Synergistic activity and mechanism of cytarabine and MCL-1 inhibitor AZD5991 against acute myeloid leukemia.

The 5-year overall survival rate of acute myeloid leukemia (AML) is less than 30%. Improving clinical outcomes is still a clinical challenge for AML treatment. Simultaneous use of chemotherapeutic drugs and targeting of apoptosis pathways has become a first-line clinical treatment for AML. Myeloid cell leukemia 1 (MCL-1) is a candidate target for AML treatment. In this study, we demonstrated that inhibition of the anti-apoptotic protein MCL-1 by AZD5991 synergistically increased chemotherapeutic agent cytarabine (Ara-C)-induced apoptosis in AML cell lines and primary patient samples. Apoptosis induced by a combination of Ara-C and AZD5991 was partially dependent on caspase activity and Bak/Bax. The downregulation of MCL-1 by Ara-C and the enhancement of Ara-C-induced DNA damage through inhibition of MCL-1 are potential mechanisms underlying the synergistic anti-AML activity between Ara-C and AZD5991. Our data support the application of MCL-1 inhibitor in combination with the conventional chemotherapeutic agent for the clinical treatment of AML.

Jacobians of single-scattering optical properties of super-spheroids computed using neural networks.

In atmospheric aerosol remote sensing and data assimilation studies, the Jacobians of the optical properties of non-spherical aerosol particles are required. Specifically, the partial derivatives of the extinction efficiency factor, single-scattering albedo, asymmetry factor, and scattering matrix should be obtained with respect to microphysical parameters, such as complex refractive indices, shape parameters and size parameters. When a look-up table (LUT) of optical properties of particles is available, the Jacobians traditionally can be calculated using the finite difference method (FDM), but the accuracy of the process depends on the resolution of microphysical parameters. In this paper, a deep learning scheme was proposed for computing Jacobians of the optical properties of super-spheroids, which is a flexible model of non-spherical atmospheric particles. Using the neural networks (NN), the error of the Jacobians in the FDM can be reduced by more than 60%, and the error reduction rate of the Jacobians of the scattering matrix elements can be more than 90%. We also tested the efficiency of the NN for computing the Jacobians. The computation takes 30 seconds for one million samples on a host with an NVIDIA GeForce RTX 3070 GPU. The accuracy and efficiency of the present NN scheme proves it is promising for applications in remote sensing and data assimilation studies.

MiR-596 activated by EP300 controls the tumorigenesis in epithelial ovarian cancer by declining BRD4 and KPNA4.

BACKGROUND: Epithelial ovarian cancer (EOC), a subclass of ovarian cancer (OC), is usually diagnosed at advanced stages due to the lack of effective screening means. Mounting reports have disclosed the vitally important roles of microRNAs (miRNAs) in carcinogenesis. Here, we aimed to find out possible miRNAs participating in EOC development. METHODS: qRT-PCR ad western blot respectively examined the mRNA and protein levels of studied genes. CCK-8, colony formation, flow cytometry, TUNEL and spheroid formation assays were appropriately employed for examining cell proliferation, cell cycle, apoptosis and stemness. The interaction between molecules was affirmed by luciferase reporter, RNA pull down and ChIP assays. RESULTS: In consistent with the observation of a past study, miR-596 expression was relatively low in EOC cells. Up-regulating miR-596 suppressed EOC cell proliferation and stemness. EP300 transcriptionally activated miR-596 to serve as a tumor-repressor in EOC. Then BRD4 and KPNA4, whose knockdown led to restraining effects on cell growth and stemness, were both revealed to be targeted by miR-596 in EOC. Lastly, rescue assays affirmed the tumor-restraining role of miR-596-BRD4/KPNA4 axis in EOC. CONCLUSION: EP300-activated miR-596 hampered cell growth and stemness via targeting BRD4 and KPNA4 in EOC, proofing miR-596 as a promising therapeutic target in treating EOC patients.

