The SET oncoprotein promotes estrogen-induced transcription by facilitating establishment of active chromatin.

SET is a multifunctional histone-binding oncoprotein that regulates transcription by an unclear mechanism. Here we show that SET enhances estrogen-dependent transcription. SET knockdown abrogates transcription of estrogen-responsive genes and their enhancer RNAs. In response to 17ß-estradiol (E2), SET binds to the estrogen receptor α (ERα) and is recruited to ERα-bound enhancers and promoters at estrogen response elements (EREs). SET functions as a histone H2 chaperone that dynamically associates with H2A.Z via its acidic C-terminal domain and promotes H2A.Z incorporation, ERα, MLL1, and KDM3A loading and modulates histone methylation at EREs. SET depletion diminishes recruitment of condensin complexes to EREs and impairs E2-dependent enhancer-promoter looping. Thus, SET boosts E2-induced gene expression by establishing an active chromatin structure at ERα-bound enhancers and promoters, which is essential for transcriptional activation.

COL1A1::PDGFB fusion uterine sarcoma with a TERT promoter mutation.

COL1A1::PDGFB fusion uterine sarcoma is a rare uterine mesenchymal tumor with some clinicopathological features that overlap with those of soft tissue dermatofibrosarcoma protuberans. However, the varied clinicopathologic and genetic characteristics have not been fully revealed, which may be a potential pitfall for diagnosis. Here, we present a case of COL1A1::PDGFB fusion-positive uterine sarcoma in a 49-years-old female. Histologically, the tumor from the initial marginal excision predominantly exhibited high-grade fibrosarcomatous and myxofibrosarcoma-like appearances, while a low-grade focal area displaying storiform growth was identified in the residual tumor after subsequently extended resection. Immunohistochemically, the high-grade components mainly exhibited focal positivity for CD34 and mutated-type p53 immunoreactivity, whereas the low-grade component showed diffuse positivity for CD34 and wild-type p53 staining. The COL1A1::PDGFB fusion was confirmed by fluorescence in situ hybridization and next-generation sequencing. In addition, the TERT-124 C > T mutation was further identified in this lesion's fibrosarcomatous and classic storiform components. To the best of our knowledge, this is the first described case of COL1A1::PDGFB fusion uterine sarcoma with a TERT promoter mutation, which might be a novel genetic finding associated with tumorigenesis of this rare tumor.

Transcription factors NtHD9 and NtHD12 control long glandular trichome formation via jasmonate signaling.

Glandular trichomes are universal epidermal structures that produce abundant specialized metabolites. However, knowledge of the initiation of glandular heads in glandular trichomes is limited. Herein, we found an intrinsic link of morphogenesis between glandular trichomes and non-glandular trichomes. Two novel homeodomain leucine zipper II members in tobacco (Nicotiana tabacum), NtHD9 and NtHD12, played important roles in long glandular trichome formation: NtHD9 was responsible for glandular head formation, while NtHD12 simultaneously controlled the formation of stalks and glandular heads. DAP-seq analysis suggested that NtHD9 can bind to the KKGCATTWAWTR motif of the cytochromes P450 94C1 (NtCYP94C1) promoter, which is involved in jasmonoyl-isoleucine oxidation. RNA-seq analysis of non-transformed tobacco and nthd9 plants revealed that NtHD9 modulates the expression of jasmonate (JA) signaling- and six trichome development-related genes. Notably, MeJA treatment restored the morphogenesis of long glandular trichomes in nthd9 and nthd12 plants, and the size of glandular heads increased with increasing MeJA concentration. However, the phenotype of long glandular trichome absence in double mutants of NtHD9 and NtHD12 could not be restored by MeJA. Our data demonstrate that NtHD9 and NtHD12 have distinct major functions yet overlapping roles in long glandular trichome formation via JA signaling.

Antiviral activity and underlying mechanisms of baicalin against porcine reproductive and respiratory syndrome virus in vitro.

