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Bacterial wilt, caused by the soil-borne bacterium Ralstonia solanacearum, is a lethal disease of tomato, but the molecular mechanisms of the host resistance responses to R. solanacearum remain unclear. In this study, we report the first work describing the transcriptome of cultivar resistance and susceptible tomato cultivar after inoculation with R. solanacearum. To elucidate the characteristics of resistance early in the interaction, we analyzed microarrays for resistant cultivar LS-89 and susceptible cultivar Ponderosa 1 day after stem inoculation. No change in gene expression was detected for Ponderosa, but expression levels of over 140 genes, including pathogenesis-related, hormone signaling and lignin biosynthesis genes, increased in LS-89. Expression of β-1,3-glucanase genes increased substantially. In an immunohistochemical study, glucanase in LS-89 accumulated in the xylem and pith tissues surrounding xylem vessels filled with R. solanacearum. The expression of these genes also increased in four other resistant cultivars, but changed little in four susceptible cultivars in response to R. solanacearum, suggesting that similar reactions occur in other cultivars. These gene expression profiles will serve as fundamental information to elucidate the molecular mechanisms in the resistance response to R. solanacearum in tomato.

Symptoms on virus-infected plants are often very specific to the given virus. The molecular mechanisms involved in viral symptom induction have been extensively studied, but are still poorly understood. Cucumber mosaic virus (CMV) Y satellite RNA (Y-sat) is a non-coding subviral RNA and modifies the typical symptom induced by CMV in specific hosts; Y-sat causes a bright yellow mosaic on its natural host Nicotiana tabacum. The Y-sat-induced yellow mosaic failed to develop in the infected Arabidopsis and tomato plants suggesting a very specific interaction between Y-sat and its host. In this study, we revealed that Y-sat produces specific short interfering RNAs (siRNAs), which interfere with a host gene, thus inducing the specific symptom. We found that the mRNA of tobacco magnesium protoporphyrin chelatase subunit I (ChlI, the key gene involved in chlorophyll synthesis) had a 22-nt sequence that was complementary to the Y-sat sequence, including four G-U pairs, and that the Y-sat-derived siRNAs in the virus-infected plant downregulate the mRNA of ChlI by targeting the complementary sequence. ChlI mRNA was also downregulated in the transgenic lines that express Y-sat inverted repeats. Strikingly, modifying the Y-sat sequence in order to restore the 22-nt complementarity to Arabidopsis and tomato ChlI mRNA resulted in yellowing symptoms in Y-sat-infected Arabidopsis and tomato, respectively. In 5'-RACE experiments, the ChlI transcript was cleaved at the expected middle position of the 22-nt complementary sequence. In GFP sensor experiments using agroinfiltration, we further demonstrated that Y-sat specifically targeted the sensor mRNA containing the 22-nt complementary sequence of ChlI. Our findings provide direct evidence that the identified siRNAs derived from viral satellite RNA directly modulate the viral disease symptom by RNA silencing-based regulation of a host gene.

