The abscisic acid-responsive element binding factors MAPKKK18 module regulates abscisic acid-induced leaf senescence in Arabidopsis.

The mitogen-activated protein kinase kinase kinase 18 (MAPKKK18) has been reported to play a role in abiotic stress priming in long-term abscisic acid (ABA) response including drought tolerance and leaf senescence. However, the upstream transcriptional regulators of MAPKKK18 remain to be determined. Here, we report ABA-responsive element binding factors (ABFs) as upstream transcription factors of MAPKKK18 expression. Mutants of abf2, abf3, abf4, and abf2abf3abf4 dramatically reduced the transcription of MAPKKK18. Our electrophoresis mobility shift assay and dual-luciferase reporter assay demonstrated that ABF2, ABF3, and ABF4 bound to ABA-responsive element cis-elements within the promoter of MAPKKK18 to transactivate its expression. Furthermore, enrichments of the promoter region of MAPKKK18 by ABF2, ABF3, and ABF4 were confirmed by in vivo chromatin immunoprecipitation coupled with quantitative PCR. In addition, we found that mutants of mapkkk18 exhibited obvious delayed leaf senescence. Moreover, a genetic study showed that overexpression of ABF2, ABF3, and ABF4 in the background of mapkkk18 mostly phenocopied the stay-green phenotype of mapkkk18 and, expression levels of five target genes of ABFs, that is, NYE1, NYE2, NYC1, PAO, and SAG29, were attenuated as a result of MAPKKK18 mutation. These findings demonstrate that ABF2, ABF3, and ABF4 act as transcription regulators of MAPKKK18 and also suggest that, at least in part, ABA acts in priming leaf senescence via ABF-induced expression of MAPKKK18.

Prophylactic antibiotic treatment with TMP-SMX decreased the incidence of interstitial pneumonia in patients with B-cell lymphoma on chemotherapy.

BACKGROUND: Several studies have reported the incidence of interstitial pneumonia (IP) among patients with non-Hodgkin lymphoma (NHL) that are undergoing combination chemotherapy plus rituximab; however, the effective prophylactic treatment for IP remains unclear. This study aims to explore the prophylactic effect of trimethoprim-sulfamethoxazole (TMP-SMX) on IP and identify IP-associated risk factors in NHL patients. METHODS: Between March 2013 and April 2018, 498 patients (264 males, 53%) with B-cell NHL undergoing first-line RCHOP-like chemotherapy treatment with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone were enrolled in this study. RESULTS: These patients had a median age of 56 years, and 311 of the 498 patients (62.4%) were administered once daily with the prophylactic treatment of TMP-SMX. IP occurred in 65 patients (13.1%), indicating a significant reduction in the IP incidence rate (21.4% vs. 8.0%; p < 0.001). Among patients treated with TMP-SMX, 2 (1.2%) exhibited rashes, 38 (12.2%) suffered from nausea and vomiting, 52 (16.7%) showed signs of neutropenia, and 18 (5.8%) suffered from kidney dysfunction. Both univariate and multivariate analysis showed that gender (male), history of diabetes, and absence of prophylactic TMP-SMX treatment were significant risk factors associated with IP. Disease progression was observed in 55/311 (17.7%) patients that underwent prophylactic TMP-SMX treatment and in 63/187 (33.7%) patients that did not (p < 0.001). CONCLUSIONS: This study revealed that the occurrence of IP was common in B-cell NHL patients undergoing combined chemotherapy plus rituximab treatment. IP could be reduced with prophylactic treatment of once-daily oral TMP-SMX.

Can computed tomography-based radiomics potentially discriminate between anterior mediastinal cysts and type B1 and B2 thymomas?