Overexpression of eukaryotic initiation factor 5A2 (EIF5A2) is associated with cancer progression and poor prognosis in patients with early-stage cervical cancer.

AIMS: As one of the only two isoforms of the eukaryotic initiation factor (EIF)5A family, EIF5A2 plays an important role in tumour progression and prognosis evaluation. The aim of this study was to investigate EIF5A2 expression in International Federation of Gynecology and Obstetrics (FIGO) stage I-II cervical cancer and to evaluate its clinical significance. METHODS AND RESULTS: The mRNA and protein expression levels of EIF5A2 were analysed in 20 tissue samples of FIGO stage I-II cervical cancer and paired surrounding non-tumour cervical tissues by real-time polymerase chain reaction and western blot analysis. Immunohistochemistry was performed to examine EIF5A2 protein expression in paraffin-embedded tissues from 314 patients with cervical cancer. The mRNA and protein expression levels of EIF5A2 were significantly elevated in tumour tissues. The increased EIF5A2 expression was correlated with higher FIGO stage (P < 0.001), deep cervical stromal invasion (P = 0.026), lymphovascular space involvement (P = 0.002), pelvic lymph node metastasis (P < 0.001) and postoperative recurrence (P < 0.001) in patients with cervical cancer. Patients with tumours showing high EIF5A2 expression had a poorer survival time than those with normal EIF5A2 expression, especially the patients with negative pelvic lymph nodes and FIGO stage II. In addition, multivariate Cox analysis showed that high EIF5A2 expression was an independent prognostic factor for overall survival [hazard ratio 1.949; 95% confidence interval (CI) 1.116-3.404; P = 0.019] and disease-free survival (hazard ratio 1.980; 95% CI 1.189-3.297; P = 0.009). CONCLUSIONS: EIF5A2 overexpression may contribute to cancer progression and poor prognosis. Therefore, EIF5A2 could be a novel potential prognostic marker for FIGO stage I-II cervical cancer.

Response patterns of the microbiome during hexavalent chromium remediation by Tagetes erecta L.

Chromium pollution, particularly hexavalent chromium [Cr(VI)], may threaten the environment and human health. This study investigated the potential of Tagetes erecta L. (Aztec marigold) for phytoremediation of soil contaminated with Cr(VI), and focused on the effects of varying concentrations of Cr(VI) on both the physicochemical properties of soil and microbiome of Tagetes erecta L. We observed that Tagetes erecta L. showed tolerance to Cr(VI) stress and maintained normal growth under these conditions, as indicated by bioconcentration factors of 0.33-0.53 in shoots and 0.39-0.70 in roots. Meanwhile, the structure and diversity of bacterial communities were significantly affected by Cr(VI) pollution. Specifically, Cr(VI) had a more significant effect on the microbial community structure in the endophytic of Tagetes erecta L. than in the rhizosphere (p < 0.05). The genera Devosia and Methylobacillus were positively correlated with Cr(VI) concentrations. Biomarkers such as Bacilli and Pseudonocardia were identified under the different Cr(VI)-contaminated treatments using LEfSe. In addition, the interaction and stability of the endophytic microbiome were enhanced under Cr(VI) stress. This study explored the interactions between heavy metals, microorganisms, and plants, providing valuable insights for developing in situ bioremediation of Cr(VI)-contaminated soils.

Impacts of emissions and meteorological conditions in three different phases of aerosol pollution during 2013-2022 in Anhui, China.

