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Abstract Background Acute myeloid leukemia (AML) is a hematopoietic malignancy with poor outcomes, especially in older AML patients. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is considered a promising anticancer drug because it selectively induces the extrinsic apoptosis of tumor cells without affecting normal cells. However, clinical trials have shown that the responses of patients to TRAIL are significantly heterogeneous. It is necessary to explore predictable biomarkers for the preselection of AML patients with better responsiveness to TRAIL. Here, we investigated the critical role of tumor protein p53 inducible nuclear protein 2 (TP53INP2) in the AML cell response to TRAIL treatment. Methods First, the relationship between TP53INP2 and the sensitivity of AML cells to TRAIL was determined by bioinformatics analysis of Cancer Cell Line Encyclopedia datasets, Cell Counting Kit-8 assays, flow cytometry (FCM) and cell line-derived xenograft (CDX) mouse models. Second, the mechanisms by which TP53INP2 participates in the response to TRAIL were analyzed by Western blot, ubiquitination, coimmunoprecipitation and immunofluorescence assays. Finally, the effect of TRAIL alone or in combination with the BCL-2 inhibitor venetoclax (VEN) on cell survival was explored using colony formation and FCM assays, and the effect on leukemogenesis was further investigated in a patient-derived xenograft (PDX) mouse model. Results AML cells with high TP53INP2 expression were more sensitive to TRAIL in vitro and in vivo. Gain- and loss-of-function studies demonstrated that TP53INP2 significantly enhanced TRAIL-induced apoptosis, especially in AML cells with nucleophosmin 1 (NPM1) mutations. Mechanistically, cytoplasmic TP53INP2 maintained by mutant NPM1 functions as a scaffold bridging the ubiquitin ligase TRAF6 to caspase-8 (CASP 8), thereby promoting the ubiquitination and activation of the CASP 8 pathway. More importantly, simultaneously stimulating extrinsic and intrinsic apoptosis signaling pathways with TRAIL and VEN showed strong synergistic antileukemic activity in AML cells with high levels of TP53INP2. Conclusion Our findings revealed that TP53INP2 is a predictor of responsiveness to TRAIL treatment and supported a potentially individualized therapeutic strategy for TP53INP2-positive AML patients.

Abstract Background Skin cutaneous melanoma (SKCM) is an extremely malignant tumor that is associated with a poor prognosis. LSM2 has been found to be related to different types of tumors; however, its role in SKCM is poorly defined. We aimed to determine the value of LSM2 as a prognostic biomarker for SKCM. Methods The expression profile of LSM2 mRNA was compared between tumor and normal tissues in public databases, such as TCGA, GEO, and BioGPS. LSM2 protein expression was explored using immunohistochemistry (IHC) on a tissue microarray containing 44 SKCM tissues and 8 normal samples collected at our center. Kaplan-Meier analysis was performed to assess the prognostic value of LSM2 expression in patients with SKCM. SKCM cell lines with LSM2 knockdown were used to determine the effects of LSM2. Cell counting kit-8 (CCK8) and colony formation assays were conducted to assess cell proliferation, whereas wound healing and transwell assays were carried out to assess the migration and invasion abilities of SKCM cells. Results LSM2 was more highly expressed at the mRNA and protein levels in SKCM than that in normal skin. Moreover, elevated expression of LSM2 was associated with shorter survival time and early recurrence in patients with SKCM. The in vitro results revealed that the silencing of LSM2 in SKCM cells significantly inhibited cell proliferation, migration, and invasion. Conclusion Overall, LSM2 contributes to malignant status and poor prognosis in patients with SKCM and may be identified as a novel prognostic biomarker and therapeutic target.

Abstract Background WRINKLED1 (WRI1) encodes a transcription factor, belonging to the APETALA2 (AP2) family, and plays a key role in regulating plant oil biosynthesis. As a newly woody oil crop, tree peony (Paeonia rockii) was notable for the abundant unsaturated fatty acids in its seed oil. However, the role of WRI1 during the accumulation of P. rockii seeds oil remains largely unknown. Results In this study, a new member of the WRI1 family was isolated from P. rockii and was named PrWRI1. The ORF of PrWRI1 consisted of 1269 nucleotides, encoding a putative protein of 422 amino acids, and was highly expressed in immature seeds. Subcellular localization analysis in onion inner epidermal cells showed that PrWRI1 was located at the nucleolus. Ectopic overexpression of PrWRI1 could significantly increase the total fatty acid content in Nicotiana benthamiana leaf tissue and even PUFAs in transgenic Arabidopsis thaliana seeds. Furthermore, the transcript levels of most genes related to fatty acids (FA) synthesis and triacylglycerol (TAG) assembly were also up-regulated in transgenic Arabidopsis seeds. Conclusions Together, PrWRI1 could push carbon flow to FA biosynthesis and further enhance the TAG amount in seeds with a high proportion of PUFAs.

