LMO2 promotes the development of AML through interaction with transcription co-regulator LDB1.

One of the characteristics of leukemia is that it contains multiple rearrangements of signal transduction genes and overexpression of non-mutant genes, such as transcription factors. As an important regulator of hematopoietic stem cell development and erythropoiesis, LMO2 is considered an effective carcinogenic driver in T cell lines and a marker of poor prognosis in patients with AML with normal karyotype. LDB1 is a key factor in the transformation of thymocytes into T-ALL induced by LMO2, and enhances the stability of carcinogenic related proteins in leukemia. However, the function and mechanism of LMO2 and LDB1 in AML remains unclear. Herein, the LMO2 gene was knocked down to observe its effects on proliferation, survival, and colony formation of NB4, Kasumi-1 and K562 cell lines. Using mass spectrometry and IP experiments, our results showed the presence of LMO2/LDB1 protein complex in AML cell lines, which is consistent with previous studies. Furthermore, in vitro and in vivo experiments revealed that LDB1 is essential for the proliferation and survival of AML cell lines. Analysis of RNA-seq and ChIP-Seq results showed that LDB1 could regulate apoptosis-related genes, including LMO2. In LDB1-deficient AML cell lines, the overexpression of LMO2 partially compensates for the proliferation inhibition. In summary, our findings revealed that LDB1 played an important role in AML as an oncogene, and emphasize the potential importance of the LMO2/LDB1 complex in clinical treatment of patients with AML.

Suppression of endoplasmic reticulum stress-dependent autophagy enhances cynaropicrin-induced apoptosis via attenuation of the P62/Keap1/Nrf2 pathways in neuroblastoma.

Autophagy has dual roles in cancer, resulting in cellular adaptation to promote either cell survival or cell death. Modulating autophagy can enhance the cytotoxicity of many chemotherapeutic and targeted drugs and is increasingly considered to be a promising cancer treatment approach. Cynaropicrin (CYN) is a natural compound that was isolated from an edible plant (artichoke). Previous studies have shown that CYN exhibits antitumor effects in several cancer cell lines. However, it anticancer effects against neuroblastoma (NB) and the underlying mechanisms have not yet been investigated. More specifically, the regulation of autophagy in NB cells by CYN has never been reported before. In this study, we demonstrated that CYN induced apoptosis and protective autophagy. Further mechanistic studies suggested that ER stress-induced autophagy inhibited apoptosis by activating the p62/Keap1/Nrf2 pathways. Finally, in vivo data showed that CYN inhibited tumour growth in xenografted nude mice. Overall, our findings suggested that CYN may be a promising candidate for the treatment of NB, and the combination of pharmacological inhibitors of autophagy may hold novel therapeutic potential for the treatment of NB. Our paper will contribute to the rational utility and pharmacological studies of CYN in future anticancer research.

Application of Smart Wearable Fitness Equipment and Smart Health Management Based on the Improved Algorithm.

IoT technology has scientific, advanced, and practical characteristics in wearable fitness equipment and artificial intelligence health management. On this basis, this paper discusses the intelligent health management system based on IoT technology. By building an IoT health management system, the design principles and algorithm design of wearable fitness equipment are introduced around the device, and various noises that affect the accuracy of the equipment and how to better filter out various noises are also analyzed. The authors selected cloud service platforms and also investigated and analyzed the application prospects of wearable fitness equipment in the community. From the perspective of real-time monitoring, scientific management, and intelligent decision-making, we ensure high-quality, standardized, scientific, efficient, and accurate wearable fitness equipment applications and intelligent health management. In addition to simply viewing IoT technology as an information dissemination platform, IoT technology can also expand many other functions. According to the survey results of this article, 90% of people will use the APP with the function of sports and fitness in social media. One of the most concerned issues in the current society is the application of social media in national fitness activities.

Prenatal Ultrasound Diagnosis of Persistent Hyperplastic Primary Vitreous with Retinoblastoma.

