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

Impulse Strong Mirror Field for High-Energy Particle Handlings

The technologies for generating strong magnetic flux density of 10 T ~ 1000 T have been developed and become to be utilized for fundamental science studies, especially for solid-state physics. These technologies enable to control the high-energy particles in a compact region, and explore the new frontier of nuclei conversions and nuclear fusion studies. The methods to generate strong mirror field for high-energy particle confinement and handlings are described in this paper

Japanese VLBI Network observations of radio-loud narrow-line Seyfert 1 galaxies

We performed phase-reference very long baseline interferometry (VLBI) observations on five radio-loud narrow-line Seyfert 1 galaxies (NLS1s) at 8.4 GHz with the Japanese VLBI Network (JVN). Each of the five targets (RXS J08066+7248, RXS J16290+4007, RXS J16333+4718, RXS J16446+2619, and B3 1702+457) in milli-Jansky levels were detected and unresolved in milli-arcsecond resolutions, i.e., with brightness temperatures higher than 10^7 K. The nonthermal processes of active galactic nuclei (AGN) activity, rather than starbursts, are predominantly responsible for the radio emissions from these NLS1s. Out of the nine known radio-loud NLS1s, including the ones chosen for this study, we found that the four most radio-loud objects exclusively have inverted spectra. This suggests a possibility that these NLS1s are radio-loud due to Doppler beaming, which can apparently enhance both the radio power and the spectral frequency.Comment: 8 pages, 2 figures, accepted for publication in PAS

VLBI Detections of Parsec-Scale Nonthermal Jets in Radio-Loud Broad Absorption Line Quasars

We conducted radio detection observations at 8.4 GHz for 22 radio-loud broad absorption line (BAL) quasars, selected from the Sloan Digital Sky Survey (SDSS) Third Data Release, by a very-long-baseline interferometry (VLBI) technique. The VLBI instrument we used was developed by the Optically ConnecTed Array for VLBI Exploration project (OCTAVE), which is operated as a subarray of the Japanese VLBI Network (JVN). We aimed at selecting BAL quasars with nonthermal jets suitable for measuring their orientation angles and ages by subsequent detailed VLBI imaging studies to evaluate two controversial issues of whether BAL quasars are viewed nearly edge-on, and of whether BAL quasars are in a short-lived evolutionary phase of quasar population. We detected 20 out of 22 sources using the OCTAVE baselines, implying brightness temperatures greater than 10^5 K, which presumably come from nonthermal jets. Hence, BAL outflows and nonthermal jets can be generated simultaneously in these central engines. We also found four inverted-spectrum sources, which are interpreted as Doppler-beamed, pole-on-viewed relativistic jet sources or young radio sources: single edge-on geometry cannot describe all BAL quasars. We discuss the implications of the OCTAVE observations for investigations for the orientation and evolutionary stage of BAL quasars.Comment: 10 pages, no figure, 3 tables, accepted for publication in PAS

Phase Ib/II study of nivolumab combined with palliative radiation therapy for bone metastasis in patients with HER2-negative metastatic breast cancer

Radiation therapy (RT) can enhance the abscopal effect of immune checkpoint blockade. This phase I/II study investigated the efficacy and safety of nivolumab plus RT in HER2-negative metastatic breast cancer requiring palliative RT for bone metastases. Cohort A included luminal-like disease, and cohort B included both luminal-like and triple-negative disease refractory to standard systemic therapy. Patients received 8 Gy single fraction RT for bone metastasis on day 0. Nivolumab was administered on day 1 for each 14-day cycle. In cohort A, endocrine therapy was administered. The primary endpoint was the objective response rate (ORR) of the unirradiated lesions. Cohorts A and B consisted of 18 and 10 patients, respectively. The ORR was 11% (90% CI 4–29%) in cohort A and 0% in cohort B. Disease control rates were 39% (90% CI 23–58%) and 0%. Median progression-free survival was 4.1 months (95% CI 2.1–6.1 months) and 2.0 months (95% CI 1.2–3.7 months). One patient in cohort B experienced a grade 3 adverse event. Palliative RT combined with nivolumab was safe and showed modest anti-tumor activity in cohort A. Further investigations to enhance the anti-tumor effect of endocrine therapy combined with RT plus immune checkpoint blockade are warranted

Vildagliptin Improves Glucose Tolerance and Decreases Plasma Triglycerides in Sprague-Dawley Rats

