Glioblastoma (GBM) is the most common malignant brain tumor and has “immunologically cold” features. Changing GBM to an “immunologically hot” tumor requires a strong trigger that induces initial ...immune responses in GBM. Allogeneic natural killer cells (NKCs) have gained considerable attention as promising immunotherapeutic tools against cancer, where gene-edited NKCs would result in effective anti-cancer treatment. The present study focused on the immune checkpoint molecule cytokine-inducible SH2-containing protein (CISH) as a critical negative regulator in NKCs.
We generated human primary CISH-deleted NKCs (NK dCISH) using clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9) with single guide RNA targeting genome sites on CISH coding exons. The genome-edited NKCs underwent microarray with differential expression analysis and gene set enrichment analysis (GSEA). The anti-GBM activity of the genome-edited NKCs was evaluated by apoptosis induction effects against allogeneic GBM cells and spheroids. We further detected in vivo antitumor effects using xenograft brain tumor mice.
We successfully induced human CISH-deleted NKCs (NK dCISH) by combining our specific human NKC expansion method available for clinical application and genome editing technology. CISH gene-specific guide RNA/Cas9 protein complex suppressed CISH expression in the expanded NKCs with high expansion efficacy. Comprehensive gene expression analysis demonstrated increased expression of 265 genes and decreased expression of 86 genes in the NK dCISH. Gene set enrichment analysis revealed that the enriched genes were involved in NKC effector functions. Functional analysis revealed that the NK dCISH had increased interferon (IFN) gamma and tumor necrosis factor (TNF) production. CISH deletion enhanced NKC-mediated apoptosis induction against allogeneic GBM cells and spheroids. Intracranial administration of the allogeneic NKCs prolonged the overall survival of xenograft brain tumor mice. Furthermore, the NK dCISH extended the overall survival of the mice.
The findings demonstrated the successful induction of human primary NK dCISH with CRISPR/Cas9 with efficient expansion. CISH deletion enhanced the NKC-mediated anti-tumor effects in allogeneic GBM and could be a promising immunotherapeutic alternative for patients with GBM.
Experimental studies of the collisions of heavy nuclei at relativistic energies have established the properties of the quark–gluon plasma (QGP), a state of hot, dense nuclear matter in which quarks ...and gluons are not bound into hadrons1–4. In this state, matter behaves as a nearly inviscid fluid5 that efficiently translates initial spatial anisotropies into correlated momentum anisotropies among the particles produced, creating a common velocity field pattern known as collective flow. In recent years, comparable momentum anisotropies have been measured in small-system proton–proton (p+p) and proton–nucleus (p+A) collisions, despite expectations that the volume and lifetime of the medium produced would be too small to form a QGP. Here we report on the observation of elliptic and triangular flow patterns of charged particles produced in proton–gold (p+Au), deuteron–gold (d+Au) and helium–gold (3He+Au) collisions at a nucleon–nucleon centre-of-mass energy \\sqrt {s_{{\mathrm{NN}}}\ = 200 GeV. The unique combination of three distinct initial geometries and two flow patterns provides unprecedented model discrimination. Hydrodynamical models, which include the formation of a short-lived QGP droplet, provide the best simultaneous description of these measurements.
We present new measurements of the analyzing power AN in proton-proton elastic scattering in the Coulomb-Nuclear Interference region at √s 7.7 and 21.7 GeV obtained with the polarized atomic hydrogen ...jet target at RHIC. These measurements complement our earlier results at √s 6.8 and 13.7 GeV confirming the presence of a hadronic helicity flip amplitude contribution in proton-proton elastic scattering at lower energies (√s <8 GeV) while higher energy data (√s >13 GeV) are consistent with no hadronic helicity flip contribution.
A blood isolate of Streptococcus mutans strain TW871 shows
relatively low homology with MT8148, a reference oral isolate strain, and lacks the
serotype-specific polysaccharide antigen, suggesting ...that other cell-surface
structures correlate with cariogenicity. We compared cariogenicity of TW871 with
MT8148 (serotype c) and blood isolate TW964 (serotype
f) in rats. Strain TW871 showed significantly lower cariogenicity
than MT8148 or TW964 and expressed significantly lower sucrose-independent cellular
adhesion to saliva-coated hydroxyapatite and dextran-binding activity than strain
MT8148. Strains TW871 and TW964 showed a defect in the gbpA gene by
Southern hybridization analysis, while sequencing analysis revealed
gbpC variation in TW871. These results suggest that variation in
GbpC may alter cellular adherence properties and can be correlated with the
cariogenicity of S. mutans in this strain.
Purpose
We developed a short-interval, low-intensity, slow-jogging (SJ) program consisting of sets of 1 min of SJ at walking speed and 1 min of walking. We aimed to examine the effects of an easily ...performed SJ program on skeletal muscle, fat infiltration, and fitness in older adults.
Methods
A total of 81 community-dwelling, independent, older adults (70.8 ± 4.0 years) were randomly assigned to the SJ or control group. The SJ group participants were encouraged to perform 90 min of SJ at their anaerobic threshold (AT) intensity and 90 min of walking intermittently per week. Aerobic capacity at the AT and sit-to-stand (STS) scores were measured. Intracellular water (ICW) in the legs was assessed by segmental multi-frequency bioelectrical impedance analysis. Subcutaneous (SAT) and intermuscular (IMAT) adipose tissue and muscle cross-sectional area (CSA) were measured at the mid-thigh using computed tomography.
Results
A total of 75 participants (37 SJ group, 38 controls) completed the 12-week intervention. The AT and STS improved in the SJ group compared with the controls (AT 15.7 vs. 4.9 %,
p
< 0.01; STS 12.9 vs. 4.5 %,
p
< 0.05). ICW in the upper leg increased only in the SJ group (9.7 %,
p
< 0.05). SAT and IMAT were significantly decreased only in the SJ group (
p
< 0.01).
