Alternative Splicing Factor Heterogeneous Nuclear Ribonucleoprotein U as a Promising Biomarker for Gastric Cancer Risk and Prognosis with Tumor-Promoting Properties.

Gastric cancer (GC) is a major global health concern with poor outcomes. Heterogeneous nuclear ribonucleoprotein U (HNRNPU) is a multifunctional protein that participates in pre-mRNA packaging, alternative splicing regulation, and chromatin remodeling. Its potential role in GC remains unclear. In this study, the expression characteristics of HNRNPU were analyzed by The Cancer Genome Atlas data, Gene Expression Omnibus data, and then further identified by real-time quantitative PCR and immunohistochemistry using tissue specimens. From superficial gastritis, atrophic gastritis, and hyperplasia to GC, the in situ expression of HNRNPU protein gradually increased, and the areas under the curve for diagnosis of GC and its precancerous lesions were 0.911 and 0.847, respectively. A nomogram integrating HNRNPU expression, lymph node metastasis, and other prognostic indicators exhibited an area under the curve of 0.785 for predicting survival risk. Knockdown of HNRNPU significantly inhibited GC cell proliferation, migration, and invasion and promoted apoptosis in vitro. In addition, RNA-sequencing analysis showed that HNRNPU could affect alternative splicing events in GC cells, with functional enrichment analysis revealing that HNRNPU may exert malignant biological function in GC progression through alternative splicing regulation. In summary, the increased expression of HNRNPU was significantly associated with the development of GC, with a good performance in diagnosing and predicting the prognostic risk of GC. Functionally, HNRNPU may play an oncogenic role in GC by regulating alternative splicing.

Association of mitochondrial homeostasis and dynamic balance with malignant biological behaviors of gastrointestinal cancer.

Mitochondria determine the physiological status of most eukaryotes. Mitochondrial dynamics plays an important role in maintaining mitochondrial homeostasis, and the disorder in mitochondrial dynamics could affect cellular energy metabolism leading to tumorigenesis. In recent years, disrupted mitochondrial dynamics has been found to influence the biological behaviors of gastrointestinal cancer with the potential to be a novel target for its individualized therapy. This review systematically introduced the role of mitochondrial dynamics in maintaining mitochondrial homeostasis, and further elaborated the effects of disrupted mitochondrial dynamics on the cellular biological behaviors of gastrointestinal cancer as well as its association with cancer progression. We aim to provide clues for elucidating the etiology and pathogenesis of gastrointestinal cancer from the perspective of mitochondrial homeostasis and disorder.

Value of conventional ultrasound and shear wave elastography in the assessment of muscle mass and function in elderly people with type 2 diabetes.

OBJECTIVES: We assessed muscle mass and function using ultrasound (US) and shear wave elastography (SWE) for sarcopenia in elderly patients with type 2 diabetes. METHODS: There were 84 patients with type 2 diabetes enrolled in this study; of these, 30 had sarcopenia and 54 did not. We measured appendicular skeletal muscle mass index (ASMI), handgrip strength, calf circumference, 6-m walking speed, and 5-time chair stand test. All patients were in the supine position with their knees in straight and bent poses in turn. The US-derived thickness (Tstraight, Tbent), cross-sectional area (CSAstraight, CSAbent), and SWE (SWEstraight, SWEbent) of the rectus femoris muscle (RFM) were measured and the differences (ΔT, ΔCSA, ΔSWE) were calculated. We assessed the correlations of clinical indicators with US and SWE features. We then compared the clinical indicators and US and SWE features between patients with and without sarcopenia to determine independent predictors. Diagnostic models were established based on these independent predictors. RESULTS: The ASMI was correlated with Tbent (r = 0.57, p < 0.001) and CSAbent (r = 0.50, p < 0.001). Handgrip strength was correlated with Tbent (r = 0.53, p < 0.001) and CSAbent (r = 0.51, p < 0.001). Between patients with and without sarcopenia, the indicators of age, ΔCSA, and ΔSWE were statically different (all p ≤ 0.001). Based on these results, a diagnostic model for sarcopenia was established with 83.3% sensitivity, 83.3% specificity, and 83.3% accuracy. CONCLUSIONS: In elderly people with type 2 diabetes, sarcopenia patients had smaller muscle CSA and less stiffness than non-sarcopenia patients. US and SWE might be useful to screen them. KEY POINTS: • Sarcopenia is common in elderly people with type 2 diabetes. • Ultrasound and shear wave elastography might be useful methods for quantitatively assessing muscle mass and strength. • Ultrasound and shear wave elastography might be useful methods for screening sarcopenia in elderly patients with type 2 diabetes.

