analysis, we identified pathogenic somatic mutations, namely, TP53 p.C176F (c.527G > T) in case 3 and TP53 p.R282W (c.844 C > T) in case 4. No pathogenic variants were identified in the PI3K/AKT or RAS/RAF pathways. The p53 immunohistochemical examination revealed a wild-type expression pattern in cases 1–3 and strong expression in case 4. The results of p16 immunostaining were negative in all cases. Conclusions: We described four previously unreported genetic characteristics of dorsal tongue SCC. Somatic TP53 mutations may contribute to the development of a subset of dorsal tongue SCC; however, more cases with genetic analysis need to be accumulated

VERTECS: 6U CubeSat Mission to Study Star-Formation History by Observation of Visible Extragalactic Background Light

We describe an astronomical 6U CubeSat mission VERTECS (Visible Extragalactic background RadiaTion Exploration by CubeSat). The scientific purpose of VERTECS is to reveal star-formation history of the universe by observation of the extragalactic background light (EBL) in visible wavelengths. Earlier observations by sounding rockets and infrared astronomical satellites have shown that the near-infrared EBL is several times brighter than the integrated light of known galaxies. As candidates for the excess light, first-generation stars in the early universe or low-redshift intra-halo light have been proposed, but it has not been concluded. Since these objects are expected to show different emission spectra in visible wavelengths, precise visible observation is important to reveal the origin of excess light. Since detection sensitivity of the EBL is determined by the product of telescope aperture and field of view, a small wide-field telescope system enables the EBL observation with high sensitivity. In VERTECS mission, we develop a 6U CubeSat equipped with a 3U size telescope optimized for observation of visible EBL. The telescope is composed of lens optics and a CMOS sensor of 3k times 3k array format, which is designed to observe the sky in four photometric bands in 400-800nm. The satellite bus is composed of on-board computer (OBC), electric power system (EPS), communication (COM), attitude determination and control system (ACDS), and thermal structure. Design of OBC and EPS is based on heritage of CubeSats developed at Kyushu Institute of Technology, but deployable solar array wings is added to EPS to supply sufficient power to the VERTECS subsystems. In COM system, S-band is used for command uplink and X-band is used for high-speed downlink of large-size images captured by the telescope. Since the EBL measurement need discrimination of the background light from discrete foreground stars, VERTECS requires 10 arcseconds pointing stability (1 sigma) over 1 minute exposure. In 2022, VERTECS was selected for JAXA-Small Satellite Rush Program (JAXA-SMASH Program), a new program that encourages universities, private companies and JAXA to collaborate to realize small satellite missions utilizing commercial small launch opportunities, and to diversify transportation services in Japan. We have been working on functionality and interface teast using Bread Board Model (BBM), and enviroonmental tests by using the satellite structure thermal model. Launch of the satellite is planned in FY2025. We aim at developing the satellite and obtaining scientific results much more quickly than recent large astronomical-satellite missions

Forward-central two-particle correlations in p-Pb collisions at root s(NN)=5.02 TeV

Two-particle angular correlations between trigger particles in the forward pseudorapidity range (2.5 2GeV/c. (C) 2015 CERN for the benefit of the ALICE Collaboration. Published by Elsevier B. V.Peer reviewe

Event-shape engineering for inclusive spectra and elliptic flow in Pb-Pb collisions at root(NN)-N-S=2.76 TeV

Peer reviewe

Nationwide surveillance of bacterial respiratory pathogens conducted by the surveillance committee of Japanese Society of Chemotherapy, the Japanese Association for Infectious Diseases, and the Japanese Society for Clinical Microbiology in 2010: General view of the pathogens\u27 antibacterial susceptibility

The nationwide surveillance on antimicrobial susceptibility of bacterial respiratory pathogens from patients in Japan, was conducted by Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases and Japanese Society for Clinical Microbiology in 2010.The isolates were collected from clinical specimens obtained from well-diagnosed adult patients with respiratory tract infections during the period from January and April 2010 by three societies. Antimicrobial susceptibility testing was conducted at the central reference laboratory according to the method recommended by Clinical and Laboratory Standard Institutes using maximum 45 antibacterial agents.Susceptibility testing was evaluable with 954 strains (206 Staphylococcus aureus, 189 Streptococcus pneumoniae, 4 Streptococcus pyogenes, 182 Haemophilus influenzae, 74 Moraxella catarrhalis, 139 Klebsiella pneumoniae and 160 Pseudomonas aeruginosa). Ratio of methicillin-resistant S.aureus was as high as 50.5%, and those of penicillin-intermediate and -resistant S.pneumoniae were 1.1% and 0.0%, respectively. Among H.influenzae, 17.6% of them were found to be β-lactamase-non-producing ampicillin (ABPC)-intermediately resistant, 33.5% to be β-lactamase-non-producing ABPC-resistant and 11.0% to be β-lactamase-producing ABPC-resistant strains. Extended spectrum β-lactamase-producing K.pneumoniae and multi-drug resistant P.aeruginosa with metallo β-lactamase were 2.9% and 0.6%, respectively.Continuous national surveillance of antimicrobial susceptibility of respiratory pathogens is crucial in order to monitor changing patterns of susceptibility and to be able to update treatment recommendations on a regular basis

Elliptic flow of muons from heavy-flavour hadron decays at forward rapidity in Pb-Pb collisions at root s(NN)=2.76TeV

The elliptic flow, v(2), of muons from heavy-flavour hadron decays at forward rapidity (2.5 <y <4) is measured in Pb-Pb collisions at root s(NN)= 2.76TeVwith the ALICE detector at the LHC. The scalar product, two- and four-particle Q cumulants and Lee-Yang zeros methods are used. The dependence of the v(2) of muons from heavy-flavour hadron decays on the collision centrality, in the range 0-40%, and on transverse momentum, p(T), is studied in the interval 3 <p(T)<10 GeV/c. A positive v(2) is observed with the scalar product and two-particle Q cumulants in semi-central collisions (10-20% and 20-40% centrality classes) for the p(T) interval from 3 to about 5GeV/c with a significance larger than 3 sigma, based on the combination of statistical and systematic uncertainties. The v(2) magnitude tends to decrease towards more central collisions and with increasing pT. It becomes compatible with zero in the interval 6 <p(T)<10 GeV/c. The results are compared to models describing the interaction of heavy quarks and open heavy-flavour hadrons with the high-density medium formed in high-energy heavy-ion collisions. (C) 2015 CERN for the benefit of the ALICE Collaboration. Published by Elsevier B.V.Peer reviewe