Inhibitory mechanisms of LAG-3–dependent T cell suppression

T cell activation is tightly regulated by both stimulatory and inhibitory co-receptors and has been a focus in the development of interventions for managing cancer or autoimmune diseases. Targeting the inhibitory co-receptors programmed cell death 1 (PD-1) and cytotoxic T lymphocyte–associated protein 4 (CTLA-4) has successfully eradicated tumors but induced immune-related adverse events in humans and mice. The beneficial and adverse effects of targeting these co-receptors highlight their importance in cancer immunity and also autoimmunity. Although the therapeutic potencies of other inhibitory co-receptors are under extensive investigation, their inhibitory mechanisms and their functional differences are not well understood. Here we analyzed the inhibitory mechanisms of lymphocyte activation gene-3 (LAG-3), another inhibitory co-receptor, by using an in vitro T cell activation system and a high-affinity anti-LAG-3 antibody that strongly interferes with the binding of LAG-3 to its ligand. We found that the expression level of LAG-3 strongly correlates with the inhibitory function of LAG-3, suggesting that LAG-3 functions as a rheostat rather than as a breaker of T cell activation. By evaluating the inhibitory capacities of various LAG-3 variants relative to their expression levels, we found that LAG-3 transduces two independent inhibitory signals through an FXXL motif in the membrane-proximal region and the C-terminal EX repeat. These motifs have not been reported previously for inhibitory co-receptors, suggesting that LAG-3 inhibits T cell activation through a nonredundant inhibitory mechanisms along with the other inhibitory co-receptors. Our findings provide a rationale for combinatorial targeting of LAG-3 and the other inhibitory co-receptors to improve cancer immunotherapy

The Optical/Near-Infrared Light Curves of SN 2002ap for the First 140 Days after Discovery

Supernova (SN) 2002ap in M74 was observed in the $UBVRIJHK$ bands for the first 40 days following its discovery (2002 January 29) until it disappeared because of solar conjunction, and then in June after it reappeared. The magnitudes and dates of peak brightness in each band were determined. While the rate of increase of the brightness before the peak is almost independent of wavelength, the subsequent rate of decrease becomes smaller with wavelength from the $U$ to the $R$ band, and is constant at wavelengths beyond $I$. The photometric evolution is faster than in the well-known ``hypernovae'' SNe~1998bw and 1997ef, indicating that SN 2002ap ejected less mass. The bolometric light curve of SN 2002ap for the full period of observations was constructed. The absolute magnitude is found to be much fainter than that of SN 1998bw, but is similar to that of SN 1997ef, which lies at the faint end of the hypernova population. The bolometric light curve at the early epochs was best reproduced with the explosion of a C+O star that ejects 2.5~M_\sun with kinetic energy $E_{\rm K}=4\times 10^{51}~{\rm ergs}$. A comparison of the predicted brightness of SN 2002ap with that observed after solar conjunction may imply that $\gamma$-ray deposition at the later epochs was more efficient than in the model. This may be due to an asymmetric explosion.Comment: 15 pages, 6 figures, quality of figure1 is reduced for smaller filesize, accepted for publication in Ap

Nebular Phase Observations of the Type Ib Supernova 2008D/X-ray Transient 080109: Side-Viewed Bipolar Explosion

We present optical spectroscopic and photometric observations of supernova (SN) 2008D, associated with the luminous X-ray transient 080109, at >300 days after the explosion (nebular phases). We also give flux measurements of emission lines from the H II region at the site of the SN, and estimates of the local metallicity. The brightness of the SN at nebular phases is consistent with the prediction of the explosion models with an ejected 56Ni mass of 0.07 Msun, which explains the light curve at early phases. The [O I] line in the nebular spectrum shows a double-peaked profile while the [Ca II] line does not. The double-peaked [O I] profile strongly indicates that SN 2008D is an aspherical explosion. The profile can be explained by a torus-like distribution of oxygen viewed from near the plane of the torus. We suggest that SN 2008D is a side-viewed, bipolar explosion with a viewing angle of > 50^{\circ} from the polar direction.Comment: 6 pages, 7 figures, Accepted for publication in Ap

Isolation and characterization of a novel 2-sec-butylphenol-degrading bacterium Pseudomonas sp. strain MS-1

