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Trimetazidine exhibits great therapeutic potential in cardiovascular diseases and mitochondria-mediated cardioprotection by trimetazidine has been widely reported. In this study, to enhance its cardioprotection, the triphenylphosphonium-based modification of trimetazidine was conducted to deliver it specifically to mitochondria. Fifteen triphenylphosphonium (TPP) conjugated trimetazidine analogs were designed and synthesized. Their protective effects were evaluated in vivo using a tert-butyl hydroperoxide (t-BHP) induced zebrafish injury model. Structure-activity relationship correlations revealed the best way to couple the TPP moiety to trimetazidine, and led to a new conjugate (18a) with enhanced therapeutic properties. Compared to trimetazidine, 18a effectively protects against heart injury in the zebrafish model at a much lower concentration. Further study in t-BHP treated zebrafish and H9c2 cells demonstrated that 18a protects against cardiomyocyte death and damage by inhibiting excessive production of ROS, maintaining mitochondrial morphology, and preventing mitochondrial dysfunction. Consequently, 18a can be regarded as a potential therapeutic agent for cardioprotection.

Glioblastoma (GBM) is an aggressive primary brain tumor in adults featured with low overall survival (OS) of around 10-16 months, which is estimated to cause about 200,000 deaths related to the tumors of central nervous systems every year. Therefore, precise therapy on newly diagnosed GBM and increase median OS through concurrent tumor treating fields (TTFields) and chemoradiotherapy (the standard-of-care treatment proposed by NCCN) is of great significance. Though introducing latex-free sponge media was reported beneficial for improving concurrent TTFields and chemoradiotherapy efficacy on GBM, the specific enhancement mechanism and physical/chemical parameters of sponge media has not been studied as far as we know. Herein, different latex-free polyurethane sponges were selected based on SPARE phase II clinical research to investigate their impact on the concurrent TTFields and chemoradiotherapy efficacy on GBM. As computed tomography (CT) imaging of tumor and radiation dose are two vital factors for radiotherapy, the Hounsfield unit (HU) values of sponges were tested under Micro-CT firstly and the results suggest that the sponges with HU value lower than -750 have almost no impact on CT image, and clearer CT image is obtained upon the sponge with lower HU value. Moreover, eight clinical IMRT/VMAT plans were selected randomly and delivered into the bare (as a reference) or each-of-samples-surrounded CIRS head phantom with built-in EBT film to evaluate dosimetry effect. Film-based Gamma Passing Rate (2%/2 mm criteria, 20% threshold) analysis indicates that all the dose distributions upon three sponges (99.55±0.23, 99.54±0.22 and 99.59±0.19, respectively) are in good consistence with that over the reference (99.31%~99.98%). Importantly, the enhancement mechanism of latex-free sponge on concurrent TTFields and radiotherapy efficacy was studied and it corroborated that the introduced sponge could reduce the artifacts of target delineation generated in the presence of transducer array, decrease the position error of transducer array movement/replacement on scalp, lower constrictive injury during TTFields therapy (especially for locating transducer array position upon CT imaging), and reduce the adverse event of TTFields including irritant or allergic contact dermatitis caused by transducer array in the period of radiotherapy. This work corroborates that introducing low-HU-value sponge media into concurrent TTFields and chemoradiotherapy for GBM is a promising strategy to enhance therapy efficacy and thus improve or maintain the quality of patients’ life. Citation Format: Jiajun Zheng, Huanfeng Zhu, Wenjie Guo, Jiahao Guo, Chechen Cao, Li Sun, Geng Xu, Zhi Wang, Baoying Dai, Ning Gu, Xia He. Investigation of sponge property for enhanced concurrent tumor treating fields and radiotherapy for glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2825.

Iron is one of the most important strategic materials in national production, and the demand for iron ore is huge in the world. High quality iron ore reserves have been almost exhausted, and it is necessary to develop a technology that utilizes low-grade iron ore. Limonite is a representative low-grade iron ore due to its complex mineral and elemental composition. In this paper, the union process was employed to separate the iron elements in low-grade limonite. Firstly, a rough iron concentrate was obtained under 1.0 T of magnetic field intensity and −0.074 mm > 94.84% of grinding fineness; then, the rough iron concentrate was magnetization roasted under a temperature of 700 °C, 60 min of retention time, 3 wt% of biochar consumption, and 0.15 T of magnetic field intensity. The grade of iron concentrate was 59.57% and the recovery of iron was 90.72%. Finally, the red iron pigment was produced via a high temperature hydrothermal method in order to increase the additional value of this ultra-low-grade limonite. The optimal parameters were 10.0 g/L of solution acidity, a 200 °C reaction temperature, 5 h of reaction time, and a 6:1 solid-to-liquid ratio. The reaction mechanism was also discussed.

