Promotion of non-small cell lung cancer tumor growth by FHL2 via inducing angiogenesis and vascular permeability.

Background: Antiangiogenetic therapy is one of the effective strategies for non-small cell lung cancer (NSCLC) treatment. Four-and-a-half LIM-domain protein 2 (FHL2) serves as a key function in cell growth and metastasis of multiple cancers, but the role of FHL2 in NSCLC angiogenesis has not been intensely examined. Methods: FHL2 expression in NSCLC tissues and cell lines and its correlation with patients prognosis were investigated by using The Cancer Genome Atlas (TCGA) database and quantitative polymerase chain reaction (qPCR). Cell Counting Kit-8 (CCK-8) assay, EdU (5-ethynyl-2'-deoxyuridine) assay, and a xenograft model were used to investigate the effects of FHL2 on NSCLC progression in vitro and in vivo. CCK-8, wound-healing, Transwell invasion, tube formation, and permeability assays were performed to determine the roles of FHL2 in angiogenesis and vascular permeability. Vascular endothelial growth factor A (VEGFA) enzyme-linked immunosorbent assay (ELISA) assay, Western blot analysis, and MK-2206 were used to investigate the specific mechanism mediated by FHL2. Results: We demonstrated that FHL2 was significantly upregulated in NSCLC tissues and cell lines and was associated with poor prognosis. FHL2 overexpression enhanced the cell viability of NSCLC cells, as well as the proliferation, migration, invasion, and tube formation of human umbilical vein endothelial cells (HUVECs). In addition, we determined that FHL2 activated the AKT-mTOR signaling pathway in HUVECs by promoting VEGFA secretion from NSCLC cells, thereby inducing angiogenesis and vascular leakiness. We further confirmed that FHL2 also promoted NSCLC tumor growth in vivo. Conclusions: Our study revealed the role of FHL2 in NSCLC and the mechanism by which FHL2 promotes NSCLC tumorigenesis, providing novel insights into targeted therapy for NSCLC.

Mebendazole induces apoptosis and inhibits migration via the reactive oxygen species-mediated STAT3 signaling downregulation in non-small cell lung cancer.

Background: The incidence and mortality of non-small cell lung cancer (NSCLC) are extremely high. Previous research has confirmed that the signal transducer and activator of the transcription 3 (STAT3) protein critically participate in the tumorigenesis of NSCLC. Mebendazole (MBZ) has exerts a larger number of pharmacological activities and has anticancer effects in lung cancer, but its mechanism of action remains unclear. This study thus aimed to clarify the impacts of MBZ on NSCLC cell. Methods: Cell proliferation, migration, and apoptosis were investigated via cell counting kit 8 (CCK-8) assay, Transwell assay, colony formation assay, wound-healing assay, and flow cytometry. Reactive oxygen species (ROS) were detected with a multifunctional microplate reader. Markers of cell migration and apoptosis were detected with Western blotting. The transcriptional activity of STAT3 was detected via luciferase assay. ROS scavenger N-acetylcysteine (NAC) was used to determine the effect of MBZ on NSCLC via ROS-regulated STAT3 inactivation and apoptosis. A xenograft model was constructed in vivo to investigate the role of MBZ in NSCLC tumor growth. Results: The findings demonstrated that MBZ inhibited NSCLC cell proliferation and migration while promoting apoptosis through triggering ROS generation. In addition, the Janus kinase 2 (JAK2)-STAT3 signaling pathway was abrogated with the treatment of MBZ. NAC could distinctly weaken MBZ-induced apoptosis and STAT3 inactivation. Moreover, MBZ inhibited the tumor growth of NSCLC in vivo. Conclusions: In summary, MBZ inhibited NSCLC cell viability and migration by inducing cell apoptosis via the ROS-JAK2-STAT3 signaling pathway. These data provide a theoretical basis for the use of MBZ in treating NSCLC.