INTRODUCTION: Persistent hyperplastic primary vitreous (PHPV) involves a spectrum of congenital ocular abnormalities characterized by the presence of a vascular membrane behind the lens. Retinoblastoma is a life-threatening intraocular malignancy that can cause blindness, eye loss, or even death. PHPV and retinoblastoma are extremely rare prenatal diseases. CASE PRESENTATION: Here, we present a case of fetal PHPV with retinoblastoma diagnosed using prenatal ultrasound. The unilateral lenses were hyperechoic, and irregular echogenic bands between the lenses and posterior eye walls were observed. In cases where the blood flow signal continues in the band-shaped hyperechoic area, PHPV with retinoblastoma should be suspected. CONCLUSION: PHPV with retinoblastoma can be prenatally diagnosed.

Super-enhancer-associated INSM2 regulates lipid metabolism by modulating mTOR signaling pathway in neuroblastoma.

BACKGROUND: Abnormal lipid metabolism is one of the most prominent metabolic changes in cancer. Studies have shown that lipid metabolism also plays an important role in neuroblastoma. We recently discovered that the insulinoma-associated 2 gene (INSM2) could regulate lipid metabolism in neuroblastoma (NB) and is improperly controlled by super enhancers, a mammalian genome region that has been shown to control the expression of NB cell identity genes. However, the specific molecular pathways by which INSM2 leads to NB disease development are unknown. RESULTS: We identified INSM2 as a gene regulated by super enhancers in NB. In addition, INSM2 expression levels were significantly upregulated in NB and correlated with poor prognosis in patients. We found that INSM2 drives the growth of NB cell lines both in vitro and in vivo. Knocking down INSM2 inhibited fatty acid metabolism in NB cells. Mechanistically, INSM2 regulates the expression of SREBP1 by regulating the mTOR signaling pathway, which in turn affects lipid metabolism, thereby mediating the occurrence and development of neuroblastoma. CONCLUSION: INSM2 as a super-enhancer-associated gene could regulates lipid metabolism by modulating mTOR signaling pathway in neuroblastoma.

BRD4 inhibitor MZ1 exerts anti-cancer effects by targeting MYCN and MAPK signaling in neuroblastoma.

Neuroblastoma(NB) is a common childhood solid tumor, and most patients in the high-risk group with MYCN gene amplification have a poor prognosis. Inhibition of bromodomain and extra terminal (BET) proteins has shown considerable promise in the investigation of MYCN-driven malignancies in recent years. MZ1 is a novel BET inhibitor that employs proteolytic-targeting chimera (PROTAC) technology for proteasomal degradation of target proteins and has shown excellent effects in some tumors, but its role in neuroblastoma remains poorly understood. Herein, we observed that MZ1 suppressed MYC-amplified NB cell proliferation and normal cell cycle, while simultaneously boosting cell apoptosis. MZ1 also provides a significant therapeutic impact in vivo. Mechanistically, MZ1 exhibits anti-tumor effect in NB cells by suppressing the expression of N-Myc or C-Myc as well as the MAPK signaling pathway. Overall, our data imply that MZ1 might be exploited as a possible therapeutic method for NB therapy.

BRD4 inhibitor GNE987 exerts anti-cancer effects by targeting super-enhancers in neuroblastoma.

BACKGROUND: Neuroblastoma (NB) is a common extracranial malignancy with high mortality in children. Recently, super-enhancers (SEs) have been reported to play a critical role in the tumorigenesis and development of NB via regulating a wide range of oncogenes Thus, the synthesis and identification of chemical inhibitors specifically targeting SEs are of great urgency for the clinical therapy of NB. This study aimed to characterize the activity of the SEs inhibitor GNE987, which targets BRD4, in NB. RESULTS: In this study, we found that nanomolar concentrations of GNE987 markedly diminished NB cell proliferation and survival via degrading BRD4. Meanwhile, GNE987 significantly induced NB cell apoptosis and cell cycle arrest. Consistent with in vitro results, GNE987 administration (0.25 mg/kg) markedly decreased the tumor size in the xenograft model, with less toxicity, and induced similar BRD4 protein degradation to that observed in vitro. Mechanically, GNE987 led to significant downregulation of hallmark genes associated with MYC and the global disruption of the SEs landscape in NB cells. Moreover, a novel candidate oncogenic transcript, FAM163A, was identified through analysis of the RNA-seq and ChIP-seq data. FAM163A is abnormally transcribed by SEs, playing an important role in NB occurrence and development. CONCLUSION: GNE987 destroyed the abnormal transcriptional regulation of oncogenes in NB by downregulating BRD4, which could be a potential therapeutic candidate for NB.

