Nagoya Journal of Medical Science最新文献

Calcium/calcineurin/nuclear factor of activated T-cell signaling is a vital regulator of the development and function of immune, nervous, cardiovascular, and musculoskeletal systems. The dysregulation of calcineurin activity has been implicated in various pathological conditions, including certain cancers, cardiac hypertrophy, and neurodegenerative disorders. Calcineurin is highly expressed in certain cancers and stabilizes and activates factors that promote cancer cell proliferation. Research has shown that protein dephosphorylation by calcineurin contributes to tumor formation and progression. Thus, elucidating molecular mechanisms of calcineurin-mediated tumorigenesis and tumor cell growth and targeting signaling pathways downstream of calcineurin may lead to new cancer therapies. This study reviewed the multiple roles of calcineurin in cell cycle progression and its potential as a target for cancer treatment.

Combination regimen consisting of gemcitabine, cisplatin, and durvalumab (GCD) has been employed for unresectable biliary tract cancer (BTC) since the end of 2022 in Japan. Here, we summarize our experience with GCD to demonstrate the clinical outcomes in a practical setting. Patients who underwent GCD for unresectable/recurrent BTC between January and December 2023 were investigated retrospectively. Data for maximal response rate (RR), disease control rate (DCR), and adverse events (AEs) were collected. Progression-free survival (PFS) and overall survival (OS) curves were generated using the Kaplan-Meyer method. Fifty (initially unresectable, n = 32; recurrence after surgery, n = 18) consecutive patients were enrolled, 19 of whom started GCD as second-line therapy or later. Overall RR was 24.0% including complete response in 1 (2%) patient and partial response in 11 (22%) patients; DCR was 68.0%. The median PFS and OS were 7.1 months and not reached, respectively. During a median follow-up period of 8.5 months, 8 (16%) patients underwent surgical resection. A total of 36 (72%) patients suffered Grade 3-5 AE, and 3 immune-related AE were controlled with injection of corticosteroid or observation. The efficacy of GCD for unresectable/recurrent BTC was confirmed in the practical setting, with acceptable toxicity, prolonged survival, and potential probability of resection.

Scar formation after spinal cord injury (SCI) hampers axonal regeneration and functional recovery. Previous studies have shown that scar formation is attributable to both gliosis and fibrosis, the latter requiring fibroblast proliferation and extracellular matrix deposition. In this setting, there are essentially two cell types generating new fibroblasts: pericytes and tissue-resident fibroblasts. Here, we showed that Meflin, a glycosylphosphatidylinositol-anchored protein (a specific marker of fibroblasts across multiple organs) is expressed by fibroblasts in the normal mouse spinal cord. An in situ hybridization analysis showed that Meflin⁺ cells arose from the meninges and perivascular region of the spinal parenchyma after spinal cord compression injury. That finding was corroborated by single-cell transcriptomic data from normal and injured mouse spinal cords. Interestingly, Meflin⁺ cells are positive for the fibroblast markers collagen type I and platelet-derived growth factor receptor (PDGFR) α but not for pericyte markers such as PDGFRβ and chondroitin sulfate proteoglycan 4 in the normal spinal cord. Those findings are consistent with the recent view that tissue-resident fibroblasts play a central role in many other types of fibrotic disease. A lineage-tracing experiment using a knock-in mouse line that expressed inducible Cre recombinase under the control of the Meflin promoter showed that Meflin⁺ cells yield PDGFRβ⁺ myofibroblasts but not glial cells positive for glial fibrillary acidic protein. These findings suggest that the Meflin⁺ population contains the cells of origin of myofibroblasts that are involved in scar formation after SCI.

Better identification of individuals at high risk for type 2 diabetes mellitus (T2DM) requires risk-prediction models incorporating novel predictors. Accordingly, this study aimed to evaluate the merits of including long-term systolic blood pressure variability (SBPV) in predicting T2DM incidence in a Japanese cohort of 3017 participants (2446 men, 571 women; age, 36-65 years) in 2007, who were followed up until March 2019. Consecutive SBP values, recorded between 2003 and 2007, were regressed annually for each participant. The slope and root-mean-square error of the regression line were calculated for each individual to represent SBPV. The significance of SBPV was examined by adding it to a multivariate Cox model incorporating age, sex, smoking status, regular exercise, family history of diabetes, body mass index, blood levels of triglycerides, high-density lipoprotein cholesterol, and fasting blood glucose. The c-index, net reclassification improvement (NRI), and integrated discrimination improvement (IDI) were used to compare the performance of the prediction models without (Model 1) and with (Model 2) SBPV. During the 9.8-year follow-up period, 135 participants developed T2DM. Although a statistically significant difference in c-index between Model 1 (0.785) and Model 2 (0.786) was not found, the NRI (8.312% [p < 0.001]) and IDI (0.700% [p = 0.012]) demonstrated that the performance of Model 2 improved compared with Model 1. In conclusion, results suggested that long-term SBPV slightly improved predictive utility for T2DM when added to a conventional prediction model. The study was registered at University Hospital Medical Information Network Clinical Trial registry (UMIN000052544, https://www.umin.ac.jp/).