The interaction of financial toxicity and social support on social functioning in post-chemotherapy breast cancer patients: a cross-sectional study.

PURPOSE: To explore the correlation between financial toxicity, social support, and social functioning in post-chemotherapy breast cancer patients, as well as any possible interaction of financial toxicity and social support on social functioning. METHODS: Post-chemotherapy breast cancer patients admitted to the thyroid and breast surgery departments of three first-class general hospitals in East China from December 2020 to January 2022 were recruited by convenience sampling for a cross-sectional survey. The survey instruments included the general information form, the comprehensive scores for financial toxicity based on the patient-reported outcome measures (COST-PROM), the social roles and activity participation subscale from the patient-reported outcomes measurement system-breast-chemotherapy (PROMS-B-C) (score range: 8-40), and the social support subscale from PROMS-B-C (score range: 16-80). RESULTS: The results showed that low social functioning (low score) in post-chemotherapy breast cancer patients was positively correlated with high financial toxicity (low score) as well as poor economic resources (low score) and poor psychosocial responses (low score) (P<0.01) and negatively correlated with low economic expenditures (low score) (P<0.01); high social functioning (high score) was positively correlated with high social support (high score) (P<0.01). The interaction analysis results showed an additive interaction between financial toxicity and social support in social functioning. CONCLUSION: There was an additive interaction of financial toxicity and social support in the social functioning of post-chemotherapy breast cancer patients. Those patients with high financial toxicity and low social support are the most likely to benefit from relevant intervention measures compared to other breast cancer populations.

Which Exercise Approaches Work for Relieving Cancer-Related Fatigue? A Network Meta-analysis.

OBJECTIVE: To determine the most effective exercise modalities for managing cancer-related fatigue during and after cancer treatment. DESIGN: Network meta-analysis (NMA) of randomized controlled trials. LITERATURE SEARCH: Seven electronic databases were systematically searched from inception to January 2022. STUDY SELECTION CRITERIA: Randomized controlled trials testing the effects of exercise on relieving cancer-related fatigue in adult patients with cancer. DATA SYNTHESIS: An NMA of 56 studies was conducted, and the PRISMA-NMA guidelines were followed when reporting results. To determine the most effective interventions, the surface under the cumulative ranking curve (SUCRA) value was calculated for each exercise modality. RESULTS: Combined aerobic and resistance exercise (standardized mean difference [SMD], 1.57; credible interval [CrI], 1.03-2.10), yoga (SMD, 1.02; CrI: 0.44, 1.60), and regular physical activity (SMD, 1.07; CrI: 0.21, 1.92) could significantly alleviate cancer-related fatigue compared to control groups (usual care, wait-list, and regular physical activity). Combined aerobic and resistance exercise (SUCRA, 97.2%) had the highest probability of efficacy, followed by yoga (SUCRA, 75.5%) and regular physical activity (SUCRA, 74.1%). During cancer treatment, combined aerobic and resistance exercise (SUCRA, 94.5%) ranked first in efficacy, followed by regular physical activity (SUCRA, 82.1%) and yoga (SUCRA, 73.8%). After cancer treatment, only combined aerobic and resistance exercise (SMD, 0.99; CrI: 0.13, 1.84) had a significant effect on cancer-related fatigue. CONCLUSION: Combined aerobic and resistance exercise, yoga, and regular physical activity were the most effective exercise modalities for alleviating cancer-related fatigue. Combined aerobic and resistance exercise is recommended during and after cancer treatment. J Orthop Sports Phys Ther 2023;53(6):1-10. Epub: 23 March 2023. doi:10.2519/jospt.2023.11251.

Bacterium-Sculpted Porphyrin-Protein-Iron Sulfide Clusters for Distinction and Inhibition of Staphylococcus aureus.