The PM2.5 concentrations in Anhui, which links the Yangtze River Delta region, China's fastest growing economy area, with the Beijing-Tianjin-Hebei (BTH) region, China's most polluted region, are influenced not only by emissions, but also by variation of meteorological conditions. A comprehensive understanding of the relative impacts of meteorology and emissions on heavy pollution in Anhui at three phases (i.e., phase1: from 2013 to 2017; phase2: from 2018 to 2020; phase 3: from 2021 to 2022) from 2013 to 2022, which can provide suggestions for pollution prevention and control in the future. The decrease in pollutant concentrations from 2013 to 2022 is mainly attributed to the continued reduction in emissions, while the year-to-year fluctuations in pollutant concentrations are largely influenced by meteorological conditions. Although emissions are decreasing, the proportions of residential biofuel combustion and cement are increasing. In addition to the effects of prevailing northeasterly and northwesterly winds (i.e., Type1 and Type2), there is also concern about the influences of static weather and neighboring regional transport (i.e., Type5 and Type6), especially in 2016. The contribution of emissions is greater in phase 2 and phase 3, with a 17 % increase compared to phase 1. Overall, approximately 57 % of explosive growth in PM2.5 concentration during the cumulative stage (CS) can be regarded as the feedback effect of the deteriorating meteorological conditions. Therefore, statistical analyses show that limiting PM2.5 concentrations below about 73 µg m-3 would weaken the feedback effects, which in turn would avoid most of the explosive growth processes in the CS of the 60 heavy pollution processes, which can provide a reference for the government to set a target for sustained emission reduction.

Invert global and China's terrestrial carbon fluxes over 2019-2021 based on assimilating richer atmospheric CO2 observations.

With China's commitment to reach carbon peak by 2030 and achieve carbon neutrality by 2060, it is particularly important to obtain terrestrial ecosystem carbon fluxes with low uncertainty both globally and in China. The use of more observation data may help reduce the uncertainty of inverting carbon fluxes. This study uses the observation data from global stations, background stations and provincial stations in China, as well as the OCO-2 satellite, and uses the China Carbon Monitoring, Verification and Supporting System for Global (CCMVS-G) to estimate the carbon fluxes of global and Chinese terrestrial ecosystems from 2019 to 2021. The results revealed that the global terrestrial ecosystem carbon sink was approximately -3.40 Pg C/yr from 2019 to 2021. The carbon sinks in the Northern Hemisphere are large, especially in Asia, North America, and Europe. From 2019 to 2021, the carbon sink of China's terrestrial ecosystem was approximately -0.44 Pg C/yr. Carbon sinks exhibit significant seasonal and interannual variations in China. After assimilating the observation data, the uncertainty of the posterior flux is smaller than that of the prior flux, a more reasonable distribution of carbon sources and sinks can be obtained, and more accurate boundary conditions can be provided for the China Carbon Monitoring, Verification and Supporting System for Regional (CCMVS-R). In the future, it is important to establish a well-designed CO2 ground-based observation network.

Panobinostat sensitizes AraC-resistant AML cells to the combination of azacitidine and venetoclax.

The majority of acute myeloid leukemia (AML) patients respond to intensive induction therapy, consisting of cytarabine (AraC) and an anthracycline, though more than half experience relapse. Relapsed/refractory (R/R) AML patients are difficult to treat, and their clinical outcomes remain dismal. Venetoclax (VEN) in combination with azacitidine (AZA) has provided a promising treatment option for R/R AML, though the overall survival (OS) could be improved (OS ranges from 4.3 to 9.1 months). Overexpression of c-Myc is associated with chemoresistance in AML. Histone deacetylase (HDAC) inhibitors have been shown to suppress c-Myc and enhance the antileukemic activity of VEN, as well as AZA, though combination of all three has not been fully explored. In this study, we investigated the HDAC inhibitor, panobinostat, in combination with VEN + AZA against AraC-resistant AML cells. Panobinostat treatment downregulated c-Myc and Bcl-xL and upregulated Bim, which enhanced the antileukemic activity of VEN + AZA against AraC-resistant AML cells. In addition, panobinostat alone and in combination with VEN + AZA suppressed oxidative phosphorylation and/or glycolysis in AraC-resistant AML cells. These findings support further development of panobinostat in combination with VEN + AZA for the treatment of AraC-resistant AML.