BACKGROUND: Anterior mediastinal cysts (AMC) are often misdiagnosed as thymomas and undergo surgical resection, which caused unnecessary treatment and medical resource waste. The purpose of this study is to explore potential possibility of computed tomography (CT)-based radiomics for the diagnosis of AMC and type B1 and B2 thymomas. METHODS: A group of 188 patients with pathologically confirmed AMC (106 cases misdiagnosed as thymomas in CT) and thymomas (82 cases) and underwent routine chest CT from January 2010 to December 2018 were retrospectively analyzed. The lesions were manually delineated using ITK-SNAP software, and radiomics features were performed using the artificial intelligence kit (AK) software. A total of 180 tumour texture features were extracted from enhanced CT and unenhanced CT, respectively. The general test, correlation analysis, and LASSO were used to features selection and then the radiomics signature (radscore) was obtained. The combined model including radscore and independent clinical factors was developed. The model performances were evaluated on discrimination, calibration curve. RESULTS: Two radscore models were constructed from the unenhanced and enhanced phases based on the selected four and three features, respectively. The AUC, sensitivity, and specificity of the enhanced radscore model were 0.928, 89.3%, and 83.8% in the training dataset and 0.899, 84.6%, and 87.5% in the test dataset (higher than the unenhanced radscore model). The combined model of enhanced CT including radiomics features and independent clinical factors yielded an AUC, sensitivity and specificity of 0.941, 82.1%, and 94.6% in the training dataset and 0.938, 92.3%, and 87.5% in the test dataset (higher than the unenhanced combined model and enhanced radscore model). CONCLUSIONS: The study suggested the possibility that the combined model in enhanced CT provided a potential tool to facilitate the differential diagnosis of AMC and type B1 and B2 thymomas.

Rapeseed PP2C37 Interacts with PYR/PYL Abscisic Acid Receptors and Negatively Regulates Drought Tolerance.

Global water deficit is a severe abiotic stress threatening the yielding and quality of crops. Abscisic acid (ABA) is a phytohormone that mediates drought tolerance. Protein kinases and phosphatases function as molecular switches in eukaryotes. Protein phosphatases type 2C (PP2Cs) are a major family that play essential roles in ABA signaling and stress responses. However, the role and underlying mechanism of PP2C in rapeseed (Brassica napus L.) mediating drought response has not been reported yet. Here, we characterized a PP2C family member, BnaPP2C37, and its expression level was highly induced by ABA and dehydration treatments. It negatively regulates drought tolerance in rapeseed. We further identified that BnaPP2C37 interacted with multiple PYR/PYL receptors and a drought regulator BnaCPK5 (calcium-dependent protein kinase 5) through yeast two-hybrid (Y2H) and bimolecular fluorescence complementation (BiFC) assays. Specifically, BnaPYL1 and BnaPYL9 repress BnaPP2C37 phosphatase activity. Moreover, the pull-down assay and phosphatase assays show BnaPP2C37 interacts with BnaCPK5 to dephosphorylate BnaCPK5 and its downstream BnaABF3. Furthermore, a dual-luciferase assay revealed BnaPP2C37 transcript level was enhanced by BnaABF3 and BnaABF4, forming a negative feedback regulation to ABA response. In summary, we identified that BnaPP2C37 functions negatively in drought tolerance of rapeseed, and its phosphatase activity is repressed by BnaPYL1/9 whereas its transcriptional level is upregulated by BnaABF3/4.

Efficacy and safety of anlotinib combined with the STUPP regimen in patients with newly diagnosed glioblastoma: a multicenter, single-arm, phase II trial.

OBJECTIVE: Glioblastomas are highly vascularized malignant tumors. We determined the efficacy and safety of the anti-angiogenic multi-kinase inhibitor, anlotinib, for a newly diagnosed glioblastoma. METHODS: This multicenter, single-arm trial (NCT04119674) enrolled 33 treatment-naïve patients with histologically proven glioblastomas between March 2019 and November 2020. Patients underwent treatment with the standard STUPP regimen [fractionated focal irradiation in daily fractions of 1.8-2 Gy given 5 d/w × 6 w (total = 54-60 Gy)] or radiotherapy plus continuous daily temozolomide (TMZ) (75 mg/m2 of body surface area/d, 7 d/w from the first to the last day of radiotherapy), followed by 6 cycles of adjuvant TMZ (150-200 mg/m2 × 5 d during each 28-d cycle) plus anlotinib (8 mg/d on d 1-14 of each 3-w cycle for 2 cycles during concomitant chemoradiotherapy, 8 maximal cycles as adjuvant therapy, followed by maintenance at 8 mg/d. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS) and adverse events (AEs). RESULTS: Thirty-three patients received the planned treatment. The median PFS was 10.9 months (95% CI, 9.9-18.7 months) and the 12-month PFS rate was 48.5%. The median OS was 17.4 months (95% CI, 14.5-21.1 months) and the 12-month OS rate was 81.8%. The most common AEs included hypertriglyceridemia [58% (n = 19)], hypoalbuminemia [46% (n = 15)], and hypercholesterolemia [46% (n = 15)] during concurrent chemoradiotherapy and leukopenia [73% (n = 24)], hypertriglyceridemia [67% (n = 22)], and neutropenia [52% (n = 17)] during adjuvant therapy. Five patients discontinued treatment due to AEs. HEG1 (HR, 5.6; 95% CI, 1.3-23.7; P = 0.021) and RP1L1 alterations (HR, 11.1; 95% CI, 2.2-57.2; P = 0.004) were associated with a significantly shorter PFS. CONCLUSIONS: Anlotinib plus the STUPP regimen has promising anti-tumor activity against glioblastoma and manageable toxicity. HEG1 and RP1L1 alterations might be novel predictive biomarkers of the response to anlotinib.

