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Sex hormones and their receptors play critical roles in the development and progression of the breast and prostate cancers. Here we report that a novel type of transfer RNA (tRNA)-derived small RNA, termed Sex HOrmone-dependent TRNA-derived RNAs (SHOT-RNAs), are specifically and abundantly expressed in estrogen receptor (ER)-positive breast cancer and androgen receptor (AR)-positive prostate cancer cell lines. SHOT-RNAs are not abundantly present in ER ⁻ breast cancer, AR ⁻ prostate cancer, or other examined cancer cell lines from other tissues. ER-dependent accumulation of SHOT-RNAs is not limited to a cell culture system, but it also occurs in luminal-type breast cancer patient tissues. SHOT-RNAs are produced from aminoacylated mature tRNAs by angiogenin-mediated anticodon cleavage, which is promoted by sex hormones and their receptors. Resultant 5′- and 3′-SHOT-RNAs, corresponding to 5′- and 3′-tRNA halves, bear a cyclic phosphate (cP) and an amino acid at the 3′-end, respectively. By devising a “cP-RNA-seq” method that is able to exclusively amplify and sequence cP-containing RNAs, we identified the complete repertoire of 5′-SHOT-RNAs. Furthermore, 5′-SHOT-RNA, but not 3′-SHOT-RNA, has significant functional involvement in cell proliferation. These results have unveiled a novel tRNA-engaged pathway in tumorigenesis of hormone-dependent cancers and implicate SHOT-RNAs as potential candidates for biomarkers and therapeutic targets. Although transfer RNAs (tRNAs) are best known as adapter molecules essential for translation, recent biochemical and computational evidence has led to a previously unexpected conceptual consensus that tRNAs are not always end products but can further serve as a source of small functional RNAs. Here we report that a novel type of tRNA-derived small RNA, termed SHOT-RNAs, are specifically and abundantly expressed in sex hormone-dependent breast and prostate cancers. SHOT-RNAs are produced from aminoacylated mature tRNAs by angiogenin-mediated cleavage of the anticodon loop, which is promoted by sex hormones and their receptors. We identified the complete repertoire of SHOT-RNAs, and also found their functional significance in cell proliferation. These results have unveiled a novel tRNA-engaged pathway in tumorigenesis.

Advanced glycation end-products (AGEs) deteriorate bone strength. Among over 40 species identified in vivo, AGEs other than pentosidine were roughly estimated as total fluorescent AGEs (tfAGEs) due to technical difficulties. Using LC-QqTOF-MS, we established a system that enabled the quantitation of five AGEs (CML, CEL, MG-H1, CMA and pentosidine) as well as two mature and three immature enzymatic crosslinks. Human bone samples were collected from 149 patients who underwent total knee arthroplasty. Their clinical parameters were collected to investigate parameters that may be predictive of AGE accumulation. All the analytes were quantitated and showed significant linearity with high sensitivity and precision. The results showed that MG-H1 was the most abundant AGE, whereas pentosidine was 1/200–1/20-fold less abundant than the other four AGEs. The AGEs were significantly and strongly correlated with pentosidine, while showing moderate correlation with tfAGEs. Interestingly, multiple linear regression analysis revealed that gender contributed most to the accumulation of all the AGEs, followed by age, tartrate-resistant acid phosphatase-5b and HbA1c. Furthermore, the AGEs were negatively correlated with immature crosslinks. Mass spectrometric quantitation of AGEs and enzymatic crosslinks is crucial to a better understanding of ageing- and disease-related deterioration of bone strength.