Porcine reproductive and respiratory syndrome (PRRS) is a major challenge for the global swine industry, causing huge economic losses worldwide. To date, there are no effective measures to prevent and control the spread of PRRS virus (PRRSV). Baicalin (BA) is a natural flavonoid with various pharmacological effects, including antiviral, anti-inflammatory, antioxidant and immunomodulatory. Here, we demonstrate that BA exhibits potent anti-PRRSV activity in vitro, BA concentrations in the range of 5-20 µg/mL significantly inhibited PRRSV infection in a dose-dependent manner and were independent of PRRSV strain. Mechanistically, BA inhibited PRRSV replication by directly interacting with virions, thereby affecting multiple stages of the virus life cycle. Meanwhile, the preventive effect of BA on PRRSV could be realized by inhibiting CD151 and CD163 expression. Furthermore, BA reduced the PRRSV-induced expression of PAMs cytokines (IFN-α, IL-6, IL-8, and TNF-α), suggesting that BA-induced antiviral cytokines may help BA inhibit PRRSV infection. Taken together, BA can be used as an inhibitor of PRRSV infection in vitro, which provides a theoretical basis for the clinical application of BA and the prevention and control of PRRSV infection, which is worthy of further in vivo studies in swine.

The effect of matrine and glycyrrhizic acid on porcine reproductive and respiratory syndrome virus in Vitro and in vivo.

Porcine reproductive and respiratory syndrome (PRRS) is endemic worldwide, seriously affecting the development of the pig industry, but vaccines have limited protective effects against PRRSV transmission. The aim of this study was to identify potential anti-PRRSV drugs. We examined the cytotoxicity of seven compounds formulated based on the mass ratio of glycyrrhizic acid to matrine and calculated their inhibition rates against PRRSV in vitro. The results showed that the seven compounds all had direct killing and therapeutic effects on PRRSV, and the compounds inhibited PRRSV replication in a time- and dose-dependent manner. The compound with the strongest anti-PRRSV effect was selected for subsequent in vivo experiments. Pigs were divided into a control group and a medication group for the in vivo evaluation. The results showed that pigs treated with the 4:1 compound had 100% morbidity after PRRSV challenge, and the mortality rate reached 75% on the 8th day of the virus challenge. These results suggest that this compound has no practical anti-PRRSV effect in vivo and can actually accelerate the death of infected pigs. Next, we further analyzed the pigs that exhibited semiprotective effects following vaccination with the compound to determine whether the compound can synergize with the vaccine in vivo. The results indicated that pigs treated with the compound had higher mortality rates and more severe clinical reactions after PRRSV infection (p < 0.05). The levels of proinflammatory cytokines (IL-6, IL-8, IL-1ß, IFN-γ, and TNF-α) were significantly greater in the compound-treated pigs than in the positive control-treated pigs (p < 0.05), and there was no synergistic enhancement with the live attenuated PRRSV vaccine (p < 0.05). The compound enhanced the inflammatory response, prompted the body to produce excessive levels of inflammatory cytokines and caused body damage, preventing a therapeutic effect. In conclusion, the present study revealed that the in vitro effectiveness of these agents does not indicate that they are effective in vivo or useful for developing anti-PRRSV drugs. Our findings also showed that, to identify effective anti-PRRSV drugs, comprehensive drug screening is needed, for compounds with solid anti-inflammatory effects both in vitro and in vivo. Our study may aid in the development of new anti-PRRSV drugs.

Grass carp (Ctenopharyngodon idella) NIK up-regulates the expression of IL-8 by activating the NF-κB canonical pathway.