Background To evaluate factors associated with osteoradionecrosis of the jaw (ORNJ) in patients with head and neck squamous cell carcinoma (HNSCC), focusing on jaw-related dose–volume histogram (DVH) parameters. Methods We retrospectively reviewed the medical records of 616 patients with HNSCC treated with curative-intent or postoperative radiation therapy (RT) during 2008–2018. Patient-related (age, sex, history of smoking or alcohol use, diabetes mellitus, performance status, pre-RT dental evaluation, pre- or post-RT tooth extraction), tumor-related (primary tumor site, T-stage, nodal status), and treatment-related (pre-RT surgery, pre-RT mandible surgery, induction or concurrent chemotherapy, RT technique) variables and DVH parameters (relative volumes of the jaw exposed to doses of 10 Gy–70 Gy [V10–70]) were investigated and compared between patients with and without ORNJ. The Mann–Whitney U test was used to compare RT dose parameters. Univariate and multivariate Cox regression analyses were used to assess factors associated with ORNJ development. Kaplan–Meier analyses were performed for cumulative ORNJ incidence estimation. Results Forty-six patients (7.5%) developed ORNJ. The median follow-up duration was 40 (range 3–145) months. The median time to ORNJ development was 27 (range 2–127) months. DVH analysis revealed that V30–V70 values were significantly higher in patients with than in those without ORNJ. In univariate analyses, primary tumor site, pre-RT mandible surgery, post-RT tooth extraction, and V60 > 14% were identified as important factors. In multivariate analyses, V60 > 14% ( p  = 0.0065) and primary tumor site ( p  = 0.0059) remained significant. The 3-year cumulative ORNJ incidence rates were 2.5% and 8.6% in patients with V60 ≤ 14% and > 14%, respectively ( p  < 0.0001), and 9.3% and 1.4% in patients with oropharyngeal or oral cancer and other cancers, respectively ( p  < 0.0001). Conclusions V60 > 14% and oropharyngeal or oral cancer were found to be independent risk factors for ORNJ. These findings might be useful to minimize ORNJ incidence in HNSCC treated with curative RT.

Cine-magnetic resonance imaging (MRI) has been used to track respiratory-induced motion of the liver and tumor and assist in the accurate delineation of tumor volume. Recent developments in compressed sensitivity encoding (SENSE; CS) have accelerated temporal resolution while maintaining contrast resolution. This study aimed to develop and assess hepatobiliary phase (HBP) cine-MRI scans using CS. Phantom was imaged using cine-MRI and signal intensity (SI) and contrast ratio (CR) measured to determine the optimal flip-angle turbo field echo (TFE) prepulse delay. We performed cine-MRI in 20 patients for one minute, with images taken every 0.5 s after administration of gadoxetic acid contrast agent. Acquired images had three different acceleration factors (SENSE, CS without denoising [CS-no], and CS with strong denoising [CS-strong]). The image quality of the HBP cine MRI was quantitatively and qualitatively analyzed. In the phantom study, a flip angle of 30 °and TFE prepulse delay of 150 ms were optimal for clinical imaging. In a clinical study, CS-strong showed the highest signal-to-noise ratio and comparable contrast ratio among the three sequences. The CS-strong group showed a significantly higher image quality ( P  < 0.01), except for motion smoothness ( P  = 0.11). CS with denoising improved the tumor-to-liver contrast and image quality in high-temporal-resolution HBP cine MRI.

Background Concurrent chemoradiotherapy (CCRT) followed by durvalumab is the standard of care for unresectable locally-advanced non-small cell carcinoma (LA-NSCLC). However, a major concern about administration of durvalumab after CCRT is whether the incidence of symptomatic radiation pneumonitis (RP) may increase or not. In the present analysis, we report the initial results of CCRT followed by durvalumab in patients with LA-NSCLC in a real-world setting with focus on predicting factors for symptomatic RP. Methods Patients who were pathologically diagnosed as NSCLC and initiated treatment with CCRT followed by durvalumab between July 2018 to December 2019 were eligible for this study. Patients were included if they completed the planned CRT course and administered at least one course of durvalumab. We retrospectively investigated the preliminary survival outcome and incidence and predicting factors for symptomatic RP. Results Of the 67 patients who planned CCRT, 63 patients completed the entire CCRT course. Of these, 56 patients proceeded to consolidation with durvalumab. The median time to eternal discontinuation of durvalumab was 9.7 months. The cumulative proportion of the patients who exhibited symptomatic RP was 30, 40 and 44% at 3, 6 and 12 months, respectively. In multivariate analyses, pulmonary fibrosis score and lung V40 were significant predictive factors for symptomatic RP ( p  < 0.001, HR: 7.83, 95% CI: 3.38–18.13, and p  = 0.034, HR: 3.17, 95% CI: 1.09–9.19, respectively). Conclusions Pulmonary fibrosis sore and lung V40 were significant predictive factors for symptomatic RP. We should be cautious about the administration of durvalumab for patients having subclinical pulmonary fibrosis. To our best knowledge, this is one of the first report showing the predictive value of high dose volumes to the lung in patients with LA-NSCLC who received CCRT followed by durvalumab.