Microbe-catalyzed surface modification is a promising method for the production of special targeting nanomaterials. A bacterium-selective material can be obtained by investigating the microbe-catalyzed mineralization of proteins. Herein, a novel method was fabricated for the biosynthesis of FeS-decorated porphyrin-protein clusters (P-CA@BE) via E. coli (Escherichia coli)-catalyzed bio-Fe(III) reduction and bio-sulfidation of porphyrin (P), caffeic acid (CA), and protein [bovine serum albumin (BSA)] assemblies. The assembly (P-CA@BSA) was identified by spectroscopic methods. Next, the P-CA@BSA assembly was transferred into FeS-decorated porphyrin-protein clusters (P-CA@BE) catalyzed by E. coli. There are partial ß-folding proteins in P-CA@BE, which selectively recognize S. aureus (Staphylococcus aureus) and show different antibacterial properties against E. coli and S. aureus. Results demonstrate that the E. coli-catalyzed mineralization of the porphyrin-protein assembly is an effective method for the biosynthesis of S. aureus-sensitive metal-protein clusters.

Total femur replacement with 18 years of follow-up: A case report.

BACKGROUND: Osteosarcoma is one of the most common primary malignant bone tumors and is more common in adolescents. The femur is the most common site of osteosarcoma, and many patients require total femur replacement. We reviewed the relevant literature and case findings, summarized and analyzed this case in combination with relevant literature, and in doing so improved the understanding of the technology. CASE SUMMARY: The case we report was a 15-year-old patient who was admitted to the hospital 15 days after the discovery of a right thigh mass. The diagnosis was osteosarcoma of the right femoral shaft. After completion of neoadjuvant chemotherapy and preoperative preparation, total right femoral resection + artificial total femoral replacement was performed. Then, chemotherapy was continued after surgery. The patient recovered well after treatment, and the function of the affected limb was good. No recurrence, metastasis, prosthesis loosening, dislocation, fracture or other complications were found during 18 years of follow-up. At present, the patient can still work and lives normally. The results of the medium- and long-term follow-up were satisfactory. CONCLUSION: Artificial total femur replacement is a feasible limb salvage operation for patients with femoral malignant tumors, and the results of medium- and long-term follow-up are satisfactory.

Aromatherapy with single essential oils can significantly improve the sleep quality of cancer patients: a meta-analysis.

OBJECTIVE: To investigate the effect of aromatherapy on sleep quality in cancer patients. METHODS: Published literature on the effect of aromatherapy in cancer patients with sleep disorders in the form of randomized controlled trials (RCTs) were systematically retrieved and screened from PubMed, Cochrane Library, Embase, CBM, CNKI, VIP, and Wanfang databases from inception to November 2021. The methodological quality of the included studies was critically and independently evaluated by two reviewers using the Cochrane Risk of Bias Assessment Tool for RCTs. The correlated data were extracted using the pre-designed form, and all analyses were performed using Reviewer Manager version 5.4. Due to the difference in sleep quality instruments, the data extracted in this study were in the form of standard mean difference (SMD). RESULTS: Ten RCTs included 933 patients (experimental group: 474, control group: 459), and the risk of bias in the included studies was moderate. Aromatherapy could significantly improve the sleep quality of cancer patients [SMD = - 0.79, 95% CI (- 0.93, - 0.66), p < 0.01], especially those with breast cancer [SMD = - 0.98, 95% CI (- 1.57, - 0.40), p < 0.01]. Aromatherapy with single essential oil had a better effect on sleep quality [SMD = -0.94, 95%CI (- 1.25, - 0.62), p < 0.01], of which lavender essential oil had the best effect [SMD = -1.06,95%CI (- 1.49, - 0.63), p < 0.01] while compound essential oils had no effect on sleep quality improvement in cancer patients [SMD = -0.21, 95%CI (- 0.57, 0.14), p = 0.23]. Four of the ten RCTs reported the occurrence of adverse events, of which only one RCT indicated that patients had headache and sneezing while the remaining six did not. CONCLUSIONS: This meta-analysis of 10 RCTs reveals that aromatherapy with single essential oil had a substantial effect on the sleep quality of cancer patients and should be recommended as a beneficial complementary therapy to promote sleep quality in cancer patients.