NIK (NF-κB inducing kinase) belongs to the mitogen-activated protein kinase family, which activates NF-κB and plays a vital role in immunology, inflammation, apoptosis, and a series of pathological responses. In NF-κB noncanonical pathway, NIK and IKKα have been often studied in mammals and zebrafish. However, few have explored the relationship between NIK and other subunits of the IKK complex. As a classic kinase in the NF-κB canonical pathway, IKKß has never been researched with NIK in fish. In this paper, the full-length cDNA sequence of grass carp (Ctenopharyngodon idella) NIK (CiNIK) was first cloned and identified. The expression level of CiNIK in grass carp cells was increased under GCRV stimuli. Under the stimulation of GCRV, poly (I:C), and LPS, the expression of NIK in various tissues of grass carp was also increased. This suggests that CiNIK responds to viral stimuli. To study the relationship between CiNIK and CiIKKß, we co-transfected CiNIK-FLAG and CiIKKB-GFP into grass carp cells in coimmunoprecipitation and immunofluorescence experiments. The results revealed that CiNIK interacts with CiIKKß. Besides, the degree of autophosphorylation of CiNIK was enhanced under poly (I:C) stimulation. CiIKKß was phosphorylated by CiNIK and then activated the activity of p65. The activity change of p65 indicates that NF-κB downstream inflammatory genes will be functioning. CiNIK or CiIKKß up-regulated the expression of IL-8. It got higher when CiNIK and CiIKKß coexisted. This paper revealed that NF-κB canonical pathway and noncanonical pathway are not completely separated in generating benefits.

Extramedullary relapsed acute lymphoblastic leukemia presenting as asymptomatic acute kidney injury after hematopoietic stem cell transplantation.

Acute kidney injury (AKI) is a common complication in children with hematological malignancies. Although AKI due to infiltration of tumor cells in children is rare, it negatively impacts treatment outcomes and increases the risk of mortality. We introduce a case of a child with acute lymphoblastic leukemia (ALL) who experienced kidney relapse resulting in asymptomatic AKI after remission from treatment, to remind clinicians not to overlook the primary disease in clinical judgment. In cases of unexplained AKI, kidney biopsy should be performed when feasible to get an accurate diagnosis and scientific treatment. In brief, children with leukemia who have achieved remission after treatment still need regular monitoring of urine routine and kidney function.

Nanopore targeted sequencing-based diagnosis of central nervous system infections in HIV-infected patients.

BACKGROUND: Early and accurate etiological diagnosis is very important for improving the prognosis of central nervous system (CNS) infections in human immunodeficiency virus (HIV)-infected patients. The goal is not easily achieved by conventional microbiological tests. We developed a nanopore targeted sequencing (NTS) platform and evaluated the diagnostic performance for CNS infections in HIV-infected patients, with special focus on cryptococcal meningitis (CM). We compared the CM diagnostic performance of NTS with conventional methods and cryptococcal polymerase chain reaction (PCR). METHODS: This study included 57 hospitalized HIV-infected patients with suspected CNS infections from September 2018 to March 2022. The diagnosis established during hospitalization includes 27 cases of CM, 13 CNS tuberculosis, 5 toxoplasma encephalitis, 2 cytomegalovirus (CMV) encephalitis and 1 Varicella-zoster virus (VZV) encephalitis. The 2 cases of CMV encephalitis also have co-existing CM. Target-specific PCR amplification was used to enrich pathogen sequences before nanopore sequencing. NTS was performed on stored cerebrospinal fluid (CSF) samples and the results were compared with the diagnosis during hospitalization. RESULTS: 53 (93.0%) of the patients were male. The median CD4 cell count was 25.0 (IQR: 14.0-63.0) cells/uL. The sensitivities of CSF culture, India ink staining, cryptococcal PCR and NTS for CM were 70.4% (95%CI: 51.5 - 84.1%), 76.0% (95%CI: 56.6 - 88.5%), 77.8% (59.2 - 89.4%) and 85.2% (95%CI: 67.5 - 94.1%), respectively. All those methods had 100% specificity for CM. Our NTS platform could identify Cryptococcus at species level. Moreover, NTS was also able to identify all the 5 cases of toxoplasma encephalitis, 2 cases of CMV encephalitis and 1 VZV encephalitis. However, only 1 of 13 CNS tuberculosis cases was diagnosed by NTS, and so did Xpert MTB/RIF assay. CONCLUSIONS: NTS has a good diagnostic performance for CM in HIV-infected patients and may have the ability of simultaneously detecting other pathogens, including mixed infections. With continuing improving of the NTS platform, it may be a promising alterative microbiological test for assisting with the diagnosis of CNS infections.