Sarcopenia is an independent survival predictor in several tumor types. Computed tomography (CT) is the standard measurement for body composition assessment. Radiomics analysis of CT images allows for the precise evaluation of skeletal muscles. This study aimed to construct a prognostic survival model for patients with esophageal cancer who underwent radical irradiation using skeletal muscle radiomics. We retrospectively identified patients with esophageal cancer who underwent radical irradiation at our institution between April 2008 and December 2017. Skeletal muscle radiomics were extracted from an axial pretreatment CT at the third lumbar vertebral level. The prediction model was constructed using machine learning coupled with the least absolute shrinkage and selection operator (LASSO). The predictive nomogram model comprised clinical factors with radiomic features. Three prediction models were created: clinical, radiomics, and combined. Ninety-eight patients with 98 esophageal cancers were enrolled in this study. The median observation period was 57.5 months (range=1-98 months). Thirty-five radiomics features were selected by LASSO analysis, and a prediction model was constructed using training and validation data. The average of the accuracy, specificity, sensitivity, and area under the concentration-time curve for predicting survival in esophageal cancer in the combined model were 75%, 92%, and 0.86, respectively. The C-indices of the clinical, radiomics, and combined models were 0.76, 0.80, and 0.88, respectively. A prediction model with skeletal muscle radiomics and clinical data might help determine survival outcomes in patients with esophageal cancer treated with radical radiotherapy.

To develop and investigate the feasibility of sub-second temporal resolution volumetric T1-weighted four-dimensional (4D-) MRI in comparison with 4D-CT for respiratory-correlated motion assessment using an MRI/CT-compatible phantom. Sub-second high temporal resolution (0.5 s) gradient-echo T1-weighted 4D-MRI was developed using a volumetric acquisition scheme with compressed sensing. An MRI/CT-compatible motion phantom (simulated liver tumor) with three sinusoidal movements of amplitudes and two respiratory patterns was introduced and imaged with 4D-MRI and 4D-CT to investigate the geometric accuracy of the target movement. The geometric accuracy, including centroid position, volume, similarity index of dice similarity coefficient (DSC), and Hausdorff distance (HD), was systematically evaluated. Proposed 4D-MRI achieved a similar geometric accuracy compared with 4D-CT regarding the centroid position, volume, and similarity index. The observed position differences of the absolute average centroid were within 0.08 cm in 4D-MRI and 0.03 cm in 4D-CT, less than the 1-pixel resolution for each modality. The observed volume difference in 4D-MRI/4D-CT was within 0.73 cm 3 (4.5%)/0.29 cm 3 (2.1%) for a large target and 0.06 cm 3 (11.3%)/0.04 cm 3 (11.6%) for a small target. The observed DSC values for 4D-MRI/4D-CT were at least 0.93/0.95 for the large target and 0.83/0.84 for the small target. The maximum HD values were 0.25 cm/0.31 cm for the large target and 0.21 cm/0.15 cm for the small target. Although 4D-CT potentially exhibit superior numerical accuracy in phantom studies, the proposed high temporal resolution 4D-MRI demonstrates sub-millimetre geometric accuracy comparable to that of 4D-CT. These findings suggest that the 4D-MRI technique is a viable option for characterizing motion and generating phase-dependent internal target volumes within the realm of radiotherapy.