Functional Characterization of the Soybean Glycine max Actin Depolymerization Factor GmADF13 for Plant Resistance to Drought Stress.

Abiotic stress significantly affects plant growth and has devastating effects on crop production. Drought stress is one of the main abiotic stressors. Actin is a major component of the cytoskeleton, and actin-depolymerizing factors (ADFs) are conserved actin-binding proteins in eukaryotes that play critical roles in plant responses to various stresses. In this study, we found that GmADF13, an ADF gene from the soybean Glycine max, showed drastic upregulation under drought stress. Subcellular localization experiments in tobacco epidermal cells and tobacco protoplasts showed that GmADF13 was localized in the nucleus and cytoplasm. We characterized its biological function in transgenic Arabidopsis and hairy root composite soybean plants. Arabidopsis plants transformed with GmADF13 displayed a more robust drought tolerance than wild-type plants, including having a higher seed germination rate, longer roots, and healthy leaves under drought conditions. Similarly, GmADF13-overexpressing (OE) soybean plants generated via the Agrobacterium rhizogenes-mediated transformation of the hairy roots showed an improved drought tolerance. Leaves from OE plants showed higher relative water, chlorophyll, and proline contents, had a higher antioxidant enzyme activity, and had decreased malondialdehyde, hydrogen peroxide, and superoxide anion levels compared to those of control plants. Furthermore, under drought stress, GmADF13 OE activated the transcription of several drought-stress-related genes, such as GmbZIP1, GmDREB1A, GmDREB2, GmWRKY13, and GmANK114. Thus, GmADF13 is a positive regulator of the drought stress response, and it may play an essential role in plant growth under drought stress conditions. These results provide new insights into the functional elucidation of soybean ADFs. They may be helpful for breeding new soybean cultivars with a strong drought tolerance and further understanding how ADFs help plants adapt to abiotic stress.

Ongoing CO2 monitoring verify CO2 emissions and sinks in China during 2018-2021.

Accurate estimating CO2 emissions and sinks is crucial in achieving carbon neutrality in China. However, CO2 emissions from bottom-up inventories are uncertain at regional scales and lack independent verification from atmospheric perspectives. Here we integrated 39 high-precision CO2 stations in China to top-down invert emission-sink variations at 45 km × 45 km and achieved a full range of inventories verification. The results show that China's CO2 emissions are 15% higher than those of five bottom-up inventories, to an annual total of 3.40 Pg C a-1 for 2018-2021. After deducting human and livestock respiration, the annual CO2 emissions were 3.13 Pg C a-1 (11.48 Pg CO2 a-1). The annual increase in emissions slowed from 3.7% in 2019 to 1.1% in 2020 and resumed growth to 4.0% in 2021, consistent with observed CO2 growth rates in China. China's land CO2 sink, deducting farmland sinks and lateral fluxes, was 0.57 Pg C a-1 (2.09 Pg CO2 a-1) for 2018-2021 (higher than most global inverse models), accounting for ∼16.9% of anthropogenic CO2 emissions. The land sink in China decreased by -19.3% in 2019 due to a weak El Niño event and increased by 3.2% in 2020 and 13.7% in 2021. It is worth noting that inverse CO2 emissions and sinks in western China still face large uncertainty due to limited CO2 monitoring. Overall, our top-down estimates demonstrate spatiotemporal variations in CO2 emissions and sinks from atmospheric perspectives and highlight challenges for different provinces in achieving 2060 carbon neutrality with verified estimates.

Genome-wide identification of actin-depolymerizing factor gene family and their expression patterns under various abiotic stresses in soybean (Glycine max).