Cutaneous melanoma is the most aggressive form of skin cancer. This aggressiveness appears to be due to the cancer cells' ability to reversibly switch between phenotypes with non‐invasive and invasive potential, and microphthalmia‐associated transcription factor (MITF) is known to play a central role in this process. The transcription factor glioma‐associated oncogene homolog 1 (GLI1) is a component of the canonical and noncanonical sonic hedgehog pathways. Although GLI1 has been suggested to be involved in melanoma progression, its precise role and the mechanism underlying invasion remain unclear. Here we investigated whether and how GLI1 is involved in the invasive ability of melanoma cells. Gli1 knockdown (KD) melanoma cell lines, established by using Gli1‐targeting lentiviral short hairpin RNA, exhibited a markedly reduced invasion ability, but their MITF expression and activity were the same as controls. Gli1 KD melanoma cells also led to less lung metastasis in mice compared with control melanoma cells. Furthermore, the Gli1 KD melanoma cells underwent a mesenchymal‐to‐epithelial‐like transition, accompanied by downregulation of the epithelial‐to‐mesenchymal transition (EMT)‐inducing transcription factors (EMT‐TF) Snail1, Zeb1 and Twist1, but not Snail2 or Zeb2. Collectively, these results indicate that GLI1 is important for maintaining the invasive and mesenchymal‐like properties of melanoma cells independent of MITF, most likely by modulating a subset of EMT‐TF. Our findings provide new insight into how heterogeneity and plasticity are achieved and regulated in melanoma. The aggressiveness of cutaneous melanoma appears to be due to the cancer cells' ability to reversibly switch between phenotypes with non‐invasive and invasive potentials, and MITF is known to play a central role in this process. We found that Gli1 knockdown in melanoma cell lines exhibited markedly reduced invasion activity and underwent a mesenchymal‐to‐epithelial‐like transition without affecting MITF levels. This study indicates that GLI1 is important for maintaining the invasive and mesenchymal‐like properties of melanoma cells independent of MITF.

An increasing number of people are visiting hospital websites to seek better services and treatments compared to the past. It is therefore important for hospitals to develop websites to meet the needs of their patients. However, few studies have investigated whether and how the current hospital websites meet the patient's needs. Above all, in radiation departments, it may be difficult for patients to obtain the desired information regarding modality and diagnosis because such information is subdivided when described on a website. The purpose of this study is to suggest a hospital website search behavior model by analyzing the browsing behavior model using a Bayesian network from the perspective of one-to-one marketing. First, we followed the website access log of Hokkaido University Hospital, which was collected from September 1, 2016, to August 31, 2017, and analyzed the access log using Google Analytics. Second, we specified the access records related to radiology from visitor browsing pages and keywords. Third, using these resources, we structured 3 Bayesian network models based on specific patient needs: radiotherapy, nuclear medicine examination, and radiological diagnosis. Analyzing each model, this study considered why some visitors could not reach their desired page and improvements to meet the needs of visitors seeking radiology-related information. The radiotherapy model showed that 74% (67/90) of the target visitors could reach their requested page, but only 2% (2/90) could reach the Center page where inspection information, one of their requested pages, is posted. By analyzing the behavior of the visitors, we clarified that connecting with the radiotherapy and radiological diagnosis pages is useful for increasing the proportion of patients reaching their requested page. We proposed solutions for patient web-browsing accessibility based on a Bayesian network. Further analysis is necessary to verify the accuracy of the proposed model in comparison to other models. It is expected that information provided on hospital websites will be improved using this method.

The Japan Clinical Oncology Group–Radiation Therapy Study Group (JCOG-RTSG) has initiated several multicenter clinical trials for high-precision radiotherapy, which are presently ongoing. When conducting multi-center clinical trials, a large difference in physical quantities, such as the absolute doses to the target and the organ at risk, as well as the irradiation localization accuracy, affects the treatment outcome. Therefore, the differences in the various physical quantities used in different institutions must be within an acceptable range for conducting multicenter clinical trials, and this must be verified with medical physics consideration. In 2011, Japan’s first Medical Physics Working Group (MPWG) in the JCOG-RTSG was established to perform this medical-physics-related verification for multicenter clinical trials. We have developed an auditing method to verify the accuracy of the absolute dose and the irradiation localization. Subsequently, we credentialed the participating institutions in the JCOG multicenter clinical trials that were using stereotactic body radiotherapy (SBRT) for lungs, intensity-modulated radiotherapy (IMRT) and volumetric-modulated arc therapy (VMAT) for several disease sites, and proton beam therapy (PT) for the liver. From the verification results, accuracies of the absolute dose and the irradiation localization among the participating institutions of the multicenter clinical trial were assured, and the JCOG clinical trials could be initiated.