The role of ultrasound in screening subclinical psoriatic arthritis in patients with moderate to severe psoriasis.

OBJECTIVE: To identify patients in the subclinical psoriatic arthritis (Sub-PsA) phase by ultrasound (US) and provide a solution to screen them. METHODS: A total of 490 participants with moderate-to-severe psoriasis were evaluated. Among them, 384 participants without arthritis symptoms were enrolled into the silent psoriasis group and 106 participants with arthritis symptoms, called prodromal/active PsA phase, were enrolled into the clinical PsA group. Another 80 non-psoriasis participants were enrolled into the control group. Each participant received clinical assessments and US examinations of 60 joints, 38 tendons, and 40 entheses. We compared the incidences of synovio-enthesitis, synovitis, tenosynovitis, erosion, and dactylitis detected on US among the three groups. Subsequently, on the basis of significant US findings, we distinguished Sub-PsA from psoriasis alone (PsO) in the silent psoriasis group and analyzed the clinical characteristics, mainly including basic clinical characteristics, body surface area (BSA), and Psoriasis Area and Severity Index (PASI) score. RESULTS: Only synovio-enthesitis significantly differed between the control group and the silent psoriasis group (1.3% vs. 16.1%, p < 0.001). The knee was the most commonly involved site of synovio-enthesitis (79.0%). Taking synovio-enthesitis as the standard, 16.1% of silent psoriasis participants and 12.7% of all psoriasis participants were in the Sub-PsA phase. Furthermore, there were no differences in BSA and PASI among the three phases of PsO, Sub-PsA, and prodromal/active PsA. CONCLUSIONS: Since the psoriasis patients in Sub-PsA phase was as high as 12.7% in all patients with moderate-to-severe psoriasis, US-detected synovio-enthesitis was recommended routinely for screening them regardless of arthritis symptoms, especially in the lower limbs. KEY POINTS: • Synovio-enthesitis on ultrasound was significantly associated with subclinical psoriatic arthritis, especially in the lower limbs. • Routine ultrasound evaluation could help screen psoriasis patients in the subclinical psoriatic arthritis phase, which was as high as 12.7% in all psoriasis patients.

Risk stratification of gallbladder masses by machine learning-based ultrasound radiomics models: a prospective and multi-institutional study.

OBJECTIVE: This study aimed to evaluate the diagnostic performance of machine learning (ML)-based ultrasound (US) radiomics models for risk stratification of gallbladder (GB) masses. METHODS: We prospectively examined 640 pathologically confirmed GB masses obtained from 640 patients between August 2019 and October 2022 at four institutions. Radiomics features were extracted from grayscale US images and germane features were selected. Subsequently, 11 ML algorithms were separately used with the selected features to construct optimum US radiomics models for risk stratification of the GB masses. Furthermore, we compared the diagnostic performance of these models with the conventional US and contrast-enhanced US (CEUS) models. RESULTS: The optimal XGBoost-based US radiomics model for discriminating neoplastic from non-neoplastic GB lesions showed higher diagnostic performance in terms of areas under the curves (AUCs) than the conventional US model (0.822-0.853 vs. 0.642-0.706, p < 0.05) and potentially decreased unnecessary cholecystectomy rate in a speculative comparison with performing cholecystectomy for lesions sized over 10 mm (2.7-13.8% vs. 53.6-64.9%, p < 0.05) in the validation and test sets. The AUCs of the XGBoost-based US radiomics model for discriminating carcinomas from benign GB lesions were higher than the conventional US model (0.904-0.979 vs. 0.706-0.766, p < 0.05). The XGBoost-US radiomics model performed better than the CEUS model in discriminating GB carcinomas (AUC: 0.995 vs. 0.902, p = 0.011). CONCLUSIONS: The proposed ML-based US radiomics models possess the potential capacity for risk stratification of GB masses and may reduce the unnecessary cholecystectomy rate and use of CEUS. CLINICAL RELEVANCE STATEMENT: The machine learning-based ultrasound radiomics models have potential for risk stratification of gallbladder masses and may potentially reduce unnecessary cholecystectomies. KEY POINTS: • The XGBoost-based US radiomics models are useful for the risk stratification of GB masses. • The XGBoost-based US radiomics model is superior to the conventional US model for discriminating neoplastic from non-neoplastic GB lesions and may potentially decrease unnecessary cholecystectomy rate for lesions sized over 10 mm in comparison with the current consensus guideline. • The XGBoost-based US radiomics model could overmatch CEUS model in discriminating GB carcinomas from benign GB lesions.