Application of diffusional kurtosis imaging for insights into structurally aberrant topology in Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) has been regarded as a disconnection syndrome with functional and structural disturbances. However, as the anatomic determinants, the structural disconnections in PD have yet to be fully elucidated. PURPOSE: To non-invasively construct structural networks based on microstructural complexity and to further investigate their potential topological abnormalities in PD given the technical superiority of diffusion kurtosis imaging (DKI) to the quantification of microstructure. MATERIAL AND METHODS: The microstructural data of gray matter in both the PD group and the healthy control (HC) group were acquired using DKI. The structural networks were constructed at the group level by a covariation approach, followed by the calculation of topological properties based on graph theory and statistical comparisons between groups. RESULTS: A total of 51 patients with PD and 50 HCs were enrolled. Individuals were matched between groups with respect to demographic characteristics (P >0.05). The constructed structural networks in both the PD and HC groups featured small-world properties. In comparison with the HC group, the PD group exhibited significantly altered global properties, with higher normalized characteristic path lengths, clustering coefficients, local efficiency values, and characteristic path lengths and lower global efficiency values (P <0.05). In terms of nodal centralities, extensive nodal disruptions were observed in patients with PD (P <0.05); these disruptions were mainly distributed in the sensorimotor network, default mode network, frontal-parietal network, visual network, and subcortical network. CONCLUSION: These findings contribute to the technical application of DKI and the elucidation of disconnection syndrome in PD.

Astragaloside IV targeting autophagy of T cells improves inflammation of asthma.

Astragaloside IV (AST) has been confirmed to have antiasthmatic effects. However, the underline mechanism is unclear. The study aimed to explore the treatment mechanism of AST based on autophagy of memory T cells. AST treatment significantly decreased the number of T effector cells in asthma mice blood and the nude mice that received AST-treated TCMs had relieved inflammation compared with the untreated group; meanwhile, we found that AST significantly decreased the autophagy level and inhibited OX40/OX40L signal pathway of lymphocytes. The results highlighted that AST regulated autophagy to inhibit differentiation of effector T-cell phenotype.

Hydrochemical characterization and health risk assessment of different types of water bodies in Fenghuang Mountain Area, Northeast China.

Groundwater, as an essential resource, holds significant importance for human production and livelihoods. With the deterioration of the water environment, the issue of groundwater quality has become an urgent international concern. This study focused on the Fenghuang Mountain Area (FMA) and collected a total of 41 sets of samples including pore groundwater (PGW), fissure groundwater (FGW), karst groundwater (KGW), and river water (RW). Hydrochemical analysis methods were employed to identify the hydrochemical characteristics and controlling factors. The entropy-weighted water quality index (EWQI) and health risk assessment model were utilized to assess the groundwater quality and nitrate health risk, respectively. The results indicated that the dominant anion and cation in both groundwater and surface water in the FMA were HCO3- and Ca2+, respectively, with the main hydrochemical type being HCO3-Ca. Groundwater and surface water in the FMA were primarily controlled by rock weathering process, with ion concentrations influenced mainly by the dissolution of halite, sylvite, carbonates (calcite and dolomite), silicates, and gypsum, as well as by reverse anion exchange process. PGW was significantly affected by agricultural activities, with NO3- concentration closely related to human activities. The water quality of FGW was relatively good, with Class I and Class II water accounting for the highest proportion, reaching 84.62%. The high-value area of EWQI in PGW was influenced by human activities. The impact of nitrate health risk on children was significantly greater than on adults, with FGW having the lowest health risk and PGW having the highest health risk. The research results can provide important guarantees for the rational development and utilization of water resources in the FMA and the sustainable development of the economy in Northeast China.

