Cellular senescence triggers intracellular acidification and lysosomal pH alkalinized via ATP6AP2 attenuation in breast cancer cells

がん治療薬による乳がん細胞の老化とpH調整の解明 --新規細胞老化のメカニズム解明に貢献--. 京都大学プレスリリース. 2023-11-27.Several chemotherapeutic drugs induce senescence in cancer cells; however, the mechanisms underlying intracellular pH dysregulation in senescent cells remain unclear. Adenosine triphosphatase H+ transporting accessory protein 2 (ATP6AP2) plays a critical role in maintaining pH homeostasis in cellular compartments. Herein, we report the regulatory role of ATP6AP2 in senescent breast cancer cells treated with doxorubicin (Doxo) and abemaciclib (Abe). A decline in ATP6AP2 triggers aberrant pH levels that impair lysosomal function and cause immune profile changes in senescent breast cancer cells. Doxo and Abe elicited a stable senescent phenotype and altered the expression of senescence-related genes. Additionally, senescent cells show altered inflammatory and immune transcriptional profiles due to reprogramming of the senescence-associated secretory phenotype. These findings elucidate ATP6AP2-mediated cellular pH regulation and suggest a potential link in immune profile alteration during therapy-induced senescence in breast cancer cells, providing insights into the mechanisms involved in the senescence response to anticancer therapy

Thirteen-week Intravenous Toxicity Study of a Novel Humanized Anti-Human Death Receptor 5 Monoclonal Antibody, CS-1008, in Cynomolgus Monkeys

CS-1008, a humanized monoclonal antibody that is agonistic to human death receptor 5, was intravenously administered to cynomolgus monkeys twice a week for 13 weeks at 3 different dose levels (5, 15 and 42 mg/kg) in order to evaluate its potential toxicity. A control group received phosphate buffered saline containing 0.01% polysorbate 80. Each of the 4 groups consisted of 3 male and 3 female cynomolgus monkeys. No animal in any group died during the dosing period. No toxic changes in clinical signs, food consumption, body weight, electrocardiography, ophthalmology, urinalysis, hematology, blood chemistry, gross pathology, organ weights or histopathology were noted in any group during the dosing period. In the toxicokinetic analysis, the values for the maximum concentration of CS-1008 in plasma and the area under the curve generally increased with increasing dose. No clear differences in the toxicokinetic parameters or profiles were observed between the sexes. Development of anti-CS-1008 antibodies was not detected in any sample. The no-observed adverse-effect level (NOAEL) of CS-1008 in cynomolgus monkeys under the conditions of this study was concluded to be 42 mg/kg in both sexes, when administered intravenously twice a week for 13 weeks. This study supports the development of CS-1008 as a therapeutic biopharmaceutical

Alterations of circulating endothelial cell and endothelial progenitor cell counts around the ovulation.

Context:Circulating endothelial cells (CECs) and progenitor cells (CEPs) have been intensively studied as a promising tool for treating ischemic diseases and monitoring cancer treatments, but how the menstrual cycle affects the variation in their counts remains unclear. Objective:The aims of the study were to determine the influence of the menstrual cycle on the number of CECs and CEPs and to investigate the association of their counts with circulating hormones and angiogenesis-associated factors. Design:CEP and CEC counts by flow cytometry and the CellSearch system and circulating factor levels were measured eight times during the menstrual cycle in 18 volunteers. The menstrual cycle was divided into six phases based on hormone concentrations. Results:CEP counts peaked in the periovulatory and middle luteal phases with a drop in the early luteal phase. CEC counts showed no significant variation. There were significant correlations between the CEP counts and the serum concentrations of estradiol (E2), LH, and granulocyte colony-stimulating factor (G-CSF) (P < 0.0001, P < 0.0001, and P = 0.01, respectively). The difference in CEP counts between two adjacent phases was significantly correlated with that in E2, LH, G-CSF, and serum vascular endothelial growth factor (P < 0.0001, P < 0.0001, P = 0.02, and P = 0.006, respectively). Conclusion:CEP counts peaked in the periovulatory and middle luteal phases, with a drop in the early luteal phase, and were correlated with serum E2, LH, and G-CSF concentrations. Consideration of the variation in CEP counts would be important for the clinical application of CEPs

Exploring the baryonic effect signature in the Hyper Suprime-Cam Year 3 cosmic shear two-point correlations on small scales: the S8S_8 tension remains present

