FOXA2 activates HIF2α expression to promote tumor progression and is regulated by the E3 ubiquitin ligase VHL in renal cell carcinoma.

Renal cell carcinoma (RCC) is a frequent malignancy of the urinary system with high mortality and morbidity. However, the molecular mechanisms underlying RCC progression are still largely unknown. In this study, we identified FOXA2, a pioneer transcription factor, as a driver oncogene for RCC. We show that FOXA2 was commonly upregulated in human RCC samples and promoted RCC proliferation, as evidenced by assays of cell viability, colony formation, migratory and invasive capabilities, and stemness properties. Mechanistically, we found that FOXA2 promoted RCC cell proliferation by transcriptionally activating HIF2α expression in vitro and in vivo. Furthermore, we found that FOXA2 could interact with VHL (von Hippel‒Lindau), which ubiquitinated FOXA2 and controlled its protein stability in RCC cells. We showed that mutation of lysine at position 264 to arginine in FOXA2 could mostly abrogate its ubiquitination, augment its activation effect on HIF2α expression, and promote RCC proliferation in vitro and RCC progression in vivo. Importantly, elevated expression of FOXA2 in patients with RCC positively correlated with the expression of HIF2α and was associated with shorter overall and disease-free survival. Together, these findings reveal a novel role of FOXA2 in RCC development and provide insights into the underlying molecular mechanisms of FOXA2-driven pathological processes in RCC.

Aperture division multispectral camera for the Earth's reflected solar radiation observation based on the Lagrange L1 point of the Earth-Moon system.

We propose an aperture division multispectral camera for Earth observation (EAMC) based on the Lagrange L1 point of the Earth-Moon system to measure the Earth's reflected solar radiation (RSR), quantify the effective radiative forcing (ERF) and establish the pixel-scale multispectral angular distribution model (ADM) of the Earth's radiance. The EAMC adopts the snapshot technique to provide multispectral images in the 360-920 nm wavelength, employing nine subsystems sharing a primary system. The camera can capture the entire Earth's two-dimensional morphology and spectral fingerprints at a 10 km spatial resolution, with all spectral images acquired concurrently on a single detector. The camera's optical system is designed and simulated, and the stray light is analyzed and suppressed. Simulation and analysis results show that the camera can obtain high-quality images of the Earth's disk with a 2.5° field of view (FOV). The stray light is suppressed to less than 0.05% of the observed multispectral Earth radiation. The novel EAMC provides a new way to generate climate-relevant knowledge from the perspective of global Earth observation and has great potential for other applications in space-based remote sensing spectral imaging.

The SMARCA4R1157W mutation facilitates chromatin remodeling and confers PRMT1/SMARCA4 inhibitors sensitivity in colorectal cancer.

Genomic studies have demonstrated a high frequency of genetic alterations in components of the SWI/SNF complex including the core subunit SMARCA4. However, the mechanisms of tumorigenesis driven by SMARCA4 mutations, particularly in colorectal cancer (CRC), remain largely unknown. In this study, we identified a specific, hotspot mutation in SMARCA4 (c. 3721C>T) which results in a conversion from arginine to tryptophan at residue 1157 (R1157W) in human CRC tissues associated with higher-grade tumors and controls CRC progression. Mechanistically, we found that the SMARCA4R1157W mutation facilitated its recruitment to PRMT1-mediated H4R3me2a (asymmetric dimethylation of Arg 3 in histone H4) and enhanced the ATPase activity of SWI/SNF complex to remodel chromatin in CRC cells. We further showed that the SMARCA4R1157W mutant reinforced the transcriptional expression of EGFR and TNS4 to promote the proliferation of CRC cells and patient-derived tumor organoids. Importantly, we demonstrated that SMARCA4R1157W CRC cells and mutant cell-derived xenografts were more sensitive to the combined inhibition of PRMT1 and SMARCA4 which act synergistically to suppress cell proliferation. Together, our findings show that SMARCA4-R1157W is a critical activating mutation, which accelerates CRC progression through facilitating chromatin recruitment and remodeling. Our results suggest a potential precision therapeutic strategy for the treatment of CRC patients carrying the SMARCA4R1157W mutation.

A novel scoring system to predict the residual back pain after percutaneous kyphoplasty for osteoporotic vertebral compression fracture.