Optimization of structural connectomes and scaled patterns of structural-functional decoupling in Parkinson's disease.

Parkinson's disease (PD) is manifested with disrupted topology of the structural connection network (SCN) and the functional connection network (FCN). However, the SCN and its interactions with the FCN remain to be further investigated. This multimodality study attempted to precisely characterize the SCN using diffusion kurtosis imaging (DKI) and further identify the neuropathological pattern of SCN-FCN decoupling, underscoring the neurodegeneration of PD. Diffusion-weighted imaging and resting-state functional imaging were available for network constructions among sixty-nine patients with PD and seventy demographically matched healthy control (HC) participants. The classification performance and topological prosperities of both the SCN and the FCN were analyzed, followed by quantification of the SCN-FCN couplings across scales. The SCN constructed by kurtosis metrics achieved optimal classification performance (area under the curve 0.89, accuracy 80.55 %, sensitivity 78.40 %, and specificity 80.65 %). Along with diverse alterations of structural and functional network topology, the PD group exhibited decoupling across scales including: reduced global coupling; increased nodal coupling within the sensorimotor network (SMN) and subcortical network (SN); higher intramodular coupling within the SMN and SN and lower intramodular coupling of the default mode network (DMN); decreased coupling between the modules of DMN-fronto-parietal network and DMN-visual network, but increased coupling between the SMN-SN module. Several associations between the coupling coefficient and topological properties of the SCN, as well as between network values and clinical scores, were observed. These findings validated the clinical implementation of DKI for structural network construction with better differentiation ability and characterized the SCN-FCN decoupling as supplementary insight into the pathological process underlying PD.

MicroRNA-376b-3p Promotes Porcine Reproductive and Respiratory Syndrome Virus Replication by Targeting Viral Restriction Factor TRIM22.

Porcine reproductive and respiratory syndrome virus (PRRSV) is a major economically significant pathogen and has evolved several strategies to evade host antiviral response and provide favorable conditions for survival. In the present study, we demonstrated that a host microRNA, miR-376b-3p, was upregulated by PRRSV infection through the viral components, nsp4 and nsp11, and that miR-376b-3p can directly target tripartite motif-containing 22 (TRIM22) to impair its anti-PRRSV activity, thus facilitating the replication of PRRSV. Meanwhile, we found that TRIM22 induced degradation of the nucleocapsid protein (N) of PRRSV by interacting with N protein to inhibit PRRSV replication, and further study indicated that TRIM22 could enhance the activation of the lysosomal pathway by interacting with LC3 to induce lysosomal degradation of N protein. In conclusion, PRRSV increased miR-376b-3p expression and hijacked the host miR-376b-3p to promote PRRSV replication by impairing the antiviral effect of TRIM22. Therefore, our finding outlines a novel strategy of immune evasion exerted by PRRSV, which is helpful for better understanding the pathogenesis of PRRSV. IMPORTANCE Porcine reproductive and respiratory syndrome virus (PRRSV) causes enormous economic losses each year in the swine industry worldwide. MicroRNAs (miRNAs) play important roles during viral infections via modulating the expression of viral or host genes at the posttranscriptional level. TRIM22 has recently been identified as a key restriction factor that inhibited the replication of a number of human viruses, such as HIV, encephalomyocarditis virus (ECMV), hepatitis C virus (HCV), HBV, influenza A virus (IAV), and respiratory syncytial virus (RSV). In this study, we showed that host miR-376b-3p could be upregulated by PRRSV and functioned to impair the anti-PRRSV role of TRIM22 to facilitate PRRSV replication. Meanwhile, we found that TRIM22 inhibited the replication of PRRSV by interacting with viral N protein and accelerating its degradation through the lysosomal pathway. Collectively, the findings reveal a novel mechanism that PRRSV used to exploit the host miR-376b-3p to evade antiviral responses and provide new insight into the study of virus-host interactions.