Conclusion
The 12-week SJ program was easily performed by older adults with low skeletal muscle mass, improved aerobic capacity, muscle function, and muscle composition in older adults.
The purpose of this study was to examine characteristic profiles of Streptococcus pyogenes clinical isolates isolated in Japan during 1994–9. Genotyping of the M protein (emm typing) revealed that ...emm types 12 and 28 were the most common among 316 isolates. Most of the emm12 isolates were isolated from mucosa, while emm58 and emm89 were from skin. Moreover, the emm3 isolates were dominant in invasive infections. The distribution of 6 superantigen genes showed that all isolates harboured the mf gene and many had the speG gene. Invasive isolates were shown to have the ssa gene at a higher rate (76%) than noninvasive (37%). The distribution of superantigens was significantly different between emm types, but not between isolation sites. These results suggest that the distribution of emm types is related to isolation site, whereas superantigen distribution is related to clinical features of S. pyogenes infections.
This study aimed to ascertain if performance on the Timed Up and Go (TUG) test is associated with indicators of brain volume and cognitive functions among community-dwelling older adults with normal ...cognition or mild cognitive impairment.
Participants were 80 community-dwelling older adults aged 65–89years (44 men, 36 women), including 20 with mild cognitive impairment. Participants completed the TUG and a battery of cognitive assessments, including the Mini-Mental State Examination (MMSE), the Logical Memory I and II (LM-I, LM-II) subtests of the Wechsler Memory Scale-Revised; and the Trail Making Test A and B (TMT-A, TMT-B). Bilateral, right- and left-side medial temporal area atrophy as well as whole gray and white matter indices were determined with the Voxel-based Specific Regional Analysis System for Alzheimer's Disease. We divided participants into three groups based on TUG performance: “better” (≤6.9s); “normal” (7–10s); and “poor” (≥10.1s).
Worse TMT-A and TMT-B performance showed significant independent associations with worse TUG performance (P<0.05, P<0.01 for trend, respectively). After adjusting for covariates, severe atrophy of bilateral, right-, and left-side medial temporal areas were significantly independently associated with worse TUG performance (P<0.05 for trend). However, no significant associations were found between MMSE, LM-I, LM-II, whole gray and white matter indices, and TUG performance.
Worse TUG performance is related to poor performance on TMT-A and TMT-B, and is independently associated with severe medial temporal area atrophy in community-dwelling older adults.
•Worse TUG performance was significantly associated with severe brain atrophy.•This association remained after adjusting for cognitive functions and gait speed.•TUG may be a beneficial test associated with brain atrophy and cognitive impairment.
Previously, we isolated and characterized a new Streptococcus mutans strain (serotype k) from human blood and oral cavity samples, and found that the serological properties of serotype k strains were ...similar to those of a gluA-inactivated mutant strain of MT8148 (MT8148GD). MT8148GD showed significantly lower sucrose-dependent adhesion to glass surfaces, sucrose-independent adhesion to saliva-coated hydroxyapatite, dextran-binding activity, and cell-associated glucosyltransferase (GTF) activity than the parent strain. Further, Western blot analysis revealed reduced GTFB and GTFC expression in serotype k strains as compared to MT8148, though the caries-inducing activities of MT8148GD and a serotype k oral isolate in rats were similar to that of MT8148. We conclude that a glucose side-chain defect in the serotype-specific polysaccharide of S. mutans may be associated with its cariogenicity, though to a lesser extent than its other major surface proteins.
We present azimuthal angular correlations between charged hadrons and energy deposited in calorimeter towers in central d+Au and minimum bias p+p collisions at sNN=200 GeV. The charged hadron is ...measured at midrapidity |eta|<0.35, and the energy is measured at large rapidity (-3.7<eta< -3.1, Au-going direction). An enhanced near-side angular correlation across | Delta eta|>2.75 is observed in d+Au collisions. Using the event plane method applied to the Au-going energy distribution, we extract the anisotropy strength v2 for inclusive charged hadrons at midrapidity up to pT=4.5 GeV/c. We also present the measurement of v2 for identified pi+ or - and (anti)protons in central d+Au collisions, and observe a mass-ordering pattern similar to that seen in heavy-ion collisions. These results are compared with viscous hydrodynamic calculations and measurements from p+Pb at sNN=5.02 TeV. The magnitude of the mass ordering in d+Au is found to be smaller than that in p+Pb collisions, which may indicate smaller radial flow in lower energy d+Au collisions.
Background/aims: Bacterial infection is a major cause of periapical periodontitis. Eradication of these microorganisms from apical lesions is essential to the success of endodontic treatment. The ...aim of this study was to clarify the molecular interaction between Fusobacterium nucleatum, Porphyromonas gingivalis and other microorganisms associated with periapical periodontitis.
Methods: Microorganisms isolated from periapical lesions were inoculated into type‐I collagen‐coated polystyrene microtiter plates and maintained at 37°C under anaerobic conditions for 2 days, after which, the quantity of organized biofilm on the plates was evaluated by crystal violet staining. Growth enhancement via soluble factor was evaluated by separated coculture using a 0.4‐μm membrane filter.
Results: F. nucleatum exhibited strong adherence to type‐I collagen‐coated polystyrene microplates. Biofilm formation by F. nucleatum was significantly enhanced by P. gingivalis. It was complemented by compartmentalized coculture with P. gingivalis. Enhancement of biofilm formation by P. gingivalis was only slightly reduced by inactivation of its autoinducer‐2‐producing gene luxS.
Conclusion: The results suggest that P. gingivalis enhances biofilm formation by F. nucleatum by releasing diffusible signaling molecules other than autoinducer‐2.
PDF