BackgroundEvaluating patients’ risk for acute kidney injury (AKI) is crucial for positive outcomes following cardiac surgery. Our aims were first to select candidate risk factors from pre- or intra-operative real-world parameters collected from routine medical care and then evaluate potential associations between those parameters and risk of onset of post-operative cardiac surgery-associated AKI (CSA-AKI).MethodWe conducted two cohort studies in Japan. The first was a single-center prospective cohort study (n = 145) to assess potential association between 115 clinical parameters collected from routine medical care and CSA-AKI (≥ Stage1) risk in the population of patients undergoing cardiac surgery involving cardiopulmonary bypass (CPB). To select candidate risk factors, we employed random forest analysis and applied survival analyses to evaluate association strength. In a second retrospective cohort study, we targeted patients undergoing cardiac surgery with CPB (n = 619) and evaluated potential positive associations between CSA-AKI incidence and risk factors suggested by the first cohort study.ResultsVariable selection analysis revealed that parameters in clinical categories such as circulating inflammatory cells, CPB-related parameters, ventilation, or aging were potential CSA-AKI risk factors. Survival analyses revealed that increased counts of pre-operative circulating monocytes and neutrophils were associated with CSA-AKI incidence. Finally, in the second cohort study, we found that increased pre-operative circulating monocyte counts were associated with increased CSA-AKI incidence.ConclusionsCirculating monocyte counts in the pre-operative state are associated with increased risk of CSA-AKI development. This finding may be useful in stratifying patients for risk of developing CSA-AKI in routine clinical practice.

The SyncTraX series enables real-time tumor-tracking radiotherapy through the real-time recognition of a fiducial marker using fluoroscopic images. In this system, the isocenter should be located within approximately 5–7.5 cm from the marker, depending on the version, owing to the limited field of view. If the marker is placed away from the tumor, the isocenter should be shifted toward the marker. This study aimed to investigate stereotactic body radiotherapy (SBRT) outcomes of primary liver tumors treated with SyncTraX in cases where the isocenter was shifted marginally or outside the planning target volume (PTV). Twelve patients with 13 liver tumors were included in the analysis. Their isocenter was shifted toward the marker and was placed marginally or outside the PTV. The prescribed doses were generally 40 Gy in four fractions or 48 Gy in eight fractions. The overall survival (OS) and local control (LC) rates were calculated using the Kaplan–Meier method. All patients completed the scheduled SBRT. The median distance between the fiducial marker and PTV centroid was 56.0 (interquartile range [IQR]: 52.7–66.7) mm. By shifting the isocenter toward the marker, the median distance between the marker and isocenter decreased to 34.0 (IQR: 33.4–39.7) mm. With a median follow-up period of 25.3 (range: 6.9–70.0) months, the 2-year OS and LC rates were 100.0% (95% confidence interval: 100–100). An isocenter shift makes SBRT with SyncTraX feasible in cases where the fiducial marker is distant from the tumor.

To investigate the amount that radiation-induced secondary cancer would be reduced by using proton beam therapy (PBT) in place of intensity-modulated X-ray therapy (IMXT) in pediatric patients, we analyzed lifetime attributable risk (LAR) as an in silico surrogate marker of the secondary cancer after these treatments. From 242 pediatric patients with cancers who were treated with PBT, 26 patients were selected by random sampling after stratification into four categories: (i) brain, head and neck, (ii) thoracic, (iii) abdominal, and (iv) whole craniospinal (WCNS) irradiation. IMXT was replanned using the same computed tomography and region of interest. Using the dose–volume histograms (DVHs) of PBT and IMXT, the LARs of Schneider et al. were calculated for the same patient. All the published dose–response models were tested for the organs at risk. Calculation of the LARs of PBT and IMXT based on the DVHs was feasible for all patients. The means ± standard deviations of the cumulative LAR difference between PBT and IMXT for the four categories were (i) 1.02 ± 0.52% (n = 7, P = 0.0021), (ii) 23.3 ± 17.2% (n = 8, P = 0.0065), (iii) 16.6 ± 19.9% (n = 8, P = 0.0497) and (iv) 50.0 ± 21.1% (n = 3, P = 0.0274), respectively (one tailed t-test). The numbers needed to treat (NNT) were (i) 98.0, (ii) 4.3, (iii) 6.0 and (iv) 2.0 for WCNS, respectively. In pediatric patients who had undergone PBT, the LAR of PBT was significantly lower than the LAR of IMXT estimated by in silico modeling. Although a validation study is required, it is suggested that the LAR would be useful as an in silico surrogate marker of secondary cancer induced by different radiotherapy techniques.