Following opioid therapy initiation in opioid-naïve outpatients, cancer-related pain does not improve immediately, and pain relief is maintained after many days. This prospective study aimed to evaluate the feasibility of quick opioid introduction with injectable oxycodone for outpatient cancer-related pain and bridge to oral persistent-release tablet. Patients with Numerical Rating Scale of ≥4 for cancer-related pain were included. Injectable oxycodone 2 mg was evaluated for efficacy and safety after 30 min of administration; in case of lower efficacy, injectable oxycodone was administered for another 30 min. For patients exhibiting improvement 30 and 60 min after injectable oxycodone administration, oral persistent-release tablet 5 and 10 mg were initiated, respectively. If side effects are acceptable, oral persistent-release tablet twice daily was prescribed. The final evaluation for its efficacy and safety was conducted at revisit. Overall satisfaction (1-5 points, higher points are better) was evaluated. The study included 23 patients (26 symptoms). The Numerical Rating Scale was improved from 6.7 ± 1.9 to 2.5 ± 2.5 and 1.3 ± 1.3 at 30 min after injectable oxycodone and revisit, respectively. Five patients with six symptoms receiving 60 min of injectable oxycodone had Numerical Rating Scale of 3.7 ± 1.7 and 1.7 ± 1.2 at revisit. No patient had Grade 3 or higher side effect during injectable oxycodone and at revisit. The overall satisfaction was 4.4 ± 0.8. In conclusion, early injectable oxycodone introduction for opioid-naïve outpatients can be feasible and useful as a quick bridge to oral persistent-release tablet.

We compared the qualitative and quantitative quality of prostate conventional T2-weighted imaging and T2-weighted imaging with deep-learning reconstruction. Patients with suspected prostate cancer undergoing magnetic resonance imaging between April 2022 and June 2023 were included. Quantitative analysis was performed to determine the signal-to-noise and contrast ratios of the perirectal fat tissue, internal obturator muscle, and pubic tubercle. Eight periprostatic anatomical structures, overall image quality, and motion artifacts were evaluated by two radiologists using 5- or 4-point scales. Qualitative analysis results were compared to determine the agreement between the two radiologists. In total, 106 patients (mean age: 71 ± 8.3 years; 106 men) were included in this study. The acquisition time for conventional T2-weighted imaging and T2-weighted imaging with deep-learning reconstruction was 4 min and 16 s and 2 min and 12 s, respectively. The signal-to-noise ratio of the perirectal fat tissue and internal obturator muscle and contrast ratio of fat/muscle and bone/muscle determined via T2-weighted imaging with deep-learning reconstruction were significantly superior to those determined via conventional T2-weighted imaging (both p < 0.01). Compared with conventional T2-weighted imaging, T2-weighted imaging with deep-learning reconstruction showed significant improvement in the visualization of the periprostatic anatomy, overall image quality, and motion artifacts (both p < 0.05). Compared with conventional methods, T2-weighted imaging with deep-learning reconstruction facilitated the acquisition of good-quality magnetic resonance images of the prostate within a shorter acquisition time. T2-weighted imaging with deep-learning reconstruction will aid clinicians in diagnosing prostate cancer with shortened acquisition time while maintaining quantitative and qualitative image properties.

Deficiency of non-technical skills may increase the number of adverse events in the operating room. Sustained life-threatening hypotension due to intraoperative cardiac tamponade during robot-assisted thoracic surgery is rare, requiring prompt assessment and swift decision-making. A 54-year-old woman was scheduled to undergo robot-assisted thoracic surgery for an anterior mediastinal tumor. During the operation, hemodynamic instability occurred despite the administration of a high dose of vasopressor. Anesthesiologists and thoracic surgeons shared information regarding the situation, and decided to perform echocardiography and call other physicians for assistance. Cardiac tamponade was diagnosed during echocardiography, and an incision was made in the pericardium. The patient recovered from the critical situation and was extubated in the operating room. Particularly in robot-assisted surgery, non-technical skills are indispensable to enable the anesthesiologist to successfully manage critical hemodynamic instability owing to unexplained causes.