Abstract Background Integrative medicine is commonly used in China. Researchers prefer to report efficacy outcomes rather than safety outcomes in clinical trials; thus, evidence regarding safety in integrative medicine is unclear. Developing a core outcome set (COS) for safety outcomes is necessary. In this study, a representative example of the methodology for developing COS to assess safety outcomes of cardiovascular diseases in clinical trials investigating integrated medicine will be developed. Methods and analysis Safety information will be extracted from package inserts and through systematic reviews of treatments for cardiovascular diseases (including angina pectoris, myocardial infarction, heart failure, arrhythmia, and hypertension) to develop an extensive list of safety outcomes, which will then be categorized according to whether subjective or objective outcomes. Questionnaires for clinician-reported safety outcomes and patient-reported safety outcomes will be developed. Two rounds of the Delphi survey will then be conducted for different stakeholders (traditional Chinese medicine clinicians and researchers in cardiovascular diseases, Western medicine clinicians and researchers in cardiovascular diseases, integrated medicine clinicians and researchers of cardiovascular diseases, pharmacologists, methodologists of evidence-based medicine, and patients). After round 2 of the Delphi analysis, a face-to-face consensus meeting will be held to determine the final COS for assessing safety outcomes in cardiovascular diseases. Discussion A COS for safety outcomes in cardiovascular diseases may improve the consistency of reporting results and will help identify potential bias of selective reporting in the future. Trial registration This study was registered in the Core Outcome Measures in Effectiveness Trials database as study 1564 .

Abstract Background Traditional Chinese medicine (TCM) has gained widespread application in treating chronic heart failure (CHF) secondary to coronary heart disease (CHD). However, the sound clinical evidence is still lacking. Corresponding clinical trials vary considerably in the outcome measures assessing the efficacy of TCM, some that showed the improvement of clinical symptoms are not universally acknowledged. Rational outcome measures are the key to evaluate efficacy and safety of each treatment and significant elements of a convincing clinical trial. We aimed to summarize and analyze outcome measures in randomized controlled trials (RCTs) of TCM in treating CHF caused by CHD, subsequently identify the present problems and try to put forward solutions. Methods We systematically searched databases including Embase, PubMed, Cochrane Library, CBM, CNKI, VIP and Wanfang from inception to October 8, 2018, to identify eligible RCTs using TCM interventions for treating CHF patients caused by CHD. Cochrane Database of Systematic Reviews (CDSR) was searched to include Cochrane systematic reviews (CSRs) of CHF. Two authors independently assessed the risk of bias of the included RCTs according to the Cochrane Handbook. Outcome measures of each trial were extracted and analyzed those compared with the CSRs. We also evaluated the reporting quality of the outcome measures. Results A total of 31 RCTs were included and the methodology quality of the studies was generally low. Outcome measures in these RCTs were mortality, rehospitalization, efficacy of cardiac function, left ventricular ejection fraction (LVEF), 6 min’ walk distance (6MWD) and Brain natriuretic peptide (BNP), of which mortality and rehospitalization are clinical end points while the others are surrogate outcomes. The reporting rate of mortality and rehospitalization was 12.90% (4/31), the other included studies reported surrogate outcomes. As safety measure, 54.84% of the studies reported adverse drug reactions. Two trials were evaluated as high in reporting quality of outcomes and that of the other 29 studies was poor due to lack of necessary information for reporting. Conclusions The present RCTs of TCM in treating CHF secondary to CHD did not concentrate on the clinical end points of heart failure, which were generally small in size and short in duration. Moreover, these trials lacked adequate safety evaluation, had low quality in reporting outcomes and certain risk of bias in methodology. For objective assessment of the efficacy and safety of TCM in treating CHF secondary to CHD, future research should be rigorous designed, set end points as primary outcome measures and pay more attention to safety evaluation throughout the trial.

Abstract Background No treatment has convincingly been proven to be beneficial for microvascular obstruction (MVO) in patients with ST-elevation myocardial infarction (STEMI). Several studies have described the effects of Danhong Injection. However, evidence of a rigorously designed verification study is still lacking, and the intervention timing of Danhong Injection is uncertain. Methods The DIRECTION study is a multicenter, prospective, randomized, evaluator-blind study. A total of 336 patients with STEMI receiving percutaneous coronary intervention (PCI) will be randomly assigned to conventional treatment, the preoperative Danhong Injection, or the postoperative Danhong Injection. The primary outcome is rate of ST-segment resolution (STR) ≥ 70% at 90 min after PCI. The secondary outcomes are the degree of STR, Thrombolysis in Myocardial Infarction (TIMI) flow grade, TIMI myocardial perfusion grade, left ventricular ejection fraction, N-terminal prohormone brain natriuretic peptide, high-sensitivity C-reactive protein, and infarct size expressed as area under the curve for cardiac troponin I (cTnI) and for creatine kinase MB. The major adverse cardiovascular events and hospital readmission events will be recorded. Health quality will be assessed with the 12-item Short Form Health Survey. The safety outcomes include bleeding events, adverse events, and abnormal changes in routine blood tests. Psychological status and dietary patterns will be evaluated using Hamilton Depression Rating Scale and Food Frequency Questionnaire as the relevant indicators. Discussion This trial will evaluate the efficacy and safety of Danhong Injection, as well as its optimal timing of intervention to prevent MVO in patients with STEMI. Trial registration Chinese Clinical Trial Registry, ChiCTR1900021440. Registered on February 21, 2019.