Design, synthesis, and anticancer evaluation of arylurea derivatives as potent and selective type II irreversible covalent FGFR4 inhibitors.

Aberrant FGF19/FGFR4 signaling has been demonstrated to be an oncogenic driver of growth and survival in human hepatocellular carcinoma (HCC). At present, the development of FGFR4-specific drugs has become a hotspot in tumor-targeted therapy research. However, no selective FGFR4 inhibitors have been approved by FDA so far. Currently, most of the reported FGFR4 inhibitors that use a covalent targeting strategy to be selective are typical type I inhibitors with a single type. Here, based on Ponatinib, we designed and synthesized a series of arylurea derivatives as novel type II irreversible covalent inhibitors of FGFR4. Among them, the representative compound 6v exhibited an IC50 value of 74 nM against FGFR4 and antiproliferative potency of 0.25 µM and 0.22 µM against Huh7 and Hep3B cell lines. Western blotting results showed that compound 6v significantly inhibited the phosphorylation of FGFR4 and its downstream signaling factors AKT and ERK in a dose-dependent manner in Hep3B cell. These results showed that this series of compounds, as type II irreversible FGFR4 inhibitors, are worthy of further research and structural optimization.

Ultrasound-guided percutaneous microwave ablation for adenomyosis with abnormal uterine bleeding: clinical outcome and associated factors.

OBJECTIVE: To investigate the factors affecting the efficacy of ultrasound (US)-guided percutaneous microwave ablation (PMWA) for adenomyosis with abnormal uterine bleeding (AUB-A). METHODS: Baseline data of patients with AUB-A who underwent US-guided PMWA treatment between October 2020 and October 2021, including demography characteristics, laboratory and imaging examination results were retrospectively analyzed. 3D reconstruction of magnetic resonance imaging (MRI) was applied to quantitatively assess the local treatment responses, including ratio of non-perfusion volume to adenomyosis volume (NPVr), ablation rate of the endometrial-myometrial junction (EMJ), and surface area (SA) of the ablated part of the EMJ. Patients were followed up at 3, 6, and 12 months after treatment, and divided into two groups: group with complete relief (CR), and group with partial relief (PR) or no relief (NR). Data were compared between them. RESULTS: Thirty-one patients were analyzed with a mean age of 38.7 ± 6.8 years (range: 24-48): 48.4% (15/31), 63.3% (19/30), and 65.5% (19/29) achieved CR at 3, 6, and 12 months, respectively. In univariate analysis, compared with the PR/NR group, serum CA125 levels were significantly lower in CR group at 3 months, while ablation rates of EMJ and SA of the ablated part of the EMJ were significantly higher at the three time points. Other baseline characteristics and NPVr did not differ between the two groups. CONCLUSION: Baseline CA125 and ablation rate of the EMJ and SA of the ablated part of the EMJ are associated with the outcome of AUB-A patients after US-guided PMWA treatment.

Alteromonas Aquimaris sp. nov., Isolated from Surface Seawater.