The actin-depolymerizing factor (ADF) encoded by a family of genes is highly conserved among eukaryotes and plays critical roles in the various processes of plant growth, development, and stress responses via the remodeling of the architecture of the actin cytoskeleton. However, the ADF family and the encoded proteins in soybean (Glycine max) have not yet been systematically investigated. In this study, 18 GmADF genes (GmADF1 - GmADF18) were identified in the soybean genome and were mapped to 14 different chromosomes. Phylogenetic analysis classified them into four groups, which was confirmed by their structure and the distribution of conserved motifs in the encoded proteins. Additionally, 29 paralogous gene pairs were identified in the GmADF family, and analysis of their Ka/Ks ratios indicated their purity-based selection during the evolutionary expansion of the soybean genome. The analysis of the expression profiles based on the RNA-seq and qRT-PCR data indicated that GmADFs were diversely expressed in different organs and tissues, with most of them responding actively to drought- and salt-induced stresses, suggesting the critical roles played by them in various biological processes. Overall, our study shows that GmADF genes may play a crucial role in response to various abiotic stresses in soybean, and the highly inducible candidate genes could be used for further functional studies and molecular breeding in soybean.

Research progress on the roles of actin-depolymerizing factor in plant stress responses.

Actin-depolymerizing factors (ADFs) are highly conserved small-molecule actin-binding proteins found throughout eukaryotic cells. In land plants, ADFs form a small gene family that displays functional redundancy despite variations among its individual members. ADF can bind to actin monomers or polymerized microfilaments and regulate dynamic changes in the cytoskeletal framework through specialized biochemical activities, such as severing, depolymerizing, and bundling. The involvement of ADFs in modulating the microfilaments' dynamic changes has significant implications for various physiological processes, including plant growth, development, and stress response. The current body of research has greatly advanced our comprehension of the involvement of ADFs in the regulation of plant responses to both biotic and abiotic stresses, particularly with respect to the molecular regulatory mechanisms that govern ADF activity during the transmission of stress signals. Stress has the capacity to directly modify the transcription levels of ADF genes, as well as indirectly regulate their expression through transcription factors such as MYB, C-repeat binding factors, ABF, and 14-3-3 proteins. Furthermore, apart from their role in regulating actin dynamics, ADFs possess the ability to modulate the stress response by influencing downstream genes associated with pathogen resistance and abiotic stress response. This paper provides a comprehensive overview of the current advancements in plant ADF gene research and suggests that the identification of plant ADF family genes across a broader spectrum, thorough analysis of ADF gene regulation in stress resistance of plants, and manipulation of ADF genes through genome-editing techniques to enhance plant stress resistance are crucial avenues for future investigation in this field.

Genome-wide identification and expression analysis of the KCS gene family in soybean (Glycine max) reveal their potential roles in response to abiotic stress.

Very long chain fatty acids (VLCFAs) are fatty acids with chain lengths of 20 or more carbon atoms, which are the building blocks of various lipids that regulate developmental processes and plant stress responses. 3-ketoacyl-CoA synthase encoded by the KCS gene is the key rate-limiting enzyme in VLCFA biosynthesis, but the KCS gene family in soybean (Glycine max) has not been adequately studied thus far. In this study, 31 KCS genes (namely GmKCS1 - GmKCS31) were identified in the soybean genome, which are unevenly distributed on 14 chromosomes. These GmKCS genes could be phylogenetically classified into seven groups. A total of 27 paralogous GmKCS gene pairs were identified with their Ka/Ks ratios indicating that they had undergone purifying selection during soybean genome expansion. Cis-acting element analysis revealed that GmKCS promoters contained multiple hormone- and stress-responsive elements, indicating that GmKCS gene expression levels may be regulated by various developmental and environmental stimuli. Expression profiles derived from RNA-seq data and qRT-PCR experiments indicated that GmKCS genes were diversely expressed in different organs/tissues, and many GmKCS genes were found to be differentially expressed in the leaves under cold, heat, salt, and drought stresses, suggesting their critical role in soybean resistance to abiotic stress. These results provide fundamental information about the soybean KCS genes and will aid in their further functional elucidation and exploitation.

Inhibition of Mcl-1 Synergistically Enhances the Antileukemic Activity of Gilteritinib and MRX-2843 in Preclinical Models of FLT3-Mutated Acute Myeloid Leukemia.