Fading suppression in the Ф-OTDR system based on a phase-modulated optical frequency comb.

In this paper, what we believe to be a novel method is proposed to suppress the fading effect of the phase-sensitive optical time domain reflectometer (Ф-OTDR) by using a phase-modulated optical frequency comb. In the Ф-OTDR system, intensity distributions of Rayleigh backscattering (RBS) light are different for pulsed probe lights with different central frequencies, therefore the locations of the fading points corresponding to signals of different frequencies are differently distributed, allowing the use of frequency division multiplexing to suppress the fading effects. In the experimental system of this paper, a continuous light in the form of a frequency comb is firstly generated through phase modulation. It is then modulated into a pulsed probe light and injected into the sensing fiber to produce different RBS intensity distributions. Finally, the extracted phase is processed by using the amplitude evaluation method, so that the distorted phase can be eliminated. Fading suppression is achieved using our system, and the effect of suppression is evaluated. By using an equal-amplitude optical frequency comb containing seven frequency components, the fading probability density of the system is dramatically reduced from the range of 5.49%-9.83% to 0.08%. Compared with the conventional system using a single acoustic-optic modulator to generate the frequency shift, the method proposed in this paper features a larger modulation bandwidth and more flexible frequency combination scheme to better suppress the fading effect. This method does not sacrifice the response bandwidth of the system, and the phase delay can be precisely controlled, which helps to fully suppress the fading effect.

Identification of integrase inhibitor-related drug resistance mutations in newly diagnosed ART-naïve HIV patients.

BACKGROUND: In China, the recommended treatment regimens for HIV-infected individuals were tenofovir in combination with lamivudine or emtricitabine as NRTIs, efavirenz or rilpivirine as NNRTIs, lopinavir/ritonavir as protease inhibitors, and raltegravir or dolutegravir as INSTIs. The development of drug resistance increases the risk of viral rebound, opportunistic infections, and ultimately treatment failure such that the early detection of resistance is ideal. This study was developed to explore primary drug resistance characteristics and genotypic distributions in newly diagnosed antiretroviral therapy (ART)-naïve HIV-1 patients in Nanjing with the goal of establishing a basis for their individualized treatment in the clinic. METHODS: Samples of serum were collected from newly diagnosed ART-naïve HIV patients from the Second Hospital of Nanjing between May 2021 and May 2022. The HIV-1 integrase (IN), protease (PR), and reverse transcriptase (RT) gene coding sequences were amplified from these samples, sequenced, and assessed for drug resistance-related mutations. RESULTS: Major integrase resistance-related mutations were detected in 4/360 amplified samples, with 5 other patient samples exhibiting accessory resistance mutations. The overall prevalence of PR and RT inhibitor-related transmitted drug resistance mutations (TDRMs) in this patient population was 16.99% (61/359). The most common mutations were non-nucleoside reverse transcriptase inhibitor-related mutations (51/359; 14.21%), followed by those associated with nucleoside reverse transcriptase inhibitors (7/359; 1.95%) and protease inhibitors (7/359; 1.95%). Dual-resistant strains were also observed in a subset of patients. CONCLUSIONS: In summary, this study is the first to have surveyed the prevalence of integrase inhibitor resistance-related mutations and other drug resistance-related mutations among newly diagnosed ART-naïve HIV-positive patients in Nanjing, China. These results highlight the need for further molecular surveillance-based monitoring of the HIV epidemic in Nanjing.

Primary inflammatory myofibroblastic tumour of the liver: a clinicopathological and genetic study including a subset with ETV6::NTRK3 fusion.