Objective: To establish a scoring system to predict the residual back pain after percutaneous kyphoplasty (PKP) for osteoporotic vertebral compression fracture (OVCF). Materials and methods: We retrospectively reviewed the clinical records of 98 patients who were diagnosed of single-vertebral OVCF and underwent PKP surgery in our department from January 2015 to December 2017. The following clinical characteristics including age, gender, disease course, fracture location, fracture type, segmental kyphosis, and bone cement volume were all recorded, and the effects of these factors on postoperative pain (at 1-month and 6-month postoperative) were also analyzed respectively. Based on 6-month postoperative VAS score, the included patients were divided into two groups, namely the residual back pain group (19 patients) and the non-residual back pain group (79 patients). The independent risk factors of residual back pain after PKP were screened and the scoring system was established by the multivariate logistic regression analysis. The performance of this scoring system was also prospectively validated using the clinical data of 45 patients with single-vertebral OVCF from January 2018 to December 2019. Results: The scoring system was consist of five clinical characteristics which were confirmed as significant predictors of residual back pain after PKP, namely, age ≥60 years (P = 0.021), fracture location = thoracic or lumbar (P = 0.002), fracture type = OF4 type (P = 0.018), segmental kyphosis ≥20° (P = 0.014), and bone cement volume <5 ml (P = 0.001). Patients in the residual back pain group showed a significant higher score than the non-residual back pain group (6.84 ± 1.71 vs. 2.66 ± 1.97, t = 8.499, P < 0.001), and the optimal cut-off value for the scoring system was 5 points. The sensitivity and specificity of the scoring system for predicting residual back pain after PKP were 84.21% and 87.34%, respectively, in derivation set and 78.57% and 83.87% in validation set. Conclusion: This novel scoring system showed satisfactory diagnostic efficacy in predicting residual back pain after PKP for single-vertebral OVCF. Patients with the score of 5-9 had a high risk of postoperative residual back pain, while the patients with score of 0-4 was low.

TCF3 is epigenetically silenced by EZH2 and DNMT3B and functions as a tumor suppressor in endometrial cancer.

Endometrial cancer (EC) is the most common gynecological malignancy worldwide. However, the molecular mechanisms underlying EC progression are still largely unknown, and chemotherapeutic options for EC patients are currently very limited. In this study, we found that histone methyltransferase EZH2 and DNA methyltransferase DNMT3B were upregulated in EC samples from patients, and promoted EC cell proliferation as evidenced by assays of cell viability, cell cycle, colony formation. Mechanistically, we found that EZH2 promoted EC cell proliferation by epigenetically repressing TCF3, a direct transcriptional activator of CCKN1A (p21WAF1/Cip1), in vitro and in vivo. In addition, we found that DNMT3B specifically methylated the TCF3 promoter, repressing TCF3 expression and accelerating EC cell proliferation independently of EZH2. Importantly, elevated expression of EZH2 or DNMT3B in EC patients inversely correlated with expression of TCF3 and p21, and was associated with shorter overall survival. We show that combined treatment with GSK126 and 5-Aza-2d treatment wit synergistically inhibited methyltransferase activity of EZH2 and DNMT3B, resulting in a profound block of EC cell proliferation as well as EC tumor progression in cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) mouse models. These findings reveal that TCF3 functions as a tumor suppressor epigenetically silenced by EZH2 and DNMT3B in EC, and support the notion that targeting the EZH2/DNMT3B/TCF3/p21 axis may be a novel and effective therapeutic strategy for treatment of EC.

PRMT1-mediated H4R3me2a recruits SMARCA4 to promote colorectal cancer progression by enhancing EGFR signaling.

BACKGROUND: Aberrant changes in epigenetic mechanisms such as histone modifications play an important role in cancer progression. PRMT1 which triggers asymmetric dimethylation of histone H4 on arginine 3 (H4R3me2a) is upregulated in human colorectal cancer (CRC) and is essential for cell proliferation. However, how this dysregulated modification might contribute to malignant transitions of CRC remains poorly understood. METHODS: In this study, we integrated biochemical assays including protein interaction studies and chromatin immunoprecipitation (ChIP), cellular analysis including cell viability, proliferation, colony formation, and migration assays, clinical sample analysis, microarray experiments, and ChIP-Seq data to investigate the potential genomic recognition pattern of H4R3me2s in CRC cells and its effect on CRC progression. RESULTS: We show that PRMT1 and SMARCA4, an ATPase subunit of the SWI/SNF chromatin remodeling complex, act cooperatively to promote colorectal cancer (CRC) progression. We find that SMARCA4 is a novel effector molecule of PRMT1-mediated H4R3me2a. Mechanistically, we show that H4R3me2a directly recruited SMARCA4 to promote the proliferative, colony-formative, and migratory abilities of CRC cells by enhancing EGFR signaling. We found that EGFR and TNS4 were major direct downstream transcriptional targets of PRMT1 and SMARCA4 in colon cells, and acted in a PRMT1 methyltransferase activity-dependent manner to promote CRC cell proliferation. In vivo, knockdown or inhibition of PRMT1 profoundly attenuated the growth of CRC cells in the C57BL/6 J-ApcMin/+ CRC mice model. Importantly, elevated expression of PRMT1 or SMARCA4 in CRC patients were positively correlated with expression of EGFR and TNS4, and CRC patients had shorter overall survival. These findings reveal a critical interplay between epigenetic and transcriptional control during CRC progression, suggesting that SMARCA4 is a novel key epigenetic modulator of CRC. Our findings thus highlight PRMT1/SMARCA4 inhibition as a potential therapeutic intervention strategy for CRC. CONCLUSION: PRMT1-mediated H4R3me2a recruits SMARCA4, which promotes colorectal cancer progression by enhancing EGFR signaling.