Background Organ‐at‐risk (OAR) sparing is often assessed using an overlap volume‐based parameter, defined as the ratio of the volume of OAR that overlaps the planning target volume (PTV) to the whole OAR volume. However, this conventional overlap‐based predictive parameter (COPP) does not consider the volume relationship between the PTV and OAR. Purpose We propose a new overlap‐based predictive parameter that consider the PTV volume. The effectiveness of proposed overlap‐based predictive parameter (POPP) is evaluated compared with COPP. Methods We defined as POPP = (overlap volume between OAR and PTV/OAR volume) × (PTV volume/OAR volume). We generated intensity modulated radiation therapy (IMRT) based on step and shoot technique, and volumetric modulated arc therapy (VMAT) plans with the Auto‐Planning module of Pinnacle3 treatment planning system (v14.0, Philips Medical Systems, Fitchburg, WI) using the American Association of Physicists in Medicine Task Group (TG119) prostate phantom. The relationship between the position and size of the prostate phantom was systematically modified to simulate various geometric arrangements. The correlation between overlap‐based predictive parameters (COPP and POPP) and dose‐volume metrics (mean dose, V70Gy, V60Gy, and V37.5 Gy for rectum and bladder) was investigated using linear regression analysis. Results Our results indicated POPP was better than COPP in predicting intermediate‐dose metrics. The bladder results showed a trend similar to that of the rectum. The correlation coefficient of POPP was significantly greater than that of COPP in < 62 Gy (82% of the prescribed dose) region for IMRT and in < 55 Gy (73% of the prescribed dose) region for VMAT regarding the rectum (p < 0.05). Conclusions POPP is superior to COPP for creating predictive models at an intermediate‐dose level. Because rectal bleeding and bladder toxicity can be associated with intermediate‐doses as well as high‐doses, it is important to predict dose‐volume metrics for various dose levels. POPP is a useful parameter for predicting dose‐volume metrics and assisting the generation of treatment plans.

Purpose To investigate potential advantages of adaptive intensity‐modulated proton beam therapy (A‐IMPT) by comparing it to adaptive intensity‐modulated X‐ray therapy (A‐IMXT) for nasopharyngeal carcinomas (NPC). Methods Ten patients with NPC treated with A‐IMXT (step and shoot approach) and concomitant chemotherapy between 2014 and 2016 were selected. In the actual treatment, 46 Gy in 23 fractions (46Gy/23Fx.) was prescribed using the initial plan and 24Gy/12Fx was prescribed using an adapted plan thereafter. New treatment planning of A‐IMPT was made for the same patients using equivalent dose fractionation schedule and dose constraints. The dose volume statistics based on deformable images and dose accumulation was used in the comparison of A‐IMXT with A‐IMPT. Results The means of the Dmean of the right parotid gland (P < 0.001), right TM joint (P < 0.001), left TM joint (P < 0.001), oral cavity (P < 0.001), supraglottic larynx (P = 0.001), glottic larynx (P < 0.001), , middle PCM (P = 0.0371), interior PCM (P < 0.001), cricopharyngeal muscle (P = 0.03643), and thyroid gland (P = 0.00216), in A‐IMPT are lower than those of A‐IMXT, with statistical significance. The means of, D0.03cc, and Dmean of each sub portion of auditory apparatus and D30% for Eustachian tube and D0.5cc for mastoid volume in A‐IMPT are significantly lower than those of A‐IMXT. The mean doses to the oral cavity, supraglottic larynx, and glottic larynx were all reduced by more than 20 Gy (RBE = 1.1). Conclusions An adaptive approach is suggested to enhance the potential benefit of IMPT compared to IMXT to reduce adverse effects for patients with NPC.