FMS-like tyrosine kinase 3 (FLT3)-internal tandem duplication (FLT3-ITD) mutations occur in about 25% of all acute myeloid leukemia (AML) patients and confer a poor prognosis. FLT3 inhibitors have been developed to treat patients with FLT3-mutated AML and have shown promise, though the acquisition of resistance occurs, highlighting the need for combination therapies to prolong the response to FLT3 inhibitors. In this study, we investigated the selective Mcl-1 inhibitor AZD5991 in combination with the FLT3 inhibitors gilteritinib and MRX-2843. The combinations synergistically induce apoptosis in AML cell lines and primary patient samples. The FLT3 inhibitors downregulate c-Myc transcripts through the suppression of the MEK/ERK and JAK2/STAT5 pathways, resulting in the decrease in c-Myc protein. This suppression of c-Myc plays an important role in the antileukemic activity of AZD5991. Interestingly, the suppression of c-Myc enhances AZD5991-inudced cytochrome c release and the subsequent induction of apoptosis. AZD5991 enhances the antileukemic activity of the FLT3 inhibitors gilteritinib and MRX-2843 against FLT3-mutated AML in vitro, warranting further development.

Immune Profiling in Gastric Cancer Reveals the Dynamic Landscape of Immune Signature Underlying Tumor Progression.

The profiling of the tumor immune microenvironment (TIME) is critical for guiding immunotherapy strategies. However, how the composition of the immune landscape affects the tumor progression of gastric cancer (GC) is ill-defined. Here, we used mass cytometry to perform simultaneous in-depth immune profiling of the tumor, adjacent tissues, and blood cells from GC patients and revealed a unique GC tumor-immune signature, where CD8+ T cells were present at a lower frequency in tumor tissues compared to adjacent tissues, whereas regulatory T cells and tumor-associated macrophages (TAMs) were significantly increased, indicating strong suppressive TIME in GC. Incorporated with oncogenic genomic traits, we found that the unique immunophenotype was interactively shaped by a specific GC gene signature across tumor progression. Earlier-stage GC lesions with IFN signaling enrichment harbored significantly altered T-cell compartments while advanced GC featured by metabolism signaling activation was accumulated by TAMs. Interestingly, PD-1 expression on CD8+ T cells was relatively higher in earlier-stage GC patients, indicating that these patients may derive more benefits from PD-1 inhibitors. The dynamic properties of diverse immune cell types revealed by our study provide new dimensions to the immune landscape of GC and facilitate the development of novel immunotherapy strategies for GC patients.

Tumor-Derived Extracellular Vesicles Promote Activation of Carcinoma-Associated Fibroblasts and Facilitate Invasion and Metastasis of Ovarian Cancer by Carrying miR-630.

Ovarian cancer (OC) is a lethal gynecological malignancy. Extracellular vesicles (EVs) are crucial media in cell-to-cell communication by carrying microRNAs (miRs). The current study aims to investigate the underlying mechanism of miR-630 carried by OC cell-derived EVs in regard to invasion and metastasis of OC cells. miRs related to OC metastasis were searched and screened. The expression patterns of screened miRs in human normal fibroblasts (NFs) and carcinoma-associated fibroblasts (CAFs) were detected using RT-qPCR. miR-630 related to OC metastasis and CAFs activation was analyzed further. The levels of FAP and α-SMA were detected using Western blotting and immunofluorescence. The migration of NFs was measured using Transwell assay. OC cell-derived EVs were isolated and identified. Uptake of EVs by NFs was observed using immunofluorescence staining. The culture supernatant of NFs was collected and used to culture the low metastasis cell line OVCAR8. The migration and invasion of OC cells and epithelial mesenchymal transition (EMT) were measured. Moreover, a xenograft model was established by injecting OVCAR8 cells of different groups into nude mice. Lastly, the effect of EV-pretreated NFs on invasion and metastasis of OC cells was observed in vivo. miR-630 was upregulated in OC cells and CAFs, and further associated with CAF activation and OC metastasis. miR-630 overexpression increased the levels of FAP and α-SMA in NFs, resulting in the transformation of NFs into CAFs. EVs carried miR-630 into NFs and EVs promoted CAF activation. miR-630 targeted KLF6. miR-630 inhibition or KLF6 overexpression attenuated EVs-induced CAF activation. EVs activated the NF-κB pathway via the miR-630/KLF6 axis. The conditioned medium of NFs pretreated with EVs promoted the invasion and metastasis of OVCAR8 cells, while downregulating miR-630 in EVs partially inhibited the promotive effect of NFs. EV-pretreated NFs promoted invasion and metastasis of OC in vivo. In conclusion, EVs carried miR-630 into NFs, thereby facilitating CAF activation and promoting invasion and metastasis of OC by inhibiting KLF6 and activating the NF-κB pathway. Our findings might offer a novel mechanism of invasion and metastasis of OC from the perspective of tumor microenvironment.