A Gram-negative, aerobic, motile by flagellum, and rod-shaped bacterium, designated ASW11-7T, was isolated from coastal surface seawater sample collected from the Yellow Sea, PR China. Strain ASW11-7T grew optimally at 37℃, 4.0% (w/v) NaCl and pH 7.0. Phylogenetic analysis based on the 16S rRNA gene sequences revealed that strain ASW11-7T belongs to the genus Alteromonas and most closely related to Alteromonas ponticola MYP5T (99.6% similarity), followed by Alteromonas confluentis DSSK2-12T (98.2%), Alteromonas lipolytica JW12T (98.2%), and Alteromonas hispanica F-32T (98.0%). The draft genome of strain ASW11-7T had a length of 3,530,922 bp with a G + C content of 44.9%, predicting 3108 coding sequences, 5 rRNA, 4 ncRNAs, 49 tRNAs genes, and 18 pseudogenes. The average nucleotide identity and digital DNA-DNA hybridization values between genomic sequences of strain ASW11-7T and closely related species of Alteromonas were in ranges of 66.9-77.8% and 18.3-27.5%, respectively. The major fatty acids of strain ASW11-7T were C16:0, summed feature 3 (C16:1ω7c/C16:1ω6c), and summed feature 8 (C18:1ω7c/C18:1ω6c). The predominant respiratory quinone was Q-8 and the major polar lipids were phosphatidylethanolamine and phosphatidylglycerol. Based on the phenotypic properties, genotypic distinctiveness, and chemotaxonomic features, strain ASW11-7T is considered to represent a novel Alteromonas species, for which the name Alteromonas aquimaris sp. nov. is proposed. The type strain is ASW11-7T (= KCTC 92853T = MCCC 1K07240T).

The Value of Ultrasound for Differentiating Trichilemmal Cysts From Epidermoid Cysts.

OBJECTIVES: This study was aimed to evaluate the diagnostic performance of ultrasound (US) in differentiating trichilemmal cysts (TCs) from epidermoid cysts (ECs). METHODS: Based on clinical and ultrasound features, a prediction model was established and validated. 164 cysts in the pilot cohort and another 69 in the validation cohort diagnosed with TCs or ECs histopathologically were evaluated. The same radiologist performed all ultrasound examinations. RESULTS: For clinic features, TCs tended to occur in females compared with ECs (66.7 vs 28.5%; P < .001). In addition, TCs were prone to occur in the hairy area compared with ECs (77.8 vs 13.1%; P < .001). For ultrasound features, the internal hyperechogenicity and cystic change were more likely to appear in TCs in comparison with ECs (92.6 vs 25.5%; P < .001; 70.4 vs 23.4%; P < .001, respectively). Upon the features mentioned above, a prediction model was established with the areas under the receiver operating characteristic curves of 0.936 and 0.864 in the pilot and validation cohorts, respectively. CONCLUSIONS: US is promising for differentiating TCs from ECs and is valuable for their clinical management.

Gramella sediminis sp. nov., isolated from a tidal flat of the Yellow Sea.

A novel species of the genus Gramella, designated ASW11-100T, was isolated from a tidal flat sediment in the Yellow Sea, PR China. Phylogenetic analysis based on 16S rRNA gene sequences and single-copy orthologous clusters revealed that strain ASW11-100T belonged to the genus Gramella, and exhibited 16S rRNA gene sequence similarities of 98.9, 98.8 and 98.7 % to Gramella sabulilitoris HSMS-1T, Gramella sediminilitoris GHTF-27T and Gramella forsetii KT0803T, respectively. The genome of strain ASW11-100T harbours 2950 protein-coding genes and 105 carbohydrate-active enzymes including 38 glycoside hydrolases. Seventeen of the glycoside hydrolases are organized in five distinct polysaccharide utilization loci, which are predicted to involve in the degradation of starch, glucans, arabinoxylans, arabinomannan, arabinans and arabinogalactans. The genomic DNA G+C content was 37.3 mol%. The digital DNA-DNA hybridization and average nucleotide identity values between strain ASW11-100T and its closely related relatives were in ranges of 19.8-23.9% and 76.6-80.9 %, respectively. Cells of the isolate were Gram-negative, aerobic, non-flagellated and short rod-shaped. Carotenoid pigments were produced, but flexirubin-type pigments were absent. The major fatty acids (>10 %) were iso-C15 : 0, iso-C17 : 0 3-OH and summed feature 3 (C16 : 1 ω6c and/or C16 : 1 ω7c). The sole respiratory quinone was menaquinone-6 and the major polar lipid was phosphatidylethanolamine. Based on the above polyphasic evidence, strain ASW11-100T should be considered to represent a novel Gramella species, for which the name Gramella sediminis sp. nov. is proposed. The type strain is ASW11-100T (=KCTC 82502T=MCCC 1K05580T).

Design, synthesis, and anticancer evaluation of ammosamide B with pyrroloquinoline derivatives as novel BRD4 inhibitors.