Step detection is very important for the foot-mounted Pedestrian Dead Reckoning (PDR) system. To deal with the false detection caused by variant stepping modes and occasional disturbance, a novel robust step detection algorithm is proposed. The proposed algorithm detects the number of steps and zero-velocity phase using data from inertial sensors mounted on the user’s foot. It includes two parts: a novel anti-fault detection algorithm and a novel zero-velocity detection method, which are used to reduce the over-detection and miss-detection of steps, respectively. Field tests show that the proposed approach is robust under varying motion speeds in different step modes for different persons and the average accuracy of the proposed algorithm is 99.94% in all motion modes, which significantly exceeds conventional estimation approaches in terms of step detection accuracy.

OBJECTIVES Given the increasing importance of patient’s perspective in adverse events reporting, Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE™) has been proposed as new PRO measures in oncology; however, its implementation has not yet been evaluated in glioma patients, and standardized selection process of priority symptom terms has not been applied. METHODS A total of 16 experts (13 neurosurgeons, 2 radiotherapists, 1 psychiatrist) from 14 medical centers in China were invited to participate in a consensus-seeking 2-round online Delphi survey. Participants rated the level of their agreement with each symptom term likely to occur during adult diffuse gliomas treatment on a 5-point Likert scale. Terms not reaching consensus over the first round were modified in the second rounds. Consensus was defined as content validity index (CVI) > 0.78，coefficient of variation (CV)< 0.35 and average Likert score > 3.00. RESULTS Experts reached a consensus on 21 PRO-CTCAE™ symptom terms in the first Delphi round, and 10 terms in the second round. Likert scale scoring among all experts showed significant consistency (Round 1: Kendall’s W= 0.415，p＜0.001; Round 2: Kendall’s W = 0.351，P＜0.001). The 31 terms (38.75%) screened out of all 78 terms covered neurological symptoms(n=7), psychiatric symptoms(n=6), dermatological symptoms(n=6), gastrointestinal symptoms(n=5) and other common postoperative systemic symptoms of glioma patients. CONCLUSIONS We identified a customized PRO-CTCAE™ questionnaire containing a core set of priority symptom terms for the adult diffuse glioma through a 2-round Delphi survey. Next, a prospective, multi-center, real-word study would be performed to assess the validity, reliability and responsiveness of the customized PRO-CTCAE™ for adult diffuse glioma patients in Chinese population (VERONICA).

Purpose Lung cancer is the leading cause of cancer-related mortality. STEAP1 and STEAP2 are overexpressed in various cancers. The purpose of this study was to evaluate the expression and prognostic value of STEAP1 and STEAP2 in patients with lung cancer. Methods The mRNA expression and protein expression of STEAP1 and STEAP2 and their prognostic characteristics were examined using Oncomine, GEPIA, and Kaplan-Meier (KM) plotters. The correlation analysis of STEAP1 and STEAP2 gene and protein levels was conducted using GeneMANIA and STRING. KEGG pathway analysis was used to explore the related signal pathways of STEAP 1 and STEAP2. Immunohistochemical methods were used to compare the expression of STEAP2 in normal lung and non-small cell lung cancer (NSCLC) tissues. Real-time quantitative polymerase chain reaction, western blotting, and immunocytochemistry were used to evaluate the expression of STEAP1 and STEAP2 in three lung cancer cell lines and normal lung epithelial cell lines. Results Analysis of the Oncomine database and GEPIA showed that STEAP1 was upregulated and STEAP2 was downregulated in lung cancer tissue, and both expressions were related to the clinical stage of lung cancer. Immunohistochemical analysis showed that STEAP1 protein expression was significantly upregulated in lung cancer compared to that in adjacent tissues. The expression of STEAP1 was positively correlated with the migration and invasion abilities of lung cancer cells. Compared with paracancer tissues, the expression of STEAP2 protein in lung cancer was significantly downregulated and was correlated with the histological grade of squamous cell carcinoma, pathological classification of adenocarcinoma, tumor, lymph node, and metastasis clinical stage, and lymph node metastasis. The expression of STEAP2 was negatively correlated with the migration and invasion abilities of lung cancer cells. The KM curve showed that the downregulation of STEAP1 expression and upregulation of STEAP2 expression were related to a good lung cancer prognosis. Conclusion STEAP1 and STEAP2 are expected to be potential diagnostic and prognostic markers for lung cancer, which may provide more accurate prognostic indicators for lung cancer.