Gene therapy targeting protein trafficking regulator MOG1 in mouse models of Brugada syndrome, arrhythmias, and mild cardiomyopathy.

Brugada syndrome (BrS) is a fatal arrhythmia that causes an estimated 4% of all sudden death in high-incidence areas. SCN5A encodes cardiac sodium channel NaV1.5 and causes 25 to 30% of BrS cases. Here, we report generation of a knock-in (KI) mouse model of BrS (Scn5aG1746R/+). Heterozygous KI mice recapitulated some of the clinical features of BrS, including an ST segment abnormality (a prominent J wave) on electrocardiograms and development of spontaneous ventricular tachyarrhythmias (VTs), seizures, and sudden death. VTs were caused by shortened cardiac action potential duration and late phase 3 early afterdepolarizations associated with reduced sodium current density (INa) and increased Kcnd3 and Cacna1c expression. We developed a gene therapy using adeno-associated virus serotype 9 (AAV9) vector-mediated MOG1 delivery for up-regulation of MOG1, a chaperone that binds to NaV1.5 and traffics it to the cell surface. MOG1 was chosen for gene therapy because the large size of the SCN5A coding sequence (6048 base pairs) exceeds the packaging capacity of AAV vectors. AAV9-MOG1 gene therapy increased cell surface expression of NaV1.5 and ventricular INa, reversed up-regulation of Kcnd3 and Cacna1c expression, normalized cardiac action potential abnormalities, abolished J waves, and blocked VT in Scn5aG1746R/+ mice. Gene therapy also rescued the phenotypes of cardiac arrhythmias and contractile dysfunction in heterozygous humanized KI mice with SCN5A mutation p.D1275N. Using a small chaperone protein may have broad implications for targeting disease-causing genes exceeding the size capacity of AAV vectors.

Identification and characterization of a special type of subnuclear structure: AGGF1-coated paraspeckles.

AGGF1 is an angiogenic factor with G-Patch and FHA domains 1 described by our group. Gain-of-function mutations in AGGF1 cause Klippel-Trenaunay syndrome, whereas somatic loss-of-function mutations cause cancer. Paraspeckles are small membraneless subnuclear structures with a diameter of 0.5-1 µm, and composed of lncRNA NEAT1 as the scaffold and three core RNA-binding proteins NONO, PSPC1, and PSF. Here, we show that AGGF1 is a key regulatory and structural component of paraspeckles that induces paraspeckle formation, forms an outside rim of paraspeckles, wraps around the NONO/PSF/PSPC1/NEAT1 core, and regulates the size and number of paraspeckles. AGGF1-paraspeckles are larger (>1 µm) than conventional paraspeckles. RNA-FISH in combination with immunostaining shows that AGGF1, NONO, and NEAT1_2 co-localize in 20.58% of NEAT1_2-positive paraspeckles. Mechanistically, AGGF1 interacts with NONO, PSF, and HNRNPK, and upregulates NEAT1_2, a longer, 23 kb NEAT1 transcript with a key role in regulation of paraspeckle size and number. RNA-immunoprecipitation shows that AGGF1 interacts with NEAT1, which may be another possible mechanism underlying the formation of AGGF1-paraspeckles. NEAT1_2 knockdown reduces the number and size of AGGF1-paraspeckles. Functionally, AGGF1 regulates alternative RNA splicing as it decreases the exon skipping/inclusion ratio in a CD44 model. AGGF1 is also localized in some nuclear foci without NEAT1 or NONO, suggesting that AGGF1 is an important liquid-liquid phase separation (LLPS) driver for other types of AGGF1-positive nuclear condensates (referred to as AGGF1-bodies). Our results identify a special type of AGGF1-coated paraspeckles and provide important insights into the formation, structure, and function of paraspeckles.