SAPCD2 promotes neuroblastoma progression by altering the subcellular distribution of E2F7.

Recent studies uncovered the emerging roles of SAPCD2 (suppressor anaphase-promoting complex domain containing 2) in several types of human cancer. However, the functions and underlying mechanisms of SAPCD2 in the progression of neuroblastoma (NB) remain elusive. Herein, through integrative analysis of public datasets and regulatory network of GSK-J4, a small-molecule drug with anti-NB activity, we identified SAPCD2 as an appealing target with a high connection to poor prognosis in NB. SAPCD2 promoted NB progression in vitro and in vivo. Mechanistically, SAPCD2 could directly bind to cytoplasmic E2F7 but not E2F1, alter the subcellular distribution of E2F7 and regulate E2F activity. Among the E2F family members, the roles of E2F7 in NB are poorly understood. We found that an increasing level of nuclear E2F7 was induced by SAPCD2 knockdown, thereby affecting the expression of genes involved in the cell cycle and chromosome instability. In addition, Selinexor (KTP-330), a clinically available inhibitor of exportin 1 (XPO1), could induce nuclear accumulation of E2F7 and suppress the growth of NB. Overall, our studies suggested a previously unrecognized role of SAPCD2 in the E2F signaling pathway and a potential therapeutic approach for NB, as well as clues for understanding the differences in subcellular distribution of E2F1 and E2F7 during their nucleocytoplasmic shuttling.

Recent advances in the aetiology of recurrent aphthous stomatitis (RAS).

Recurrent aphthous stomatitis (RAS) is the most common disease of oral mucosa, which almost attacks each individual once in their lifespan. Although plenty of factors have been suggested to play a role in the pathogenesis of RAS, the aetiology of RAS is still controversial, which might lead to limited clinical therapies in accordance with each RAS patient. This review mainly illustrates recent advances in potential causes associated with RAS in detail. Deeper comprehension of the aetiology of RAS will support doctors and researchers to make a better management of RAS patients and to discover new treatments. The aetiology of RAS is complicated, hence we should take a comprehensive view into its aetiology, with multiple potential factors being considered. Sample collection of RAS patients have greatly limited the progress in the aetiology of RAS. A research model of multiagency cooperation can help achieve perfect sample collection of year-round and multiposition.

ARV-825 Demonstrates Antitumor Activity in Gastric Cancer via MYC-Targets and G2M-Checkpoint Signaling Pathways.