Long Non-coding RNA CCAT1 Sponges miR-454 to Promote Chemoresistance of Ovarian Cancer Cells to Cisplatin by Regulation of Surviving.

PURPOSE: Colon cancer-associated transcript 1 (CCAT1) was identified as an oncogenic long non-coding RNA (lncRNA) in a variety of cancers. However, there was a lack of understanding of the mechanism by which CCAT1 conferred cisplatin (also known as DDP) resistance in ovarian cancer cells. MATERIALS AND METHODS: Cell viability of A2780, SKOV3, A2780/DDP, and SKOV3/DDP cells upon cisplatin treatment was monitored by MTT assay. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) detected the expression levels of CCAT1 and miR-454. The effect of sh-CCAT1 on cisplatin response was investigated in xenografts study. Bioinformatic analysis, luciferase reporter assay and qRT-PCR were conducted to validate the direct interaction among CCAT1, miR-454, and survivin. Apoptosis was determined by flow cytometry after dual staining of Annexin-V-FITC/propidium iodide, and the expression of apoptosis-related proteins Bcl-2, Bax and survivin were detected by qRT-PCR and Western blotting. Xenograft study was conducted to monitor in vivo tumor formation. RESULTS: CCAT1 was highly expressed in cisplatin-resistant ovarian cancer cell line A2780/DDP and SKOV3/DDP. Knockdown of CCAT1 restored sensitivity to cisplatin in vitro and in vivo. Our data revealed that silencing of CCAT1 promoted cisplatin-induced apoptosis via modulating the expression of pro- or anti-apoptotic proteins Bax, Bcl-2, and survivin. CCAT1 directly interacted with miR-454, and miR-454 overexpression potentiated cisplatin-induced apoptosis. Survivin was identified as a functional target of miR-454, restoration of survivin attenuated the effect of miR-454 on cisplatin response. In addition, miR-454 inhibitor or overexpression of survivin was found to abolish sh-CCAT1-induced apoptosis upon cisplatin treatment. CONCLUSION: CCAT1/miR-454/survivin axis conferred cisplatin resistance in ovarian cancer cells.

Cotargeting of Mitochondrial Complex I and Bcl-2 Shows Antileukemic Activity against Acute Myeloid Leukemia Cells Reliant on Oxidative Phosphorylation.