Measurement of Cumulative fission product yields on 235U induced by 2.8 MeV neutrons.

Off-line gamma-ray spectrometry was used to accurately measure the Cumulative fission product yields (CFPYs) of fission products in the 235U (n, f) reaction induced by 2.8 MeV neutrons. The 2.8 MeV quasi-monoenergetic neutron beam was produced by the CPNG-600 Cockcroft Walton accelerator at the China Institute of Atomic Energy （CIAE）and the gamma spectra were measured by the HPGe γ-ray Spectrometer. After fully considering and revising the sources of uncertainty, high-precision CFPYs of 4 fission products were obtained. This study has important applications in reactor design and operation and is conducive to the establishment of an evaluated nuclear database.

A radiomics nomogram for predicting postoperative recurrence in esophageal squamous cell carcinoma.

Purpose: To establish and validate a radiomics nomogram for predicting recurrence of esophageal squamous cell carcinoma (ESCC) after esophagectomy with curative intent. Materials and methods: The medical records of 155 patients who underwent surgical treatment for pathologically confirmed ESCC were collected. Patients were randomly divided into a training group (n=109) and a validation group (n=46) in a 7:3 ratio. ​Tumor regions are accurately segmented in computed tomography images of enrolled patients. Radiomic features were then extracted from the segmented tumors. We selected the features by Max-relevance and min-redundancy (mRMR) and least absolute shrinkage and selection operator (LASSO) methods. A radiomics signature was then built by logistic regression analysis. To improve predictive performance, a radiomics nomogram that incorporated the radiomics signature and independent clinical predictors was built. Model performance was evaluated by receiver operating characteristic (ROC) curve, calibration curve, and decision curve analyses (DCA). Results: We selected the five most relevant radiomics features to construct the radiomics signature. The radiomics model had general discrimination ability with an area under the ROC curve (AUC) of 0.79 in the training set that was verified by an AUC of 0.76 in the validation set. The radiomics nomogram consisted of the radiomics signature, and N stage showed excellent predictive performance in the training and validation sets with AUCs of 0.85 and 0.83, respectively. Furthermore, calibration curves and the DCA analysis demonstrated good fit and clinical utility of the radiomics nomogram. Conclusion: We successfully established and validated a prediction model that combined radiomics features and N stage, which can be used to predict four-year recurrence risk in patients with ESCC who undergo surgery.

Radiomics based on pretreatment MRI for predicting distant metastasis of nasopharyngeal carcinoma: A preliminary study.

Objective: To explore the feasibility of predicting distant metastasis (DM) of nasopharyngeal carcinoma (NPC) patients based on MRI radiomics model. Methods: A total of 146 patients with NPC pathologically confirmed, who did not exhibit DM before treatment, were retrospectively reviewed and followed up for at least one year to analyze the DM risk of the disease. The MRI images of these patients including T2WI and CE-T1WI sequences were extracted. The cases were randomly divided into training group (n=116) and validation group (n=30). The images were filtered before radiomics feature extraction. The least absolute shrinkage and selection operator (LASSO) regression was used to develop the dimension of texture parameters and the logistic regression was used to construct the prediction model. The ROC curve and calibration curve were used to evaluate the predictive performance of the model, and the area under curve (AUC), accuracy, sensitivity, and specificity were calculated. Results: 72 patients had DM and 74 patients had no DM. The AUC, accuracy, sensitivity and specificity of the model were 0. 80 (95% CI: 0.72~0. 88), 75.0%, 76.8%, 73.3%. and0.70 (95% CI: 0.51~0.90), 66.7%, 72.7%, 63.2% in training group and validation group, respectively. Conclusion: The radiomics model based on logistic regression algorithm has application potential for evaluating the DM risk of patients with NPC.

Clinical features, treatment and risk factors for interstitial pneumonia in B-cell non-Hodgkin lymphoma patients.