Effectiveness comparisons of various psychosocial therapies for cancer-related fatigue: A Bayesian network meta-analysis.

OBJECTIVES: The purpose of this network meta-analysis (NMA) is to compare the effect of several psychosocial therapies on CRF critically. METHODS: We applied systematic strategies based on eight databases, namely the Cochrane Central Register of Controlled Trials, PubMed, Embase, PsycINFO, China Biology Medicine (CBM), Wan Fang database, VIP, and China National Knowledge Infrastructure (CNKI) database to preliminary literature retrieval to identify relevant randomized controlled trials (RCTs). Studies, including adult patients (≥18 years) diagnosed with cancer, were eligible regardless of cancer stage and current treatment. We carried out an expression analysis for comparing the efficacy of various psychosocial therapies using Bayesian NMA. A battery of analyses and assessments, such as conventional meta-analysis and risk of bias, were performed concurrently. RESULTS: We identified 41 RCTs including six different psychosocial interventions (4422 participants), namely cognitive-behavioral therapy (CBT), mindfulness-based stress reduction therapy (MBSR), psychoeducational therapy (PE), stress management therapy (SMT), meditation therapy (MT) and comprehensive therapy (CT). Our NMA results showed that three psychosocial intervention therapies were effective for CRF in cancer patients. The most effective psychosocial intervention was MBSR (SMD = -1.23, CrI: -1.88, -0.59, SUCRA = 83.33%), followed by PE (SMD = -0.86, CrI: -1.53, -0.18, SUCRA = 58.51%) and CBT (SMD = -0.84, CrI: -1.31, -0.37, SUCRA = 57.67%). CONCLUSIONS: Our study showed that MBSR was most likely to be the best psychosocial intervention to relieve CRF in cancer patients. Medical staff should pay attention to applying MBSR to cancer patients in future clinical care.

Endothelial PERK-ATF4-JAG1 axis activated by T-ALL remodels bone marrow vascular niche.

The endoplasmic reticulum unfolded protein response (UPR) is a conserved adaptive signaling in ER homeostasis and has emerged as critical in highly proliferating cells and potential treatment target for acute T-cell lymphoblastic leukemia (T-ALL). Methods: in this study, we assessed the transcriptomic and phenotypic alterations in UPR response of the bone marrow endothelial cells (ECs) in mice engrafted with T-ALL and in bone marrow specimens from patients who have T-ALL. We used PERK inhibitor and generated endothelial specific PERK knockout mice to study the impact of PERK on leukemia progression and hematopoiesis. We performed chromatin immunoprecipitation (ChIP) to study the mechanistic regulation of JAG1 by ATF4. We characterized small extracellular vesicles (SEV) from leukemia-developing mice and studied the effect of SEVs on EC function. Results: we found that T-ALL development induced a robust activation of protein kinase RNA-like endoplasmic reticulum kinase (PERK)-dominant UPR in the bone marrow endothelial vascular niche. The activation of PERK-eIF2a-ATF4 axis remodels the vascular niche, upregulates angiogenic factors including VEGFα and ATF4-regulated JAG1, and suppresses the expression of SCF and CXCL12, which are important to HSC maintenance and regeneration. Further, targeting endothelial PERK significantly improved T-ALL outcome. EC-specific deletion of PERK abolished the aberrant JAG1 up-regulation, improved HSC maintenance, promoted leukemia apoptosis, and improved overall survival. Finally, we showed that small extracellular vesicles are critical mediators of endothelial PERK-eIF2a-ATF4 activation and JAG1 up-regulation in leukemia. Corroborating animal model studies, activation of PERK-ATF4-JAG1 is prominent in human T-ALL bone marrow and T-ALL xenografts. Conclusion: our studies thus revealed for the first time that the leukemia-initiated PERK-ATF4-JAG1 axis plays a critical role in the remodeling of the bone marrow vascular niche and that targeting vascular niche UPR is a potential therapeutic opportunity in T-ALL.

