A novel interplay between the Fanconi anemia core complex and ATR-ATRIP kinase during DNA cross-link repair.

When DNA replication is stalled at sites of DNA damage, a cascade of responses is activated in the cell to halt cell cycle progression and promote DNA repair. A pathway initiated by the kinase Ataxia teleangiectasia and Rad3 related (ATR) and its partner ATR interacting protein (ATRIP) plays an important role in this response. The Fanconi anemia (FA) pathway is also activated following genomic stress, and defects in this pathway cause a cancer-prone hematologic disorder in humans. Little is known about how these two pathways are coordinated. We report here that following cellular exposure to DNA cross-linking damage, the FA core complex enhances binding and localization of ATRIP within damaged chromatin. In cells lacking the core complex, ATR-mediated phosphorylation of two functional response targets, ATRIP and FANCI, is defective. We also provide evidence that the canonical ATR activation pathway involving RAD17 and TOPBP1 is largely dispensable for the FA pathway activation. Indeed DT40 mutant cells lacking both RAD17 and FANCD2 were synergistically more sensitive to cisplatin compared with either single mutant. Collectively, these data reveal new aspects of the interplay between regulation of ATR-ATRIP kinase and activation of the FA pathway

ベタヒスチンが一側内耳破壊後のラットの前庭代償に与える影響

Background: Vestibular compensation (VC) after unilateral labyrinthectomy (UL) consists of the initial and late processes. These processes can be evaluated based on the decline in the frequency of spontaneous nystagmus (SN) and the number of MK801-induced Fos-positive neurons in the contralateral medial vestibular nucleus (contra-MVe) in rats. Histamine H3 receptors (H3R) are reported to be involved in the development of VC. Objective: We examined the effects of betahistine, an H3R antagonist, on the initial and late processes of VC in UL rats. Methods: Betahistine dihydrochloride was continuously administered to the UL rats at doses of 100 and 200 mg/kg/day using an osmotic minipump. MK801 (1.0 mg/kg) was intraperitoneally administered on days 7, 10, 12, and 14 after UL, while Fos-positive neurons were immunohistochemically stained in the contra-MVe. Results: The SN disappeared after 42 h, and continuous infusion of betahistine did not change the decline in the frequency of SN. The number of MK801-induced Fos-positive neurons in contra-MVe significantly decreased on days 7, 10, and 12 after UL in a dose-dependent manner in the betahistine-treated rats, more so than in the saline-treated rats. Conclusion: These findings suggest that betahistine facilitated the late, but not the initial, process of VC in UL rats

Effect of a Rehabilitation Program After Mesenchymal Stromal Cell Transplantation for Advanced Osteonecrosis of the Femoral Head: A 10-Year Follow-Up Study

Objective: To assess the status of 10 patients with advanced osteonecrosis of the femoral head who underwent mesenchymal stromal cell transplants and a 12-week rehabilitation program 10 years earlier. Design: Retrospective study. Setting: University clinical research laboratory. Participants: Patients (N=10) who had undergone mesenchymal stromal cell transplantation and rehabilitation for a single hip osteonecrosis of the femoral head 10 years prior to the current study were recruited by telephone. The average age was 31.7 years and all participants were men; radiographic stages were 3A in 6 patients and 3B in 4 patients before treatment. Intervention: A 12-week rehabilitation program with follow-up once every 1 to 2 years was performed after mesenchymal stromal cell transplantation. Main Outcome Measures: Radiographic analysis, clinical score, timed Up and Go test, hip function (range of motion, muscle strength), and Short Form-36 scores were assessed before treatment and 1 and 10 years after treatment. Results: Upon imaging, 5 hips were found to be stable (stable group) and 5 had progressed (progressed group); 2 of the latter group required a total hip arthroplasty. The pretreatment radiographic stage of the progressed group was more advanced than that of the stable group. Body mass index was higher in the progressed group than in the stable group. Hip function and clinical score at 1 and 10 years after treatment improved in the hips of 8 patients without total hip arthroplasty. There were no severe adverse events during the rehabilitation. Conclusions: The 12-week rehabilitation program and annual follow-up after mesenchymal stromal cell transplantation for osteonecrosis of the femoral head was associated with pain reduction, maintaining hip muscle strength, widening range of motion, and improving quality of life. The level and timing of weight-bearing and social activity should be planned according to the individual's lifestyle and body composition

Intramuscular Adipose Tissue Content Predicts Patient Outcomes after Allogeneic Hematopoietic Stem Cell Transplantation