The number of patients with lifestyle-related diseases, including type 2 diabetes, is increasing. The onset of type 2 diabetes can be prevented by dietary and exercise interventions, as well as drug therapy. Dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists have attracted attention recently as treatments for diabetes, and incretin hormones have been reported to have a protective effect on pancreatic β-cells. It is not clear whether vildagliptin (VIL) can prevent the progression of lifestyle-related disease. Thus, in the present study, Sprague-Dawley rats were fed a high-fat diet with sucrose water (HFDS) to determine whether VIL could inhibit deterioration in glucose tolerance and improve other biomarkers of lipid disorder. Four-month-old male Sprague-Dawley rats were divided into three groups (n = 7 in each group); one group was fed a normal diet for 4 months, whereas the remaining two groups were fed the HFDS, with or without VIL for 4 months. When rats were 7 months of age, they were subjected to an intraperitoneal glucose tolerance test (IPGTT); biomarkers of lipid disorder were measured in 8-month-old rats. There was a decrease in the glucose spike in the IPGTT 10min after loading in the HFDS + VIL group and plasma triglyceride (TG) levels were significantly lower in these rats compared with the HFDS group. The decreased TG levels in HFDS + VIL rats were accompanied by decreases in plasma chylomicron levels. These results suggest that VIL can prophylactically inhibit decreases in pancreatic β-cell function in type 2 diabetes and reduce the risk of cardiovascular disease due to high TG levels. Thus, VIL administration may contribute to the prevention of lifestyle-related disease

異年齢集団における協働とカリキュラム・マネジメント

令和2年1月5日，於　広島大学大学院教育学研究科（広島大学東広島キャンパス）L棟205号

Evolutionary histories of breast cancer and related clones

乳がん発生の進化の歴史を解明 --ゲノム解析による発がんメカニズムの探索--. 京都大学プレスリリース. 2023-07-28.Tracking the ol' mutation trail: Unraveling the long history of breast cancer formation. 京都大学プレスリリース. 2023-08-31.Recent studies have documented frequent evolution of clones carrying common cancer mutations in apparently normal tissues, which are implicated in cancer development1, 2, 3. However, our knowledge is still missing with regard to what additional driver events take place in what order, before one or more of these clones in normal tissues ultimately evolve to cancer. Here, using phylogenetic analyses of multiple microdissected samples from both cancer and non-cancer lesions, we show unique evolutionary histories of breast cancers harbouring der(1;16), a common driver alteration found in roughly 20% of breast cancers. The approximate timing of early evolutionary events was estimated from the mutation rate measured in normal epithelial cells. In der(1;16)(+) cancers, the derivative chromosome was acquired from early puberty to late adolescence, followed by the emergence of a common ancestor by the patient’s early 30s, from which both cancer and non-cancer clones evolved. Replacing the pre-existing mammary epithelium in the following years, these clones occupied a large area within the premenopausal breast tissues by the time of cancer diagnosis. Evolution of multiple independent cancer founders from the non-cancer ancestors was common, contributing to intratumour heterogeneity. The number of driver events did not correlate with histology, suggesting the role of local microenvironments and/or epigenetic driver events. A similar evolutionary pattern was also observed in another case evolving from an AKT1-mutated founder. Taken together, our findings provide new insight into how breast cancer evolves

Optimization of prediction methods for risk assessment of pathogenic germline variants in the Japanese population

Predicting pathogenic germline variants (PGVs) in breast cancer patients is important for selecting optimal therapeutics and implementing risk reduction strategies. However, PGV risk factors and the performance of prediction methods in the Japanese population remain unclear. We investigated clinicopathological risk factors using the Tyrer-Cuzick (TC) breast cancer risk evaluation tool to predict BRCA PGVs in unselected Japanese breast cancer patients (n = 1, 995). Eleven breast cancer susceptibility genes were analyzed using target-capture sequencing in a previous study; the PGV prevalence in BRCA1, BRCA2, and PALB2 was 0.75%, 3.1%, and 0.45%, respectively. Significant associations were found between the presence of BRCA PGVs and early disease onset, number of familial cancer cases (up to third-degree relatives), triple-negative breast cancer patients under the age of 60, and ovarian cancer history (all P < .0001). In total, 816 patients (40.9%) satisfied the National Comprehensive Cancer Network (NCCN) guidelines for recommending multigene testing. The sensitivity and specificity of the NCCN criteria for discriminating PGV carriers from noncarriers were 71.3% and 60.7%, respectively. The TC model showed good discrimination for predicting BRCA PGVs (area under the curve, 0.75; 95% confidence interval, 0.69-0.81). Furthermore, use of the TC model with an optimized cutoff of TC score ≥0.16% in addition to the NCCN guidelines improved the predictive efficiency for high-risk groups (sensitivity, 77.2%; specificity, 54.8%; about 11 genes). Given the influence of ethnic differences on prediction, we consider that further studies are warranted to elucidate the role of environmental and genetic factors for realizing precise prediction