Although trunk acceleration during walking is widely used as a measure of stability, few studies have focused on sensitive postural control in community-dwelling elderly people to detect components related to balance ability during gait initiation. This study aimed to clarify the biomechanical characteristics of movement and sensitive postural control related to balance ability, focusing on high- and low-frequency components of trunk acceleration during gait initiation. Healthy older participants were divided into two groups (high-performance older people [Older(H)], n = 11; age, 76.2 ± 3.3 years, and low-performance older people [Older(L)], n = 17; age, 75.8 ± 3.2 years) based on the Timed Up and Go Test time related to balance ability while walking at their chosen speed. Trunk acceleration data were obtained from an accelerometer on the L3-4 level spinous process. The gait velocity was measured at the first step using a motion capture system. The acceleration data were separated into high- and low-frequency components, and the root mean square was calculated. The level of significance was set at 5%. For the high-frequency component, the root mean square of acceleration in Older(L) was significantly lower than that of Older(H) in the mediolateral direction (p = 0.019) and correlated with gait velocity (r = 0.415; p < 0.001). For the low-frequency component, the root mean square of acceleration in Older(L) was significantly lower than that of Older(H) in the vertical (p = 0.034) and anteroposterior direction (p = 0.039). The results suggest that low- and high-frequency components of trunk acceleration can reveal biomechanical characteristics in community-dwelling elderly people.

Mental disorders are a major global cause of disability that involve significant disturbances in thinking, emotional regulation, or behavior. The pathogenesis of these illnesses is complicated by their obscure nature and lack of biological markers. A genetics-first approach has been proposed to address this complexity. This approach associates clinical phenotypes with disease-susceptible genomic variants, such as copy number variations and single nucleotide variants. These rare variants significantly affect disease development and are thus crucial for assessing the effects of specific variants on disease and in determining the underlying biological mechanisms. In particular, mouse models that reflect these variants are instrumental in defining the causal relationships between genetic variants and disease-relevant phenotypes. Recent studies have highlighted the importance of sensory information processing in humans and mice. Advanced technologies that are valuable in unraveling the neural circuit mechanisms of these phenotypes include optogenetics and in vivo 2-photon imaging. Furthermore, mouse models can guide the integration of findings from patients and induced pluripotent stem cells, supporting a multidimensional approach to understanding the pathophysiology of mental disorders. In this review, we briefly discuss the utility of mouse models in a genetics-first approach to elucidate the pathophysiology of mental disorders. We also present examples of our mouse models based on rare disease-susceptible variants.

The Japan Multi-Institutional Collaborative Cohort Study, the Yamagata Molecular Epidemiological Cohort Study, and the Tsuruoka Metabolomics Cohort Study use a 47-item food frequency questionnaire (FFQ) developed in central Japan in 2004. We applied regression analyses to estimate nutrient intakes in the FFQ. The regression equations, however, may not be so robust and may vary among areas, even in Japan. We aimed to evaluate the reproducibility and validity of the FFQ over an expanded area of Japan. Healthy volunteers aged 34-70 years from 13 areas of Japan provided 12-day weighed dietary records (WDRs) and completed two FFQs over 1 year. We evaluated reproducibility and validity by comparing the intakes of 27 nutrients between the two FFQs and the first FFQ (FFQ1) and WDRs, respectively. Spearman's rank correlation coefficients (SRs) between estimates from the FFQs and WDRs were calculated and corrected for intra-individual variation in the WDRs. Intakes of the selected nutrients estimated from the two FFQs were equivalent. The median energy-adjusted SRs between FFQ1 and the second FFQ were 0.66 for both men and women. Regarding validity adjusted for within-individual variation, energy-adjusted SRs for WDRs vs FFQ1 ranged from 0.13 (thiamin) to 0.79 (alcohol) for men, and the median was 0.35. The energy-adjusted SRs ranged from 0.20 (protein) to 0.71 (alcohol) for women, and the median was 0.43. The FFQ demonstrated high reproducibility and moderate validity, which suggests that it is appropriate to clarify associations between diet and health and/or disease among adults in Japan.