AIMS: Inflammatory myofibroblastic tumour (IMT) is an intermediate neoplasm and rarely occurs in the liver. The aim of this study was to analyse the clinicopathological and genetic features of the largest primary hepatic IMT. METHODS AND RESULTS: A total of 10 cases were identified (four males and six females aged 1-48 years, median = 35 years) from 2011 to 2021, which accounted for 2.5% of IMTs occurring in all organ systems. Histological findings revealed that myofibroblastic/fibroblastic cells with inflammatory infiltration and focal hypocellularity were observed in three children. Immunostaining showed ALK-diffuse cytoplasmic positive in six cases (six of 10; 60%) and pan-TRK nuclear positive in three cases (three of 10; 30%). Hypercellular pattern was detected in ALK-positive IMTs and obvious collagenous/myxoid matrix was observed in the pan-TRK-positive subgroup. ALK rearrangement was demonstrated in three of five interpretable ALK-positive IMTs by fluorescence in-situ hybridisation (FISH), and one case failed due to poor sample quality. Next-generation sequencing indicated an IMT with TFG::ALK and FCHSD2::ALK fusion and TP53 mutation. ETV6::NTRK3 fusion was confirmed by RT-PCR, but FISH-negative results were found in two of three cases with pan-TRK-positive IMTs. No genetic alteration was detected in one tumour. One patient died 1 year after biopsy, while nine patients survived without evidence of disease in the follow-up surveillance (17-119 months). CONCLUSIONS: This article describes the first example of primary paediatric hepatic IMTs with ETV6::NTRK3 fusion. Besides the common ALK-positive subgroup, the proportion of NTRK3 fusion is high. Recognising the association between clinicopathological and molecular alterations is critical to accurate diagnosis of hepatic IMTs.

Concomitant targeting of FLT3 and BTK overcomes FLT3 inhibitor resistance in acute myeloid leukemia through the inhibition of autophagy.

Strategies to overcome resistance to FMS-like tyrosine kinase 3 (FLT3)-targeted therapy in acute myeloid leukemia (AML) are urgently needed. We identified autophagy as one of the resistance mechanisms, induced by hypoxia and the bone marrow microenvironment via activation of Bruton tyrosine kinase (BTK). Suppressing autophagy/BTK sensitized FLT3- mutated AML to FLT3 inhibitor-induced apoptosis. Furthermore, co-targeting FLT3/BTK/aurora kinases with a novel multikinase inhibitor CG-806 (luxeptinib) induced profound apoptosis in FLT3-mutated AML by co-suppressing FLT3/BTK, antagonizing autophagy, and causing leukemia cell death in FLT3-wildtype AML by aurora kinase-mediated G2/M arrest and polyploidy, in addition to FLT3 inhibition. Thus, CG-806 exerted profound anti-leukemia activity against AML regardless of FLT3 mutation status. CG-806 also significantly reduced AML burden and extended survival in an in vivo patient-derived xenograft leukemia murine model of FLT3 inhibitor-resistant FLT3-ITD/TKD double-mutant primary AML. Taken together, these findings indicate that CG-806 has a unique mechanistic action and pre-clinical activity, which is presently undergoing clinical evaluation in both FLT3 wildtype and mutant AML.

Up-regulation of PPAR-γ involved in the therapeutic effect of icariin on cigarette smoke-induced inflammation.