移植の成功に重要なのは、「質の良い」筋肉 --コンピュータ断層撮影を用いて評価した骨格筋指標での検討--. 京都大学プレスリリース. 2022-07-12.During clinical courses involving allogeneic hematopoietic stem cell transplantation (allo-HSCT), multidisciplinary assessments for patients including physical functions are indispensable, and quantitative skeletal muscle loss is a poor prognostic marker. In addition, deteriorating quality of muscle due to intra-muscle adipose tissue degeneration can be important as well, because many patients are cachexic or sarcopenic before allo-HSCT, although this approach has not been employed yet. Therefore, we conducted a retrospective cohort study to evaluate the quality, as well as quantity of skeletal muscle using computed tomography (CT). Psoas muscle mass index (PMI) and radiographic density (RD) calculated by cross-sectional area and averaged CT values of the psoas major muscle at the umbilical level were used to determine the quantity and quality of muscle, respectively. In total, 186 adult patients, aged 17-68 years (median, 49) were included in this study, and 46 (24.7%) and 49 (26.3%) patients were assigned to the lower PMI and RG groups. Low RD was identified as an independent risk factor for poor overall survival after allo-HSCT (adjusted hazard ratio 2.54, p<0.01), while PMI was not significant. Decreased RD along with reduced 6-min walking distance before transplantation was also significant factor for increased non-relapse mortality (hazard ratio, 2.69, p=0.01). This study is the first to suggest the use of a qualitative skeletal muscle index to serve as a prognostic indicator following allo-HSCT. RD should be included in pre-transplant screening parameters, and approaches that include rehabilitation focused on improving both muscle quality and quantity may improve the prognosis of allo-HSCT

Higher exercise tolerance early after allogeneic hematopoietic stem cell transplantation is the predictive marker for higher probability of later social reintegration

同種造血幹細胞移植後における社会復帰の予測因子を発見 --移植後リハビリテーションがもつ重要性--. 京都大学プレスリリース. 2021-04-09.As the proportion of long-term survivors after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is on the rise, it is essential to consider the significance of quality of life (QOL), including reintegration with society (returning to school or work). This retrospective cohort study aims to illustrate the precise epidemiology of social reintegration later after allo-HSCT and determine its predictive indicators. We enrolled 56 patients, and 40 patients (71%) attained social reintegration at 2 years post-HSCT. Reintegration failure markedly correlated with an inferior performance status and concurrent chronic graft-versus-host disease. In non-reintegrated patients, the physical function at discharge measured by the 6-min walking distance (6MWD) was markedly decreased. On the multivariate risk analyses, sex (female; odds ratio (OR) 0.07; 95% confidence interval (CI) 0.01–0.54; p = 0.01), HCT-CI (≥ 2; OR 0.10; 95% CI 0.01–0.84; p = 0.03), and change in 6MWD (per 5% increase; OR 1.47; 95% CI 1.01–2.13; p = 0.04) were significant predictors of later social reintegration. This study suggests that a multidisciplinary strategy including rehabilitation is essential, especially in patients with poor predictive markers at an early phase, and we should consider suitable rehabilitation programs to prevent a decline in exercise tolerance and improve social reintegration and overall QOL in patients after allo-HSCT

Real-world effectiveness and safety analysis of carfilzomib-lenalidomide-dexamethasone and carfilzomib-dexamethasone in relapsed/refractory multiple myeloma: a multicenter retrospective analysis

Background: Little is known about the real-world survival benefits and safety profiles of carfilzomib-lenalidomide-dexamethasone (KRd) and carfilzomib-dexamethasone (Kd). Methods: We performed a retrospective analysis to evaluate their efficacy and safety in 157 patients registered in the Kansai Myeloma Forum database. Results: A total of 107 patients received KRd. Before KRd, 99% of patients had received bortezomib (54% were refractory disease), and 82% had received lenalidomide (57% were refractory disease). The overall response rate (ORR) was 68.2%. The median progression-free survival (PFS) and overall survival (OS) were 8.8 and 29.3 months, respectively. Multivariate analysis showed that reduction of the carfilzomib dose and non-IgG M protein were significantly associated with lower PFS and reduction of the carfilzomib dose and refractoriness to prior bortezomib-based regimens were significantly associated with lower OS. A total of 50 patients received Kd. Before Kd, 96% of patients had received bortezomib (54% were refractory disease). The ORR was 62.0%. The median PFS and OS were 7.1 and 20.9 months, respectively. Based on the multivariate analysis, reduction of the carfilzomib dose and International Staging System Stage III (ISS III) were significantly associated with lower PFS. Grade III or higher adverse events were observed in 48% of KRd cases and 54% of Kd cases. Cardiovascular events, cytopenia, and infections were frequent, and 4 KRd patients died due to heart failure, arrhythmia, cerebral hemorrhage, and pneumonia. Conclusion: Our analysis showed that an adequate dose of carfilzomib is important for achieving the best survival benefits in a real-world setting. Adverse effects after KRd and Kd therapy should also be considered