BACKGROUND: Interstitial pneumonia (IP) is a common and fatal adverse effect of rituximab-containing immunochemotherapy in lymphoma patients. Following prophylactic treatment with trimethoprim-sulfamethoxazole (TMP-SMX), the clinical features, treatment, and risk factors for IP development remain largely undefined. METHODS: From April 2015 and April 2018, 294 patients diagnosed with CD20+ B-cell non-Hodgkin lymphoma (NHL) were included in this study. All patients received front-line RCHOP-like chemotherapy and prophylactic treatment of TMP-SMX once daily. We summarized the clinicopathologic characteristics and treatment outcomes of IP in these patients and explored the possible risk factors of IP. RESULTS: The overall incidence of IP was 8.16%. Typical clinical symptoms included fever for 1-3 days in 11 patients, dyspnea in 4 patients, expectoration in 5 patients, and dry cough in 7 patients. A total of 8 patients showed no apparent symptoms. Prior to IP, the median number of chemotherapy cycles was 4. The median time for IP initiation was 63 days, and the median duration of IP treatment was 11 days. All patients recovered from IP after treatment. A total of 6 patients continued to receive chemotherapy without rituximab, and 14 patients received rituximab combined with chemotherapy. No patients experienced IP recurrence. In univariate and multivariate analysis, male, diabetes, low lymphocyte counts (<1.0×109/L) and low CD4/CD8 counts were identified as risk factors of IP. Patients with no risk factors were included in the low-risk group; 1 to 2 factors: intermediate-risk; ≥3: high-risk. The occurrence of IP differed across three groups (low risk, 0%; intermediate risk, 7%; high risk, 14.5%; P=0.059). CONCLUSIONS: The incidence of IP was 8.16% in patients with CD20+ B-cell NHL. Males, diabetes, low absolute lymphocyte counts (ALC) (<1.0×109/L) and low CD4/CD8 were identified as risk factors of IP.

Video-Assisted Thoracoscopic Lobectomy Versus Stereotactic Body Radiotherapy Treatment for Early-Stage Non-Small Cell Lung Cancer: A Propensity Score-Matching Analysis.

BACKGROUND: Compared the overall outcomes of video-assisted thoracoscopic surgery (VATS) versus stereotactic body radiotherapy (SBRT) for stage I-II non-small cell lung cancer (NSCLC). METHODS: We retrospectively compared overall survival (OS), cancer-specific survival (CSS), locoregional control (LRC), and disease-free survival (DFS) at our institution between January 2012 and December 2016. Propensity score-matching was performed to reduce patient selection bias based on age, gender, Karnofsky performance score, Charlson comorbidity index, pulmonary function, and tumor diameter. RESULTS: A total of 567 patients treated with SBRT (n = 109) or surgery (n = 458) were included. Of those, 104 patients were matched for further analyses. Median follow-up was 44 months. At 3 and 5 years, OS was 88.6 and 79.9% for SBRT, and 94.2 and 91.6% for surgery (p = 0.097). There were no differences noted in 5-year CSS (83.7 vs. 91.6%, respectively; p = 0.270). The cumulative incidence of LRC at 3 and 5 years was comparable (93.5 and 93.5% vs. 94.0 and 85.9%, respectively; p = 0.621). Differences in the rates of disease-free survival at 5 years were not statistically significant (79.0 and 80.5%, respectively; p = 0.624). CONCLUSIONS: This propensity score-matching analysis suggests that SBRT can be an alternative option to VATS lobectomy for stage I-II NSCLC.

Comparison of the outcomes of sublobar resection and stereotactic body radiotherapy for stage T1-2N0M0 non-small cell lung cancer with tumor size ≤ 5 cm: a propensity score matching analysis.