PRMT5-dependent transcriptional repression of c-Myc target genes promotes gastric cancer progression.

The proto-oncogene c-Myc regulates multiple biological processes mainly through selectively activating gene expression. However, the mechanisms underlying c-Myc-mediated gene repression in the context of cancer remain less clear. This study aimed to clarify the role of PRMT5 in the transcriptional repression of c-Myc target genes in gastric cancer. Methods: Immunohistochemistry was used to evaluate the expression of PRMT5, c-Myc and target genes in gastric cancer patients. PRMT5 and c-Myc interaction was assessed by immunofluorescence, co-immunoprecipitation and GST pull-down assays. Bioinformatics analysis, immunoblotting, real-time PCR, chromatin immunoprecipitation, and rescue experiments were used to evaluate the mechanism. Results: We found that c-Myc directly interacts with protein arginine methyltransferase 5 (PRMT5) to transcriptionally repress the expression of a cohort of genes, including PTEN, CDKN2C (p18INK4C), CDKN1A (p21CIP1/WAF1), CDKN1C (p57KIP2) and p63, to promote gastric cancer cell growth. Specifically, we found that PRMT5 was required to promote gastric cancer cell growth in vitro and in vivo, and for transcriptional repression of this cohort of genes, which was dependent on its methyltransferase activity. Consistently, the promoters of this gene cohort were enriched for both PRMT5-mediated symmetric di-methylation of histone H4 on Arg 3 (H4R3me2s) and c-Myc, and c-Myc depletion also upregulated their expression. H4R3me2s also colocalized with the c-Myc-binding E-box motif (CANNTG) on these genes. We show that PRMT5 directly binds to c-Myc, and this binding is required for transcriptional repression of the target genes. Both c-Myc and PRMT5 expression levels were upregulated in primary human gastric cancer tissues, and their expression levels inversely correlated with clinical outcomes. Conclusions: Taken together, our study reveals a novel mechanism by which PRMT5-dependent transcriptional repression of c-Myc target genes is required for gastric cancer progression, and provides a potential new strategy for therapeutic targeting of gastric cancer.

AURKB promotes gastric cancer progression via activation of CCND1 expression.

Aurora kinase B (AURKB) triggers the phosphorylation of serine 10 on histone H3 (H3S10ph), which is important for chromosome condensation and cytokinesis during mitosis in mammals. However, how exactly AURKB controls cell cycle and contributes to tumorigenesis as an oncoprotein under pathological conditions remains largely unknown. Here, we report that AURKB promotes gastric cancer cell proliferation in vitro and in vivo. Silencing AURKB expression inhibits gastric cell proliferation and arrests the cell cycle in G2/M phase. We demonstrate that cyclin D1 (CCND1) is a direct downstream target of AURKB that plays a key role in gastric cancer cell proliferation. AURKB is able to activate the expression of CCND1 through mediating H3S10ph in the promoter of the CCND1 gene. Furthermore, we show that AZD1152, a specific inhibitor of AURKB, can suppress the expression of CCND1 in the gastric cancer cells and inhibit cell proliferation in vitro and in vivo. Importantly, we found that high AURKB and CCND1 expression levels are correlated with shorter overall survival of gastric cancer patients. This study demonstrates that AURKB promotes gastric tumorigenesis potentially through epigenetically activating CCND1 expression, suggesting AURKB as a promising therapeutic target in gastric cancer.

Management and outcomes of spinal epidural hematoma during vertebroplasty: Case series.