Monocyte or white blood cell counts and β₂ microglobulin predict the durable efficacy of daratumumab with lenalidomide

BACKGROUND: Daratumumab is one of the most widely used treatments for relapsed/refractory multiple myeloma (MM) patients. However, not all patients achieve a lasting therapeutic response with daratumumab. OBJECTIVES: We hypothesized that a durable response to daratumumab could be predicted by the balance between the MM tumor burden and host immune status. DESIGN: We conducted a retrospective study using the real-world data in the Kansai Myeloma Forum (KMF) database. METHODS: We retrospectively analyzed 324 relapsed/refractory MM patients who were treated with daratumumab in the KMF database. RESULTS: In this study, 196 patients were treated with daratumumab, lenalidomide, and dexamethasone (DLd) regimen and 128 patients were treated with daratumumab, bortezomib, and dexamethasone (DBd) regimen. The median age at treatment, number of prior treatment regimens and time-to-next-treatment (TTNT) were 68, 4 and 8.02 months, respectively. A multivariate analysis showed that the TTNT under the DLd regimen was longer with either higher monocyte counts (analysis 1), higher white blood cell (WBC) counts (analysis 2), lower β2 microglobulin (B2MG < 5.5 mg/L) or fewer prior regimens (<4). No parameters were correlated with TTNT under the DBd regimen. CONCLUSION: We propose a simple scoring model to predict a durable effect of the DLd regimen by classifying patients into three categories based on either monocyte counts (0 points for ⩾200/μl; 1 point for <200/μl) or WBC counts (0 points for ⩾3500/μl; 1 point for <3500/μl) plus B2MG (0 points for <5.5 mg/L; 1 point for ⩾5.5 mg/L). Patients with a score of 0 showed significantly longer TTNT and significantly better survival compared to those with a score of 1 or 2 (both p < 0.001). To confirm this concept, our results will need to be validated in other cohorts

免疫組織化学法を用いた一側内耳破壊ラットの前庭代償の新しい評価法の開発

Background: Unilateral labyrinthectomy (UL) causes the disappearance of ipsilateral medial vestibular nuclear (ipsi-MVe) activity and induces spontaneous nystagmus (SN), which disappears during the initial process of vestibular compensation (VC). Ipsi-MVe-activity restores in the late process of VC. Objective: We evaluated the late process of VC after UL in rats and examined the effects of thioperamide (H3 antagonist) on VC. Materials and methods: MK801 (NMDA antagonist)-induced Fos-like immunoreactive (-LIR) neurons in contra-MVe, which had been suppressed by NMDA-mediated cerebellar inhibition in UL-rats was used as an index. Results: The number of MK801-induced Fos-LIR neurons in contra-MVe gradually decreased to the same level as that of sham-operated rats 14 days after UL. Thioperamide moved the disappearance of the MK801-induced Fos-LIR neurons 2 days earlier. The number of MK801-induced Fos-LIR neurons in thioperamide-treated rats was significantly decreased, compared with that of vehicle-rats on days 7 and 12 after UL. But, thioperamide did not influence the decline of SN frequency in UL-rats. Conclusion: There findings suggested that the number of MK801-induced Fos-LIR neurons in contra-MVe was decreased in concordance with the restoration of ipsi-MVe-activity during the late process of VC after UL and that thioperamide accelerated the late, but not the initial process of VC

Waste prevention for sustainable resource and waste management

Although the 2Rs (reduce and reuse) are considered high-priority approaches, there has not been enough quantitative research on effective 2R management. The purpose of this paper is to provide information obtained through the International Workshop in Kyoto, Japan, on 11–13 November 2015, which included invited experts and researchers in several countries who were in charge of 3R policies, and an additional review of 245 previous studies. It was found that, regarding policy development, the decoupling between environmental pressures and economy growth was recognized as an essential step towards a sustainable society. 3R and resource management policies, including waste prevention, will play a crucial role. Approaches using material/substance flow analyses have become sophisticated enough to describe the fate of resources and/or hazardous substances based on human activity and the environment, including the final sink. Life-cycle assessment has also been developed to evaluate waste prevention activities. Regarding target products for waste prevention, food loss is one of the waste fractions with the highest priority because its countermeasures have significant upstream and downstream effects. Persistent organic pollutants and hazardous compounds should also be taken into account in the situation where recycling activities are globally widespread for the promotion of a material-cycling society