A dye-andrographolide assembly as a turn-on sensor for detection of phthalate in both cells and fish.

Phthalates can penetrate the environment and enrich various aquatic organisms through the food chain, which is involved in promoting the growth of breast cancer. It is of current interest to develop new sensors for phthalates. We herein reported a hydrogen-bond competing fluorescent sensor, BANP, for the detection of dibutyl phthalate (DBP). The BANP compound was synthesized by assembling andrographolide (Andro), nitro- and cyano-substituted BODIPY dye (BCN), and polyethylene glycol derivatives (DSPE-mPEG5000). BANP was found to be a turn-on fluorescent probe for DBP in water with a detection limit of 0.13 µg/g; the DBP-water system acts as a hydrogen bond switch to turn on the fluorescence. And BANP fluorescently detected DBP in contaminated fish meat. Moreover, BANP sensed the DBP-induced growth of human breast cancer MCF-7 cells, and the release of Andro in the DBP-cultivated cancer cells inhibited the proliferation of the MCF-7 cells. Taken together, BANP is a DBP-responsive probe for sensitive DBP detection in water, cells, and fish meats. The BANP sensor may be used in both in vitro fluorescence and cellular imaging analyses. Our results show that guest-induced reassembly brings forth significant fluorescence change, which is a promising way of designing new fluorescent probes for the analysis of phthalates in the environment and food.

Receptor and Molecular Mechanism of AGGF1 Signaling in Endothelial Cell Functions and Angiogenesis.

Objective: Angiogenic factor AGGF1 (angiogenic factor with G-patch and FHA [Forkhead-associated] domain 1) promotes angiogenesis as potently as VEGFA (vascular endothelial growth factor A) and regulates endothelial cell (EC) proliferation, migration, specification of multipotent hemangioblasts and venous ECs, hematopoiesis, and vascular development and causes vascular disease Klippel-Trenaunay syndrome when mutated. However, the receptor for AGGF1 and the underlying molecular mechanisms remain to be defined. Approach and Results: Using functional blocking studies with neutralizing antibodies, we identified [alpha]5[beta]1 as the receptor for AGGF1 on ECs. AGGF1 interacts with [alpha]5[beta]1 and activates FAK (focal adhesion kinase), Src (proto-oncogene tyrosine-protein kinase), and AKT (protein kinase B). Functional analysis of 12 serial N-terminal deletions and 13 C-terminal deletions by every 50 amino acids mapped the angiogenic domain of AGGF1 to a domain between amino acids 604-613 (FQRDDAPAS). The angiogenic domain is required for EC adhesion and migration, capillary tube formation, and AKT activation. The deletion of the angiogenic domain eliminated the effects of AGGF1 on therapeutic angiogenesis and increased blood flow in a mouse model for peripheral artery disease. A 40-mer or 15-mer peptide containing the angiogenic domain blocks AGGF1 function, however, a 15-mer peptide containing a single amino acid mutation from -RDD- to -RGD- (a classical RGD integrin-binding motif) failed to block AGGF1 function. Conclusions: We have identified integrin [alpha]5[beta]1 as an EC receptor for AGGF1 and a novel AGGF1-mediated signaling pathway of [alpha]5[beta]1-FAK-Src-AKT for angiogenesis. Our results identify an FQRDDAPAS angiogenic domain of AGGF1 crucial for its interaction with [alpha]5[beta]1 and signaling.

Non-coding RNAs in necroptosis, pyroptosis and ferroptosis in cancer metastasis.

Distant metastasis is the main cause of death for cancer patients. Recently, the newly discovered programmed cell death includes necroptosis, pyroptosis, and ferroptosis, which possesses an important role in the process of tumor metastasis. At the same time, it is widely reported that non-coding RNA precisely regulates programmed death and tumor metastasis. In the present review, we summarize the function and role of necroptosis, pyrolysis, and ferroptosis involving in cancer metastasis, as well as the regulatory factors, including non-coding RNAs, of necroptosis, pyroptosis, and ferroptosis in the process of tumor metastasis.