RATIONALE: Spinal cord injury (SCI) is one of the common complications of spinal surgery. There is no definite treatment and time of decompression for spinal cord induced by epidural hematoma during vertebroplasty. PATIENT CONCERNS: A total of 6 patients with SCI during vertebroplasty were included in our research. All of them occurred sensory disturbance and motor dysfunction due to a lower or same level operative vertebral body lesion in vertebroplasty. DIAGNOSES: Neurological manifestations during vertebroplasty, postoperative magnetic resonance imaging and computed tomography. INTERVENTIONS: Once SCI occurred in vertebroplasty, four patients were underwent spinal cord decompression immediately, and two patients were done after 14 and 22 hours, respectively. OUTCOMES: Before decompression operation, one patient was Frankel A, three were Frankel B, and two were Frankel C. One day after evacuation of the SEH, three patients recovered to normal neurological function (Frankel E), one to Frankel C, and one to Frankel D, but the other one did not recover. At the last follow-up, five patients had recovered to Frankel E and one patient to Frankel D. LESSONS: According to our experience, when SCI occurs during vertebroplasty, neurological deficits are always secondary to acute SEH. Timely decompression, particularly transfer surgery, can shorten recovery time.

Analysis of Differentially Expressed Proteins in Mycobacterium avium-Infected Macrophages Comparing with Mycobacterium tuberculosis-Infected Macrophages.

Mycobacterium avium (MA) belongs to the intracellular parasitic bacteria. To better understand how MA survives within macrophages and the different pathogenic mechanisms of MA and Mycobacterium tuberculosis (MTB), tandem mass tag (TMT) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis have been used to determine the proteins which are differentially expressed in MA-infected and MTB-infected macrophages. 369 proteins were found to be differentially expressed in MA-infected cells but not in MTB-infected cells. By using certain bioinformatics methods, we found the 369 proteins were involved in molecular function, biological process, and cellular component including binding, catalytic activity, metabolic process, cellular process, and cell part. In addition, some identified proteins were involved in multiple signaling pathways. These results suggest that MA probably survive within macrophages by affecting the expression of some crucial proteins.

[BIOMECHANICAL STUDY ON KIDNEY-SHAPED NANO-HYDROXYAPATITE/POLYAMIDE 66 CAGE].

OBJECTIVE: To compare the biomechanical differences between the kidney-shaped nano-hydroxyapatite/polyamide 66 (n-HA/PA66) Cage and the bullet-shaped n-HA/PA66 Cage. METHODS: L2-L5 spinal specimens were selected from 10 adult male pigs. L2, L3 and L4, L5 served as a motor unit respectively, 20 motor units altogether. They were divided into 4 groups (n = 5): no treatment was given as control group (group A); nucleus pulposus resection was performed (group B); bullet-shaped Cage (group C), and kidney-shaped Cage (group D) were used in transforaminal lumbar interbody fusion (TLIF) through left intervertebral foramen and supplemented by posterior pedicle screw fixation. The intervertebral height (IH) and the position of Cages were observed on the X-ray films. The range of motion (ROM) was measured. RESULTS: There was no significant difference in the preoperative IH among 4 groups (F = 0.166, P = 0.917). No significant change was found in IH between at pre- and post-operation in group B (P > 0.05); it increased after operation in groups C and.D, but difference was not statistically significant (P > 0.05). There was no significant difference in the postoperative IH among groups B, C, and D (P > 0.05). The distance from Cage to the left margin was (3.06 ± 0.51) mm in group C (close to the left) and (5.68 ± 0.69) mm in group D (close to the middle), showing significant difference (t = 6.787, P = 0.000). The ROM in all directions were significantly lower in groups C and D than in groups A and B (P < 0.05), and in group A than in group B (P < 0.05). The right bending and compression ROM of group C were significantly higher than those of group D (P < 0.05), but no statistically significant difference was found in the other direction ROM (P > 0.05). CONCLUSION: The bullet-shaped and kidney-shaped Cages have similar results in restoring IH and maintaining the stability of the spine assisted by internal fixation. Kidney-shaped Cage is more stable than bullet-shaped Cage in the axial compression and the bending load opposite implant, it can be placed in the middle and back of the vertebral body more ideally.

Application of magnetic resonance imaging in cervical spondylotic myelopathy.

Cervical spondylotic myelopathy (CSM) is the most common cause of spinal cord dysfunction and is caused by static or dynamic repeated compression of the spinal cord resulting from degenerative arthritis of the cervical spine and some biological injuries to the cervical spine. The T2 signal change on conventional magnetic resonance imaging (MRI) is most commonly associated with neurological deficits. Diffusion tensor imaging and MR spectroscopy show altered microstructure and biochemistry that reflect patient-specific pathogenesis and can be used to predict neurological outcome and response to intervention. Functional MRI can help to assess the neurological functional recovery after decompression surgery for CSM.