OBJECTIVE: Suppression of bromodomain and extra terminal (BET) proteins has a bright prospect to treat MYC-driven tumors. Bromodomain containing 4 (BRD4) is one of the BET proteins. ARV-825, consisting of a BRD4 inhibitor conjugated with a cereblon ligand using proteolysis-targeting chimera (PROTAC) technology, was proven to decrease the tumor growth effectively and continuously. Nevertheless, the efficacy and mechanisms of ARV-825 in gastric cancer are still poorly understood. METHODS: Cell counting kit 8 assay, lentivirus infection, Western blotting analysis, Annexin V/propidium iodide (PI) staining, RNA sequencing, a xenograft model, and immunohistochemistry were used to assess the efficacy of ARV-825 in cell level and animal model. RESULTS: The messenger RNA (mRNA) expression of BRD4 in gastric cancer raised significantly than those in normal tissues, which suggested poor outcome of patients with gastric cancer. ARV-825 displayed higher anticancer efficiency in gastric cancer cells than OTX015 and JQ1. ARV-825 could inhibit cell growth, inducing cell cycle block and apoptosis in vitro. ARV-825 induced degradation of BRD4, BRD2, BRD3, c-MYC, and polo-like kinase 1 (PLK1) proteins in four gastric cancer cell lines. In addition, cleavage of caspase 3 and poly-ADP-ribose polymerase (PARP) was elevated. Knockdown or overexpression CRBN could increase or decrease, respectively, the ARV-825 IC50 of gastric cancer cells. ARV-825 reduced MYC and PLK1 expression in gastric cancer cells. ARV-825 treatment significantly reduced tumor growth without toxic side effects and downregulated the expression of BRD4 in vivo. CONCLUSIONS: High mRNA expression of BRD4 in gastric cancer indicated poor prognosis. ARV-825, a BRD4 inhibitor, could effectively suppress the growth and elevate the apoptosis of gastric cancer cells via transcription downregulation of c-MYC and PLK1. These results implied that ARV-825 could be a good therapeutic strategy to treat gastric cancer.

CEBPG promotes acute myeloid leukemia progression by enhancing EIF4EBP1.

BACKGROUND: Acute myeloid leukemia (AML) is a myeloid neoplasm accounts for 7.6% of hematopoietic malignancies. AML is a complex disease, and understanding its pathophysiology is contributing to the improvement in the treatment and prognosis of AML. In this study, we assessed the expression profile and molecular functions of CCAAT enhancer binding protein gamma (CEBPG), a gene implicated in myeloid differentiation and AML progression. METHODS: shRNA mediated gene interference was used to down-regulate the expression of CEBPG in AML cell lines, and knockdown efficiency was detected by RT-qPCR and western blotting. The effect of knockdown on the growth of AML cell lines was evaluated by CCK-8. Western blotting was used to detect PARP cleavage, and flow cytometry were used to determine the effect of knockdown on apoptosis of AML cells. Genes and pathways affected by knockdown of CEBPG were identified by gene expression analysis using RNA-seq. One of the genes affected by knockdown of CEBPG was Eukaryotic translation initiation factor 4E binding protein 1 (EIF4EBP1), a known repressor of translation. Knockdown of EIF4EBP1 was used to assess its potential role in AML progression downstream of CEBPG. RESULTS: We explored the ChIP-Seq data of AML cell lines and non-AML hematopoietic cells, and found CEBPG was activated through its distal enhancer in AML cell lines. Using the public transcriptomic dataset, the Cancer Cell Line Encyclopedia (CCLE) and western blotting, we also found CEBPG was overexpressed in AML. Moreover, we observed that CEBPG promotes AML cell proliferation by activating EIF4EBP1, thus contributing to the progression of AML. These findings indicate that CEBPG could act as a potential therapeutic target for AML patients. CONCLUSION: In summary, we systematically explored the molecular characteristics of CEBPG in AML and identified CEBPG as a potential therapeutic target for AML patients. Our findings provide novel insights into the pathophysiology of AML and indicate a key role for CEBPG in promoting AML progression.

MI-773, a breaker of the MDM2/p53 axis, exhibits anticancer effects in neuroblastoma via downregulation of INSM1.