The baryonic feedback effect is considered as a possible solution to the so-called $S_8$ tension indicated in cosmic shear cosmology. The baryonic effect is more significant on smaller scales, and affects the cosmic shear two-point correlation functions (2PCFs) with different scale- and redshift-dependencies from those of the cosmological parameters. In this paper, we use the Hyper Suprime-Cam Year 3 (HSC-Y3) data to measure the cosmic shear 2PCFs ($\xi_{\pm}$) down to 0.28 arcminutes, taking full advantage of the high number density of source galaxies in the deep HSC data, to explore a possible signature of the baryonic effect. While the published HSC analysis used the cosmic shear 2PCFs on angular scales, which are sensitive to the matter power spectrum at $k\lesssim 1~h{\rm Mpc}^{-1}$, the smaller scale HSC cosmic shear signal allows us to probe the signature of matter power spectrum up to $k\simeq 20~h{\rm Mpc}^{-1}$. Using the accurate emulator of the nonlinear matter power spectrum, DarkEmulator2, we show that the dark matter-only model can provide an acceptable fit to the HSC-Y3 2PCFs down to the smallest scales. In other words, we do not find any clear signature of the baryonic effects or do not find a systematic shift in the $S_8$ value with the inclusion of the smaller-scale information as would be expected if the baryonic effect is significant. Alternatively, we use a flexible 6-parameter model of the baryonic effects, which can lead to both enhancement and suppression in the matter power spectrum compared to the dark matter-only model, to perform the parameter inference of the HSC-Y3 2PCFs. We find that the small-scale HSC data allow only a fractional suppression of up to 5 percent in the matter power spectrum at $k\sim 1~h{\rm Mpc}^{-1}$, which is not sufficient to reconcile the $S_8$ tension.Comment: 30 pages, 16 figure

Thermal Infrared Imaging Experiments of C-Type Asteroid 162173 Ryugu on Hayabusa2

The thermal infrared imager TIR onboard Hayabusa2 has been developed to investigate thermo-physical properties of C-type, near-Earth asteroid 162173 Ryugu. TIR is one of the remote science instruments on Hayabusa2 designed to understand the nature of a volatile-rich solar system small body, but it also has significant mission objectives to provide information on surface physical properties and conditions for sampling site selection as well as the assessment of safe landing operations. TIR is based on a two-dimensional uncooled micro-bolometer array inherited from the Longwave Infrared Camera LIR on Akatsuki (Fukuhara et al., 2011). TIR takes images of thermal infrared emission in 8 to 12 μm with a field of view of 16×12∘ and a spatial resolution of 0.05∘ per pixel. TIR covers the temperature range from 150 to 460 K, including the well calibrated range from 230 to 420 K. Temperature accuracy is within 2 K or better for summed images, and the relative accuracy or noise equivalent temperature difference (NETD) at each of pixels is 0.4 K or lower for the well-calibrated temperature range. TIR takes a couple of images with shutter open and closed, the corresponding dark frame, and provides a true thermal image by dark frame subtraction. Data processing involves summation of multiple images, image processing including the StarPixel compression (Hihara et al., 2014), and transfer to the data recorder in the spacecraft digital electronics (DE). We report the scientific and mission objectives of TIR, the requirements and constraints for the instrument specifications, the designed instrumentation and the pre-flight and in-flight performances of TIR, as well as its observation plan during the Hayabusa2 mission

QOL after RT or OP for uterine cervix cancer

This study aimed to research the post-treatment quality of life (QOL) between radiotherapy (RT)- and operation (OP)-treated early cervical cancer survivors, using separate questionnaires for physicians and patients. We administered an observational questionnaire to patients aged 20–70 years old with Stages IB1–IIB cervical cancer who had undergone RT or OP and without recurrence as outpatients for ≥6 months after treatment. We divided 100 registered patients equally into two treatment groups (n = 50 each). The average age was 53 and 44 years in the RT and OP groups, respectively. The RT group included 34 and 66% Stage I and II patients, respectively, whereas the OP group included 66 and 34% Stage I and II patients, respectively. The OP group included 58% of patients with postoperative RT. Combination chemotherapy was performed in 84 and 48% of patients in the RT and OP groups, respectively. On the physicians’ questionnaire, we observed significant differences in bone marrow suppression (RT) and leg edema (OP). On the patients’ questionnaire, significantly more patients had dysuria and leg edema in the OP group than in the RT group, and severe (Score 4–5) leg edema was significantly higher in the post-operative RT group than in the OP only group. The frequency of sexual intercourse decreased after treatment in both groups. On the patients’ questionnaire, there were no significant differences between the two groups regarding sexual activity. These findings are useful to patients and physicians for shared decision-making in treatment choices. The guidance of everyday life and health information including sexual life after treatment is important