Targeting oxidative phosphorylation (OXPHOS) is a promising strategy to improve treatment outcomes of acute myeloid leukemia (AML) patients. IACS-010759 is a mitochondrial complex I inhibitor that has demonstrated preclinical antileukemic activity and is being tested in Phase I clinical trials. However, complex I deficiency has been reported to inhibit apoptotic cell death through prevention of cytochrome c release. Thus, combining IACS-010759 with a BH3 mimetic may overcome this mechanism of resistance leading to synergistic antileukemic activity against AML. In this study, we show that IACS-010759 and venetoclax synergistically induce apoptosis in OXPHOS-reliant AML cell lines and primary patient samples and cooperatively target leukemia progenitor cells. In a relatively OXPHOS-reliant AML cell line derived xenograft mouse model, IACS-010759 treatment significantly prolonged survival, which was further enhanced by treatment with IACS-010759 in combination with venetoclax. Consistent with our hypothesis, IACS-010759 treatment indeed retained cytochrome c in mitochondria, which was completely abolished by venetoclax, resulting in Bak/Bax- and caspase-dependent apoptosis. Our preclinical data provide a rationale for further development of the combination of IACS-010759 and venetoclax for the treatment of patients with AML.

The origins and implications of glycerol ether lipids in China coastal wetland sediments.

Coastal wetlands are terrestrial-marine transition zones harboring diverse active microbial communities. The origins of diverse glycerol ether lipids preserved in coastal wetlands are rarely investigated. 16 surface sediments were collected from the coastal wetland at Guangrao (GR), Changyi (CY) and Xiamen (XM), where both climate and sedimentary environment show significant differences. Ten groups of glycerol ether lipids, including isoprenoidal and branched glycerol dialkyl glycerol tetraethers (iGDGTs and bGDGTs), isoprenoidal and branched glycerol dialkanol diethers (iGDDs and bGDDs), hydroxylated isoprenoidal GDGTs and GDDs (OH-GDGTs and OH-GDDs), overly branched GDGTs (OB-GDGTs), sparsely branched GDGTs (SB-GDGTs), hybrid isoprenoid/branched GDGTs (IB-GDGTs) and a tentatively assigned H-shaped branched GDGTs (H-B-GDGTs) were detected and quantified. Sediments collected in the north (Guangrao and Changyi) contain, in general, a lower abundance of GDGT (3.7-55.9 ng/g sed) than samples from south (Xiamen; 251-1020 ng/g sed). iGDGTs and bGDGTs are the predominant components at all sites and account for 17.2-74.3% and 16.1-75.1% of total ether lipids, respectively. The relative abundance of iGDGTs decreases but that of bGDGTs increases with the distance from sea, suggesting a marine vs. terrestrial origin of iGDGT and bGDGTs, respectively. In addition, the methylation index (MIOB/B/SB) of branched GDGTs shows a significant inverse correlation with water content, suggesting that marine waters have a major influence on the microbial communities inhabiting wetland sediment. Such an assumption was confirmed by the distinct lipid pattern of three low water content (<5%) samples collected in an area isolated from tidal flushing. The other isoprenoidal ether lipids, such as iGDDs, OH-GDGTs and OH-GDGTs, have a similar distribution as iGDGTs, indicating a common biological source, so do the corresponding non-isoprenoidal ether lipid series with bGDGTs. The BIT value increases with increasing distance from the sea, which implies that the BIT index can be probably applied to trace past sea level change in costal wetland settings. The reconstructed temperature from TEX86 shows significant offset from observed data, but only little deviation for the MBT/CBT calculated temperature. This suggests that the MBT/CBT has the potential to reconstruct past temperatures in coastal wetland settings.

The preparation of a three dimensional terbium doped reduced graphene oxide aerogel with photoluminescence and paramagnetic properties.

A 3D reduced graphene oxide (rGO) material with good photoluminescence (PL) and magnetism properties was self-assembled using the hydrothermal method. The resultant material possessed a flower-like structure, which leads to a high surface area. To dehydrate the hydrogel for conservation, the sublimation process we use can effectively maintain the porosity as it uses the freeze drying method. Then, rGO was endowed with paramagnetism and green photoluminescence properties via the introduction of Tb ions, which also reinforces the significance of the building block. Finally, the coordination between Tb ions and the carbonyl was proven with photoluminescence excitation (PLE) spectra and the UV-vis absorption spectra, which are likely to offer an effective way to study the carbonyl compound.