Icariin (ICA) might be a potential anti-inflammatory medication in a variety of diseases including COPD, and previous studies showed that ICA could attenuate cigarette smoke (CS)-induced inflammation by inhibiting nuclear factor (NF)-κB. Peroxisome proliferator-activated receptor (PPAR) γ, a nuclear hormone receptor, has been reported to play a critical role in the inflammatory process in COPD. Whether PPAR-γ is involved in the anti-inflammatory effect of icariin on COPD has scarcely been explored. This study aimed at investigating the role of ICA in PPAR-γ expression in the CS-induced model, and then elucidating the therapeutic effects of ICA on COPD based on the PPARγ-NF-κB signaling pathway. The Beas-2B cells and H292 cells were induced with cigarette smoke extract (CSE) for 8 h after treatment with ICA for 16 h. The PPARγ expression and NF-κB pathway-related indicators were detected by western blotting, cellular immunofluorescence, and Real-time PCR. The PPARγ knock down or T0070907-treated Beas-2B cells were constructed to further investigate the relationship between the inhibition of NF-κB by ICA and PPARγ. A COPD model was established by CS exposure for 6 months, and ICA (40 mg/kg) was administrated by gastric perfusion. Then, the pulmonary function, lung histology, inflammatory cytokine levels, and protein expressions were detected. We found ICA up-regulated PPARγ protein expression in both Beas-2B cells and H292 cells, and it improved CSE-induced PPARγ down regulation and NF-κB activation. Furthermore, the inhibition of NF-κB pathway by ICA was partially dependent on PPARγ in the PPARγ knock down or T0070907-treated Beas-2B cells, suggesting that ICA attenuated CSE-induced inflammatory responses were associated with modulating the PPARγ-NF-κB pathway. Moreover, ICA showed similar effects on PPARγ and NF-κB expressions in the COPD model, and it effectively ameliorated the pulmonary function and lung inflammatory infiltration in the COPD rat model. Conclusively, the therapeutic effect of ICA on COPD was indirectly achieved by reducing airway inflammation, which was partially associated with modulating the PPARγ-NF-κB signaling pathway.

Oncoprotein SET dynamically regulates cellular stress response through nucleocytoplasmic transport in breast cancer.

SETß is the predominant isoform of oncoprotein SE translocation (SET) in various breast cancer cell lines. Interactome-transcriptome analysis has shown that SETß is intimately associated with cellular stress response. Among various exogenous stimuli, formaldehyde (FA) causes distinct biological effects in a dose-dependent manner. In response to FA at different concentrations, SET dynamically shuttles between the nucleus and cytoplasm, performing diverse biofunctions to restore homeostasis. At a low concentration, FA acts as an epidermal growth factor (EGF) and activates the HER2 receptor and downstream signaling pathways in HER2+ breast cancer cells, resulting in enhanced cell proliferation. Nucleocytoplasmic transport of SETß is controlled by the PI3K/PKCα/CK2α axis and depletion or blockade of the transport of SETß suppresses EGF-induced activation of AKT and ERK. SETß also inhibits not only stress-induced activation of p38 MAPK signaling pathway, but also assembly of stress granules by hindering formation of the G3BP1-RNA complex. Our findings suggest that SET functions as an important regulator which modulates cellular stress signaling pathways dynamically.

MiR-188-5p inhibits cell proliferation and migration in ovarian cancer via competing for CCND2 with ELAVL1.

MicroRNAs (miRNAs) were reportedly demonstrated to participate in ovarian cancer (OC) progression. Here, we inquired into the role of miR-188-5punderneath OC cell proliferation and migration. In this respect, our work examined the miR-188-5p expression and demonstrated its expression level in OC by qRT-PCR analysis. Enforced miR-188-5p expression resulted in a serious downfall of cell growth and mobility, and acceleration apoptosis in OC cells. Furthermore, we identified CCND2 as a target gene of miR-188-5p. RIP assay and luciferase reporter assay verified the interaction of miR-188-5p and CCND2 and exhibited that miR-188-5p greatly hindered the expression of CCND2. Besides, HuR stabilized CCND2 mRNA and counteracted the miR-188-5p suppressive effect on CCND2 mRNA. Functionally, rescue experiments also showed that miR-188-5p-mediated suppression on OC cell proliferation and migration was reverted by CCND2 or HuR overexpression. Our study found miR-188-5p was a tumor suppressor in OC via competing for CCND2 with ELAVL1, contributing to coming up with novel clues for OC therapies.