Hyper Suprime-Cam Year 3 Results: Cosmology from Cosmic Shear Two-point Correlation Functions

We perform a blinded cosmology analysis with cosmic shear two-point correlation functions (2PCFs) measured from more than 25 million galaxies in the Hyper Suprime-Cam three-year shear catalog in four tomographic redshift bins ranging from 0.3 to 1.5. After conservative masking and galaxy selection, the survey covers 416 deg$^2$ of the northern sky with an effective galaxy number density of 15 arcmin$^{-2}$ over the four redshift bins. The 2PCFs adopted for cosmology analysis are measured in the angular range: $7.1 < \theta/{\rm arcmin} < 56.6$ for $\xi_+$ and $31.2 <\theta/{\rm arcmin} < 248$ for $\xi_-$, with a total signal-to-noise ratio of 26.6. We apply a conservative, wide, flat prior on the photometric redshift errors on the last two tomographic bins, and the relative magnitudes of the cosmic shear amplitude across four redshift bins allow us to calibrate the photometric redshift errors. With this flat prior on redshift errors, we find $\Omega_{\rm m}=0.256_{-0.044}^{+0.056}$ and $S_8\equiv \sigma_8 \sqrt{\Omega_{\rm m}/0.3}=0.769_{-0.034}^{+0.031}$ (both 68\% CI) for a flat $\Lambda$ cold dark matter cosmology. We find, after unblinding, that our constraint on $S_8$ is consistent with the Fourier space cosmic shear and the 3$\times$2pt analyses on the same HSC dataset. We carefully study the potential systematics from astrophysical and systematic model uncertainties in our fiducial analysis using synthetic data, and report no biases (including projection bias in the posterior space) greater than $0.5\sigma$ in the estimation of $S_8$. Our analysis hints that the mean redshifts of the two highest tomographic bins are higher than initially estimated. In addition, a number of consistency tests are conducted to assess the robustness of our analysis. Comparing our result with Planck-2018 cosmic microwave background observations, we find a ~$2\sigma$ tension for the $\Lambda$CDM model.Comment: 38 pages, 32 figures, 4 tables (PRD in press.

Hyper Suprime-Cam Year 3 results: Cosmology from cosmic shear two-point correlation functions

We perform a blinded cosmology analysis with cosmic shear two-point correlation functions measured from more than 25 million galaxies in the Hyper Suprime-Cam three-year shear catalog in four tomographic redshift bins ranging from 0.3 to 1.5. After conservative masking and galaxy selection, the survey covers 416 deg2 of the northern sky with an effective galaxy number density of 15 arcmin-2 over the four redshift bins. The 2PCFs adopted for cosmology analysis are measured in the angular range; 7.1&lt;θ/arcmin&lt;56.6 for ζ+ and 31.2&lt;θ/arcmin&lt;248 for ζ-, with a total signal-to-noise ratio of 26.6. We apply a conservative, wide, flat prior on the photometric redshift errors on the last two tomographic bins, and the relative magnitudes of the cosmic shear amplitude across four redshift bins allow us to calibrate the photometric redshift errors. With this flat prior on redshift errors, we find ωm=0.256-0.044+0.056 and S8σ8ωm/0.3=0.769-0.034+0.031 (both 68% C.I.) for a flat Λ cold dark matter cosmology. We find, after unblinding, that our constraint on S8 is consistent with the Fourier space cosmic shear and the 3×2 pt analyses on the same HSC dataset. We carefully study the potential systematics from astrophysical and systematic model uncertainties in our fiducial analysis using synthetic data, and report no biases (including projection bias in the posterior space) greater than 0.5σ in the estimation of S8. Our analysis hints that the mean redshifts of the two highest tomographic bins are higher than initially estimated. In addition, a number of consistency tests are conducted to assess the robustness of our analysis. Comparing our result with Planck-2018 cosmic microwave background observations, we find a ∼2σ tension for the ΛCDM model