Neuroblastoma (NB) is a common pediatric malignancy associated with poor outcomes. Recent studies have shown that murine double minute2 homolog (MDM2) protein inhibitors are promising anticancer agents. MI-773 is a novel and specific antagonist of MDM2, however, the molecular mechanism of its anti-NB activity remains unclear. NB cell viability was measured by Cell Counting Kit-8 assay following MI-773 treatment. Cell cycle progression was analyzed using PI staining and apoptosis was assessed using Annexin V/PI staining. The molecular mechanisms by which MI-773 exerted its effects were investigated using a microarray. The results showed that disturbance of the MDM2/p53 axis by MI-773 resulted in potent suppression of proliferation, induction of apoptosis and cell cycle arrest in NB cells. In addition, microarray analysis showed that MI-773 led to significant downregulation of genes involved in the G2/M phase checkpoint and upregulation of hallmark gene associated with the p53 pathway. Meanwhile, knockdown of insulinoma-associated 1 decreased proliferation and increased apoptosis of NB cells. In conclusion, the present study demonstrated that MI-773 exhibited high selectivity and blockade affinity for the interaction between MDM2 and TP53 and may serve as a novel strategy for the treatment of NB.

Comparative Assessment of Various Low-Dissipation Combined Models for Three-Terminal Heat Pump Systems.

Thermally driven heat pump systems play important roles in the utilization of low-grade thermal energy. In order to evaluate and compare the performances of three different constructions of thermally driven heat pump and heat transformer, the low-dissipation assumption has been adopted to establish the irreversible thermodynamic models of them in the present paper. By means of the proposed models, the heating loads, the coefficients of performance (COPs) and the optimal relations between them for various constructions are derived and discussed. The performances of different constructions are numerically assessed. More importantly, according to the results obtained, the upper and lower bounds of the COP at maximum heating load for different constructions are generated and compared by the introduction of a parameter measuring the deviation from the reversible limit of the system. Accordingly, the optimal constructions for the low-dissipation three-terminal heat pump and heat transformer are determined within the frame of low-dissipation assumption, respectively. The optimal constructions in accord with previous research and engineering practices for various three-terminal devices are obtained, which confirms the compatibility between the low-dissipation model and endoreversible model and highlights the validity of the application of low-dissipation model for multi-terminal thermodynamic devices. The proposed models and the significant results obtained enrich the theoretical thermodynamic model of thermally driven heat pump systems and may provide some useful guidelines for the design and operation of realistic thermally driven heat pump systems.

[Professor WANG Yin's academic thoughts and clinical application of acupuncture for spleen-sto-mach care].

Professor WANG Yin's academic thoughts and clinical application for difficult and miscellaneous di-seases, especially acupuncture for spleen-stomach care, are introduced. Based on TCM basic theory and "ten needles for elderly" by WANG Yueting, Professor WANG Yin proposes the acupuncture for spleen-stomach care. In this method, three-element acupoint selection is applied; the conception vessel, spleen meridian of foot taiyin and stomach meridian of foot yangming were selected. The deep and penetration acupuncture with 0.4 mm×100 mm elongated needles is used at Zhongwan (CV 12), Qihai (CV 6) and Zigong (EX-CA 1), and the mild reinforcing-reducing method is used at remaining acupoints. According to the severity of diseases, fire acupuncture combined with blood-letting cupping is applied at Tianshu (ST 25), Xuehai (SP 10) and Yinlingquan (SP 9); gene-rally, two acupoints are selected and 1 to 3 mL blood-letting is appropriate. The modification based on this me-thod can be applied for various difficult and miscellaneous diseases, leading to superior efficacy.

The expression of FOXJ1 in neurogenesis after transient focal cerebral ischemia.

OBJECTIVE AND BACKGROUND: FOXJ1 is a member of the Forkhead/winged-helix (Fox) family of transcription factors, which is required for the differentiation of the cells acting as adult neural stem cells which participate in neurogenesis and give rise to neurons, astrocytes, oligodendrocytes. The expression pattern of FOXJ1 in the brain after cerebral ischemia has so far not been described. In the current study, we investigated the expression pattern of FOXJ1 in the rat brain after cerebral ischemia by animal model. METHODS: We performed a middle cerebral artery occlusion (MCAO) model in adult rats and investigated the expression of FOXJ1 in the brain by Western blotting and immunochemistry; double immunofluorescence staining was used to analyze FOXJ1's co-expression with Ki67. RESULTS: Western blot analysis showed that the expression of FOXJ1 was lower than normal and sham-operated brain after cerebral ischemia, but the level of FOXJ1 gradually increased from Day 1 to Day 14. Immuohistochemical staining suggested that the immunostaining of FOXJ1 deposited strongly in the ipsilateral and contralateral hemisphere in the cortical penumbra (CP). There was no FOXJ1 expression in the ischemic core (IC). The positive cells in the cortical penumbra might migrate to the ischemic core. In addition, double immunofluorescence staining revealed that FOXJ1 was co-expressed with mAP-2 and gFAP, and Ki67 had the colocalization with NeuN, GFAP, and FOXJ1. CONCLUSIONS: All our findings suggest that FOXJ1 plays an important role on neuronal production and neurogenesis in the adult brain after cerebral ischemia.