This study investigated the clinical characteristics and predictive factors for developing acute extended radiation pneumonitis with a focus on the presence and radiological characteristics of preexisting interstitial lung disease. Of 1429 irradiations for lung cancer from May 2006 to August 2013, we reviewed 651 irradiations involving the lung field. The presence, compatibility with usual interstitial pneumonia, and occupying area of preexisting interstitial lung disease were retrospectively evaluated by pretreatment computed tomography. Cases of non-infectious, non-cardiogenic, acute respiratory failure with an extended bilateral shadow developing within 30 days after the last irradiation were defined as acute extended radiation pneumonitis. Nine (1.4%) patients developed acute extended radiation pneumonitis a mean of 6.7 days after the last irradiation. Although preexisting interstitial lung disease was found in 13% of patients (84 patients), 78% of patients (7 patients) with acute extended radiation pneumonitis cases had preexisting interstitial lung disease, which resulted in incidences of acute extended radiation pneumonitis of 0.35 and 8.3% in patients without and with preexisting interstitial lung disease, respectively. Multivariate logistic analysis indicated that the presence of preexisting interstitial lung disease (odds ratio = 22.6; 95% confidence interval = 5.29-155; p < 0.001) and performance status (≥2; odds ratio = 4.22; 95% confidence interval = 1.06-20.8; p = 0.049) were significant predictive factors. Further analysis of the 84 patients with preexisting interstitial lung disease revealed that involvement of more than 10% of the lung field was the only independent predictive factor associated with the risk of acute extended radiation pneumonitis (odds ratio = 6.14; 95% confidence interval = 1.0-37.4); p = 0.038). Pretreatment computed tomography evaluations of the presence of and area size occupied by preexisting interstitial lung disease should be assessed for safer irradiation of areas involving the lung field.

Pancreatic cancer (PC) is difficult to treat because of its radio-resistance and metastases. Radiotherapy modifies the tumor microenvironment (TME) and affects PC progression. Exosomes are produced in response to radiation, but their nature and mechanisms of action are unclear. We investigated how exosomes from irradiated PC cells (IR-Exo) regulated metastasis both in vitro and in vivo. We isolated exosomes from three human PC cell lines: MIAPaCa-2, BxPC3, and Panc-1. The uptake of IR-Exo by irradiated PC cells decreased the migration and invasion capacities of all PC cell lines in vitro. Additionally, IR-Exos prevented liver metastasis induced by MIAPaCa-2 cells in vivo We detected 2,565 miRNAs in exosomes in a microarray. Seventeen of these genes were differentially expressed between the exosomes isolated from non-irradiated cells (0 Gy-Cells) and IR-Exo. miR-3160-5p was the most upregulated miRNA in IR-Exo. Transfection of miR-3160-5p into PC cells decreased cell migration and invasion. Furthermore, expression of Repulsive Guidance Molecule BMP Co-Receptor B (RGMB), a target molecule of miR-3160-5p, was significantly decreased by the addition of miR-3160-5p. Knockdown of RGMB expression significantly prevented cell migration and invasion. Thus, irradiation increases exosomal miR-3160-5p expression and inhibits cell migration and invasion via a decrease in RGMB expression. This points toward new treatment targets or biomarkers.

We aimed to investigate the dosimetric effects of a spacer placed between the pancreas and surrounding gastrointestinal structures in intensity-modulated radiation therapy (IMRT) planning to provide more effective radiation therapy for locally advanced pancreatic cancer (LAPC). Treatment planning was performed for six patients with LAPC based on computed tomography images without spacers and with 5-mm or 10-mm spacers virtually inserted under the supervision of a hepatobiliary pancreatic surgeon. The prescription dose was 63 Gy in 28 fractions. With the exception of one case of pancreatic head cancer, planning target volume receiving ≥95% of the prescribed dose (PTV V95) was achieved by 90% or more by inserting a spacer, and by 95% or more in all 3 cases of pancreatic body and tail cancer by inserting a 10-mm spacer. IMRT with appropriate spacer placement may help provide high-dose treatment for LAPC and improve associated patient outcomes.