Structure and biomolecular recognition of nitro-BODIPY-andrographolide assembles for cancer treatment.

Andrographolide (Andro) derivatives can interfere with a variety of enzymes. To increase the cancer cell absorption of Andro and to enhance the therapeutic effect of breast cancer, nitro group substituted boron dipyrromethene (NBDP) was used as the carrier of Andro. Two NBDP based assemblies (NBDP-Andro and nano NBDPAndro@PEG) were synthesized and characterized by spectroscopic methods. The affinity of Andro with NBDP enhanced the emission of NBDP. The interaction of the compounds with lipase was also studied. NBDP-Andro can bind with lipase and form new species with an emission at 360 nm. Results demonstrate that the Andro of NBDP-Andro drives the interaction of compounds with protein (BSA) and lipase by inter-molecular forces. The large red shift emission at 611 nm of the NBDPAndro@PEG is observed and discussed. Also, the MTT assay confirms that Nano NBDPAndro@PEG can enhance the inhibition rate of the proliferation of MCF-7 breast cancer cells. Therefore, nitro substituted BODIPY can be a carrier of andrographolide for cancer treatment.

Role of epigenetic m6 A RNA methylation in vascular development: mettl3 regulates vascular development through PHLPP2/mTOR-AKT signaling.

N6 -methyladenosine (m6A) methylation is the most prevalent RNA modification, and it emerges as an important regulatory mechanism of gene expression involved in many cellular and biological processes. However, the role of m6 A methylation in vascular development is not clear. The m6 A RNA methylation is regulated by dynamic interplay among methyltransferases, binding proteins, and demethylases. Mettl3 is a member of the mettl3-mettl14 methyltransferase complex, referred to as writers that catalyze m6A RNA methylation. Here, we used CRISPR-Cas9 genome editing to develop two lines of knockout (KO) zebrafish for mettl3. Heterozygous mettl3+/- KO embryos show defective vascular development, which is directly visible in fli-EGFP and flk-EGFP zebrafish. Alkaline phosphatase staining and whole mount in situ hybridization with cdh5, and flk markers demonstrated defective development of intersegmental vessels (ISVs), subintestinal vessels (SIVs), interconnecting vessels (ICVs) and dorsal longitudinal anastomotic vessels (DLAV) in both heterozygous mettl3+/- and homozygous mettl3-/- KO zebrafish embryos. Similar phenotypes were observed in zebrafish embryos with morpholino knockdown (KD) of mettl3; however, the vascular defects were rescued fully by overexpression of constitutively active AKT1. KD of METTL3 in human endothelial cells inhibited cell proliferation, migration, and capillary tube formation. Mechanistically, mettl3 KO and KD significantly reduced the levels of m6 A RNA methylation, and AKT phosphorylation (S473) by an increase in the expression of phosphatase enzyme PHLPP2 and reduction in the phosphorylation of mTOR (S2481), a member of the phosphatidylinositol 3-kinase-related kinase family of protein kinases. These data suggest that m6 A RNA methylation regulates vascular development via PHLPP2/mTOR-AKT signaling.

Wrist-ankle acupuncture has a positive effect on cancer pain: a meta-analysis.

BACKGROUND: Wrist-ankle acupuncture (WAA) as a kind of micro acupuncture therapy has been used to management cancer pain, however, the effects of WAA on cancer pain were controversial in the current studies. Therefore, the purpose of this meta-analysis was to critically evaluate the effect of wrist-ankle acupuncture (WAA) on cancer pain. METHODS: Seven digital databases were searched from the inception of databases to July 2020, including CNKI, Wanfang, VIP, CBM, Cochrane Library, PubMed and Embase. Randomized controlled trials conforming to the inclusion and exclusion criteria were screened and extracted; the risk of bias was evaluated using the Cochrane Collaboration criteria. The primary outcome indicators included pain relief rate and pain score, and the secondary outcome was adverse reaction incidence. All analyses were performed with Review Manager 5.3. RESULTS: A total of 13 studies with 1005 cancer patients (intervention group: 568, control group: 437) were included in this meta-analysis. The results demonstrated that the pain relief rate of experimental group (WAA / WAA + drug intervention) was better than that of control group (analgesic drug intervention), and the difference was statistically significant [RR = 1.31, 95%CI: 1.15 ~ 1.49, P < 0.01]. CONCLUSIONS: WAA has certain effect on cancer pain, and the effect of WAA combined with pharmacological intervention is better than that of drug therapy alone.