Salinity and soluble organic matter on virus sorption in sand and soil columns.

The objective of this research was to study the sorption and transport of bacteriophage MS-2 (a bacterial virus) in saturated sediments under the effect of salinity and soluble organic matter (SOM). One-dimensional column experiments were conducted on washed high-purity silica sand and sandy soil. In sand column tests, increasing salinity showed distinct effect on enhancing MS-2 sorption. However, SOM decreased MS-2 sorption. Using a two-site reversible-irreversible sorption model and the double layer theory, we explained that pore-water salinity potentially compressed the theoretical thickness of double layers of MS-2 and sand, and thus increased sorption on reversible sorption sites. On irreversible sorption sites, increasing salinity reversed charges of some sand particles from negative to positive, and thus converted reversible sorption sites into irreversible sites and enhanced sorption of MS-2. SOM was able to expand the double layer thickness on reversible sites and competed with MS-2 for the same binding place on irreversible sites. In sandy soil column tests, the bonded and dissolved (natural) soil organic matters suppressed the effects of pore-water salinity and added SOM and significantly reduced MS-2 adsorption. This was explained that the bonded soil organic matter occupied a great portion of sorption sites and significantly reduced sorption sites for MS-2. In addition, the dissolved soil organic matter potentially expanded the double layer thickness of MS-2 and sandy soil on reversible sorption sites and competed with MS-2 for the same binding place.

Structural model of the Rev regulatory protein from equine infectious anemia virus.

Rev is an essential regulatory protein in the equine infectious anemia virus (EIAV) and other lentiviruses, including HIV-1. It binds incompletely spliced viral mRNAs and shuttles them from the nucleus to the cytoplasm, a critical prerequisite for the production of viral structural proteins and genomic RNA. Despite its important role in production of infectious virus, the development of antiviral therapies directed against Rev has been hampered by the lack of an experimentally-determined structure of the full length protein. We have used a combined computational and biochemical approach to generate and evaluate a structural model of the Rev protein. The modeled EIAV Rev (ERev) structure includes a total of 6 helices, four of which form an anti-parallel four-helix bundle. The first helix contains the leucine-rich nuclear export signal (NES). An arginine-rich RNA binding motif, RRDRW, is located in a solvent-exposed loop region. An ERLE motif required for Rev activity is predicted to be buried in the core of modeled structure where it plays an essential role in stabilization of the Rev fold. This structural model is supported by existing genetic and functional data as well as by targeted mutagenesis of residues predicted to be essential for overall structural integrity. Our predicted structure should increase understanding of structure-function relationships in Rev and may provide a basis for the design of new therapies for lentiviral diseases.

Codability criterion for picking proteinlike structures from random three-dimensional configurations.

We show that the dominant eigenvectors of real protein structural contact matrices are highly correlated with their amino acid sequences. These results suggests that an ab initio sequence-independent profile exists for every protein structure and that this profile is highly effective in differentiating the ordering of amino acids in natural protein sequences from random sequences. This profile provides a structural code and is a key for understanding the unique behavior of protein structures. Using a lattice model, we show that there are special codable structures highly separated from random structures in the dominant eigenvector space of their structural contact matrices. As an example, we show our results provide a good explanation to the "designable principle" of protein structures.