Background Transcription factors (TFs) play central roles in regulating gene expression. With the rapid growth in the use of high-throughput sequencing methods, there is a need to develop a comprehensive data processing and analyzing framework for inferring influential TFs based on ChIP-seq/ATAC-seq datasets. Results Here, we introduce FindIT2 (Find Influential TFs and Targets), an R/Bioconductor package for annotating and processing high-throughput multi-omics data. FindIT2 supports a complete framework for annotating ChIP-seq/ATAC-seq peaks, identifying TF targets by the combination of ChIP-seq and RNA-seq datasets, and inferring influential TFs based on different types of data input. Moreover, benefited from the annotation framework based on Bioconductor, FindIT2 can be applied to any species with genomic annotations, which is particularly useful for the non-model species that are less well-studied. Conclusion FindIT2 provides a user-friendly and flexible framework to generate results at different levels according to the richness of the annotation information of user’s species. FindIT2 is compatible with all the operating systems and is released under Artistic-2.0 License. The source code and documents are freely available through Bioconductor (https://bioconductor.org/packages/devel/bioc/html/FindIT2.html).

To better solve the filtering problem of transfer alignment with an inaccurate measurement noise covariance matrix, a novel computationally efficient version of existing variational adaptive Kalman filter is proposed in this paper, in which an equivalent variational iteration process of the measurement noise covariance matrix is derived. The proposed filter is identical to the existing variational adaptive Kalman filter, but the total computational complexity of algorithm implementation is significantly reduced, which facilitates the application of variational adaptive Kalman filter to transfer alignment. Simulation and experiment results of transfer alignment demonstrate that the computational complexity of the proposed filter is reduced by 55.4% as compared with existing variational adaptive Kalman filter.

A series of mitochondria-targeted triphenylphosphonium conjugated C-3 modified betulin were synthesized and evaluated against tumor cells. As a result, a new derivative 13 i, the conjugate of 3-O-(3'-acetylphenylacetate)-betulin with triphenylphosphonium, was identified as the one with the best anti-tumor effect. Conjugate 13 i significantly inhibited HCT116 cells with IC

The placement of left ventricular (LV) pacing lead at the latest activation sites with viable myocardium confers better cardiac resynchronization therapy (CRT) response ([1–3][1]). However, placing LV lead at the appropriate site remains a challenge for achieving an adequate CRT response. This

DNA methylation affects gene expression and maintains genome integrity. The DNA-dependent RNA polymerase IV (Pol IV), together with the RNA-dependent RNA polymerase RDR2, produces double-stranded small interfering RNA precursors essential for establishing and maintaining DNA methylation in plants. We determined the cryo–electron microscopy structures of the Pol IV–RDR2 holoenzyme and the backtracked transcription elongation complex. These structures reveal that Pol IV and RDR2 form a complex with their active sites connected by an interpolymerase channel, through which the Pol IV–generated transcript is handed over to the RDR2 active site after being backtracked, where it is used as the template for double-stranded RNA (dsRNA) synthesis. Our results describe a ‘backtracking-triggered RNA channeling’ mechanism underlying dsRNA synthesis and also shed light on the evolutionary trajectory of eukaryotic RNA polymerases.

Significance Why the developmental transitions of multicellular organisms are unidirectional and how the rate of these transitions is determined are biological mysteries. Earlier reports have shown that both animals and plants utilize microRNA (miRNA) as a timer in regulating their developmental transitions. However, how age temporally regulates the abundance of these miRNAs is poorly understood. In plants, the progressive decline in miR156 triggers the appearance of adult traits. Here, we show that cell division in the apical meristem is a trigger for miR156 decline. The transcriptional decline in MIR156C along with cell division in the apical meristem contributes to plant maturation. This simple model explains why the developmental transitions of a plant are unidirectional and inevitable under normal growth conditions.

ObjectiveTumor metabolism has always been the focus of cancer research. SLC16A1, as a key factor in catalysis of monocarboxylate transport across the plasma membrane, has been found to be associated with the occurrence and metastasis of a variety of cancers, but its prognostic significance and mechanism in different tumors are still unclear.MethodsBased on the gene expression matrix and clinical information of human cancer tissues acquired from TCGA and GTEX databases, the differential expression of SLC16A1 in different tumors and normal tissues was analyzed. To confirm the association between its expression, the mutation of MMRS gene, and the expression level of DNMTs. Univariate Cox regression was applied to analyze the association between SLC16A1 expression and patient prognosis. The effect of SLC16A1 expression on patient survival was examined by Kaplan Meier analysis. GSEA was used to identify related signaling pathways.ResultsThe expression of SLC16A1 was differentially expressed in most tumors, especially in the urinary tract where it is commonly highly expressed, and differential expression of SLC16A1 in different clinical stages. SLC16A1 expression was significantly positively correlated with MMRS gene mutation and DNMTS expression. Moreover, high SLC16A1 expression was associated with poorer overall survival (OS) and progression-free survival (PFS) in urological cancers. In particular, the results of the enrichment analysis showed that SLC16A1 was associated with processes such as cell adhesion and many signaling pathways affecting cell cycle were significantly enriched in the group with high-expressed SLC16A1.ConclusionSLC16A1 expression was upregulated in urological cancer. SLC16A1 may promote tumor development by regulating the epigenetic process of urological cancer and demonstrated a great potential as a prognostic biomarker of urological cancer patients.