A novel bacterium capable of utilizing 2-sec-butylphenol as the sole carbon and energy source, Pseudomonas sp. strain MS-1, was isolated from freshwater sediment. Within 30 h, strain MS-1 completely degraded 1.5 mM 2-sec-butylphenol in basal salt medium, with concomitant cell growth. A pathway for the metabolism of 2-sec-butylphenol by strain MS-1 was proposed on the basis of the identification of 3 internal metabolites—3-sec-butylcatechol, 2-hydroxy-6-oxo-7-methylnona-2,4-dienoic acid, and 2-methylbutyric acid—by gas chromatography-mass spectrometry analysis. Strain MS-1 degraded 2-sec-butylphenol through 3-sec-butylcatechol along a meta-cleavage pathway. Degradation experiments with various alkylphenols showed that the degradability of alkylphenols by strain MS-1 depended strongly on the position (ortho ≫ meta = para) of the alkyl substitute, and that strain MS-1 could degrade 2-alkylphenols with various sized and branched alkyl chain (o-cresol, 2-ethylphenol, 2-n-propylphenol, 2-isopropylphenol, 2-sec-butylphenol, and 2-tert-butylphenol), as well as a dialkylphenol (namely, 6-tert-butyl-m-cresol)

Psychological process from hospitalization to death among uninformed terminal liver cancer patients in Japan

BACKGROUND: Although the attitude among doctors toward disclosing a cancer diagnosis is becoming more positive, informing patients of their disease has not yet become a common practice in Japan. We examined the psychological process, from hospitalization until death, among uninformed terminal cancer patients in Japan, and developed a psychological model. METHODS: Terminal cancer patients hospitalized during the recruiting period voluntarily participated in in-depth interviews. The data were analyzed by grounded theory. RESULTS: Of the 87 uninformed participants at the time of hospitalization, 67% (N = 59) died without being informed of their diagnosis. All were male, 51–66 years of age, and all experienced five psychological stages: anxiety and puzzlement, suspicion and denial, certainty, preparation, and acceptance. At the end of each stage, obvious and severe feelings were observed, which were called "gates." During the final acceptance stage, patients spent a peaceful time with family, even talking about their dreams with family members. CONCLUSION: Unlike in other studies, the uninformed patients in this study accepted death peacefully, with no exceptional cases. Despite several limitations, this study showed that almost 70% of the uninformed terminal cancer patients at hospitalization died without being informed, suggesting an urgent need for culturally specific and effective terminal care services for cancer patients in Japan

Periodontal Tissue Regeneration Using Fibroblast Growth Factor -2: Randomized Controlled Phase II Clinical Trial

Background: The options for medical use of signaling molecules as stimulators of tissue regeneration are currently limited. Preclinical evidence suggests that fibroblast growth factor (FGF)-2 can promote periodontal regeneration. This study aimed to clarify the activity of FGF-2 in stimulating regeneration of periodontal tissue lost by periodontitis and to evaluate the safety of such stimulation. Methodology/Principal Findings: We used recombinant human FGF-2 with 3% hydroxypropylcellulose (HPC) as vehicle and conducted a randomized double-blinded controlled trial involving 13 facilities. Subjects comprised 74 patients displaying a 2- or 3-walled vertical bone defect as measured ?3 mm apical to the bone crest. Patients were randomly assigned to 4 groups: Group P, given HPC with no FGF-2; Group L, given HPC containing 0.03% FGF-2; Group M, given HPC cotaining 0.1% FGF-2; and Group H, given HPC Containing 0.3% FGF-2. Each patient underwent flap operation during which we administered 200 μL of the appropriate investigational drug to the bone defect. Before and for 36 weeks following administration, patients underwent periodontal tissue inspections and standardized radiography of the region under investigation. As a result, a significant difference (p = 0.021) in rate of increase in alveolar bone height was identified between Group P (23.92%) and Group H (58.62%) at 36 weeks. The linear increase in alveolar bone height at 36 weeks in Group P and H was 0.95 mm and 1.85 mm, respectively (p = 0.132). No serious adverse events attribute to the investigational drug were identified. Conclusions: Although no statistically significant differences were noted for gains in clinical attachment level and alveolar bone gain for FGF-2 groups versus Group P, the significant difference in rate of increase in alveolar bone height (p = 0.021) between Groups P and H at 36 weeks suggests that some efficacy could be expected from FGF-2 in stimulating regeneration of periodontal tissue in patients with periodontitis

Astronomical Distance Determination in the Space Age: Secondary Distance Indicators

The formal division of the distance indicators into primary and secondary leads to difficulties in description of methods which can actually be used in two ways: with, and without the support of the other methods for scaling. Thus instead of concentrating on the scaling requirement we concentrate on all methods of distance determination to extragalactic sources which are designated, at least formally, to use for individual sources. Among those, the Supernovae Ia is clearly the leader due to its enormous success in determination of the expansion rate of the Universe. However, new methods are rapidly developing, and there is also a progress in more traditional methods. We give a general overview of the methods but we mostly concentrate on the most recent developments in each field, and future expectations. © 2018, The Author(s)