BACKGROUND: Surgery and stereotactic body radiotherapy (SBRT) are both suitable treatment options for early stage Non-small cell lung cancer (NSCLC), which accounts for the majority of lung cancer. This study compared the outcomes of sublobar resection (SLR) and SBRT in patients with stage T1-2N0M0 NSCLC with tumor size ≤5 cm. METHODS: Patients with T1-2N0M0 lung cancer who underwent SLR or SBRT between January, 2012 and December, 2016 were included in this retrospective study. The survival outcomes and toxicity of the SLR and SBRT cohorts were compared using Kaplan-Meier survival plots. In a second exploratory analysis, propensity score matching (PSM) was applied to reduce selection bias between the two groups of patients. RESULTS: A total of 121 SLR and 109 SBRT cases were included. The average follow-up was 49.4 months. Prior to PSM, the 5-year overall survival (OS) and cancer-specific survival (CSS) rates in the SLR group (82.8% and 89.0%, respectively) were superior to those in the SBRT group (67.0% and 75.3%; P=0.001 and P=0.013, respectively). There were no statistically significant differences in the five-year locoregional control and disease-free survival (DFS) rates between the groups. PSM identified 40 patients from each treatment group who shared similar characteristics. At 5 years, the OS rates in the SLR and SBRT groups were comparable (79.9% vs. 66.5%, respectively; P=0.154). After PSM, the rates of CSS, locoregional control, and DFS were also similar between the groups (P=0.458, 0.369, and 0.698, respectively). In the SBRT group, one patient developed grade 3 radioactive pneumonitis. No grade >3 toxicities or treatment-related deaths occurred in either group. CONCLUSIONS: SBRT may be an alternative option to SLR for patients who cannot tolerate lobectomy because of medical comorbidities and has a similar level of effectiveness.

The significance of multi-line chemotherapy for advanced gastric cancer: A retrospective analysis.

Palliative chemotherapy is known to benefit patients with advanced gastric cancer by palliating symptoms and improving survival. The aim of the present study was to evaluate the efficacy and toxicity of chemotherapy regimens that are commonly used in patients with advanced or recurrent gastric cancer. Patients with advanced or recurrent gastric cancer who were treated by at least two chemotherapy regimens between May 2006 and July 2014 at Zhejiang Cancer Hospital (Hangzhou, China) were retrospectively investigated. Survival was evaluated using the Kaplan-Meier method. A total of 248 patients were reviewed, and 158 were evaluated in the final analysis, with a median age of 57 years and a Karnofsky performance status score of ≥80. The median progression-free survival (PFS) time was 168 days for first-line chemotherapy, 96 days for second-line chemotherapy, and the median overall survival (OS) time was 356 days. Further analysis revealed that patients with the disease controlled [complete response (CR) + partial response (PR) + stable disease (SD)], no matter whether they received first-or second-line chemotherapy, may have had an improved OS compared with patients with disease progression (PD). Patients who were treated with >2 lines of chemotherapy had an improved OS compared those who ceased treatment following failure of the second-line chemotherapy. The cycle number of chemotherapy that patients received was associated with OS. The site of the primary and metastatic tumors was also associated with OS. Other factors, including gender, age, histological type, whether a radical operation was received, and chemotherapy regimens, had no evident association with survival. The toxicities were generally tolerated. Taken together, the results from the present study have demonstrated that an increased cycle number of effective chemotherapy may prolong the survival of patients with advanced gastric cancer. Differences among the chemotherapy regimens had no clear correlation with survival.

A retrospective analysis of hyperthermic intraperitoneal chemotherapy for gastric cancer with peritoneal metastasis.

Peritoneal metastasis (PM) is a poor prognostic factor in patients with gastric cancer. The aim of this study was to evaluate the efficacy and safety of hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with advanced gastric cancer with PM by retrospective analysis. A total of 54 gastric cancer patients with positive ascitic fluid cytology were included in this study: 23 patients were treated with systemic chemotherapy combined with HIPEC (HIPEC+ group) and 31 received systemic chemotherapy alone (HIPEC- group). The patients were divided into 4 categories according to the changes of ascites, namely disappear, decrease, stable and increase. The disappear + decrease rate in the HIPEC+ group was 82.60%, which was statistically significantly superior to that of the HIPEC- group (54.80%). The disappear + decrease + stable rate was 95.70% in the HIPEC+ group and 74.20% in the HIPEC- group, but the difference was not statistically significant. In 33 patients with complete survival data, including 12 from the HIPEC+ and 21 from the HIPEC- group, the median progression-free survival was 164 and 129 days, respectively, and the median overall survival (OS) was 494 and 223 days, respectively. In patients with ascites disappear/decrease/stable, the OS appeared to be better compared with that in patients with ascites increase, but the difference was not statistically significant. Further analysis revealed that patients with controlled disease (complete response + partial response + stable disease) may have a better OS compared with patients with progressive disease, with a statistically significant difference. The toxicities were well tolerated in both groups. Therefore, HIPEC was found to improve survival in advanced gastric cancer patients with PM, but the difference was not statistically significant, which may be attributed to the small number of cases. Further studies with larger samples are required to confirm our data.