Transcriptome Sequencing reveals the expressed profiles of mRNA and ncRNAs and regulate network via ceRNA mediated molecular mechanism of lung adenocarcinoma bone metastasis in Xuanwei.

BACKGROUND: The most ordinary subtype of lung cancer is lung adenocarcinoma (LuAC), which is characterized by strong metastatic ability. And LuAC rates in Xuanwei leads to the poor prognosis and high death rate. In this study, we systematically explored the molecular mechanism of LuAC bone metastasis in Xuanwei by transcriptome sequencing. METHODS: RNA Sequencing was conducted to explore the noncoding RNAs (ncRNAs) expression profiles in primary LuAC and LuAC bone metastasis. We identified differentially expressed mRNAs (DEmRNAs), miRNAs (DEmiRNAs), lncRNAs (DElncRNAs) and circRNAs (DEcircRNAs). Bioinformatics analyses the possible relationships and functions of the LuAC bone metastasis-related competing endogenous RNA (ceRNA). And qRT-PCR was performed to evaluate the expression of these differently expressed genes in serum. RESULTS: A total of 2,141 DEmRNAs, 43 DEmiRNAs, 136 DElncRNAs and 706 DEcircRNAs were identified in the Xuanwei patients with primary LuAC vs. LuAC bone metastasis, respectively. The circRNA/miRNA/mRNA and lncRNA/miRNA/mRNA networks of LuAC in Xuanwei with bone metastasis were built, and the gene expression mechanisms regulated by ncRNAs were unveiled via the ceRNA regulatory networks. We observe that lncRNA (ADAMTS9-AS2, TEX41, DLEU2, LINC00152)-miR-223-3p-SCARB1 and hsa_circ_0000053-miR-196a-5p/miR-196b-5p-HOXA5 ceRNA networks might play an important role in bone metastasis of Xuanwei LuAC. CONCLUSIONS: We comprehensively identified ceRNA regulatory networks of LuAC in Xuanwei with bone metastasis as well as revealed the contribution of different ncRNAs expression profiles. Our data demonstrate the association between mRNAs and ncRNAs in the metastasis mechanism of LuAC in Xuanwei with bone metastasis.

Angiogenic factor AGGF1 acts as a tumor suppressor by modulating p53 post-transcriptional modifications and stability via MDM2.

Angiogenesis factors are widely known to promote tumor growth by increasing tumor angiogenesis in the tumor microenvironment, however, little is known whether their intracellular function is involved in tumorigenesis. Here we show that AGGF1 acts as a tumor suppressor by regulating p53 when acting inside tumor cells. AGGF1 antagonizes MDM2 function to inhibit p53 ubiquitination, increases the acetylation, phosphorylation, stability and expression levels of p53, activates transcription of p53 target genes, and regulates cell proliferation, cell cycle, and apoptosis. AGGF1 also interacts with p53 through the FHA domain. Somatic AGGF1 variants in the FHA domain in human tumors, including p.Q467H, p.Y469 N, and p.N483T, inhibit AGGF1 activity on tumor suppression. These results identify a key role for AGGF1 in an AGGF1-MDM2-p53 signaling axis with important functions in tumor suppression, and uncover a novel trans-tumor-suppression mechanism dependent on p53. This study has potential implications in diagnosis and therapies of cancer.