Bromodomain-containing protein 4 (BRD4), which is a member of the bromodomain and extra-terminal domain (BET) family, plays an important role in the regulation of gene expression as the "reader" of epigenetic regulation. BRD4 has become a promising target to treat cancer, because the up-regulation of BRD4 expression is closely associated with the occurrence and development of various cancers. At present, several BRD4 inhibitors are in clinical trials for cancer therapy, but no BRD4 inhibitors are on the market. Here, we designed and synthesized a series of compounds bearing pyrrolo[4,3,2-de]quinolin-2(1H)-one scaffold through structural modification of natural products ammosamide B, which is a natural pyrroloquinoline derivative reported for its potential antitumor activity. All target compounds were evaluated for their BRD4 BD1 inhibition activities via the protein thermal shift assays or AlphaSceen assay. The representative compound 49 showed potent activity (IC50 = 120 nM). The co-crystal of compound 49 with BRD4 BD1 was solved to study the structure activity relationship, which showed that 49 could combine with the acetyl lysine binding site and formed a hydrogen bond with the conserved residue Asn140. The results demonstrate that compound 49 is worthy of further investigation as a promising BRD4 inhibitor.

Comparison of efficacy, safety, and patient satisfaction between thermal ablation, conventional/open thyroidectomy, and endoscopic thyroidectomy for symptomatic benign thyroid nodules.

PURPOSE: Thermal ablation (TA) is a minimally invasive treatment method for symptomatic benign thyroid nodules (BTNs). This study aimed to evaluate the value of TA by comparing the efficacy, safety, and patient satisfaction with conventional/open thyroidectomy (ConT) and endoscopic thyroidectomy (ET) for symptomatic BTNs. METHODS: Patients with symptomatic BTNs who underwent ConT, ET, or TA therapy between January 2018 and January 2020 were included. Pre-operation data of the two comparisons (TA vs. ConT and TA vs. ET) was balanced using propensity score matching. The technique efficacy (volume reduction ratio ≥50%), nodule disappearance, and regrowth rate were calculated after ablation. The operation and hospitalization time, medical cost, complications, post-operative symptoms, and cosmetic scores were recorded and compared. Patient satisfaction was evaluated using a telephone survey. RESULTS: After a median 19-month follow-up (range, 12-36 months), the technique efficacy rate, nodule disappearance, and regrowth rate were 93.2% (119/129), 6.8% (10/129), and 0.8% (1/129), respectively. Operation time, hospitalization time, and medical costs were less for patients in the TA group than for patients in the ConT and ET groups (all p < 0.001). The incidence of complications, post-operative symptoms, cosmetic scores, and overall satisfaction were not significantly different among groups (all p > 0.05). Post-operative hypothyroidism was less frequent in the TA group than in the ConT and ET groups (all p < 0.05). CONCLUSIONS: Compared to ConT and ET, TA has comparable efficacy, safety, and patient satisfaction and exhibits greater protection of thyroid function for the treatment of symptomatic BTNs.

Salinimicrobium sediminilitoris sp. nov., Isolated from a Tidal Flat.

A Gram-negative, facultatively anaerobic, motile, and rod-shaped bacterium, designated ASW11-47 T, was isolated from a tidal flat sediment taken from the coast of Qingdao, PR China. Phylogenetic analysis of 16S rRNA gene sequence showed that strain ASW11-47 T belongs to the genus Salinimicrobium and is most closely related to Salinimicrobium terrae YIM-C338T (98.68% similarity). The length of draft genome is 3,594,457 bp, and DNA G + C content is 40.8 mol%. The values of average nucleotide identity and digital DNA-DNA hybridization between strain ASW11-47 T and closely related strains were in ranges of 75.9-85.9 and 19.7-31.5%, respectively. The major fatty acids (> 10%) were iso-C15:0 and iso-C17:0 3-OH. The predominant respiratory quinone was menaquinone-6 and the major polar lipid was phosphatidylethanolamine. On the basis of genotypic, phenotypic, and chemotaxonomic analysis, strain ASW11-47 T represents a novel species within the genus Salinimicrobium, for which the name Salinimicrobium sediminilitoris sp. nov. is proposed. The type strain is ASW11-47 T (= KCTC 82501 T = MCCC 1K05586T).

Performance of common genetic variants in risk prediction for colorectal cancer in Chinese: A two-stage and multicenter study.

The efficacy of susceptible variants derived from genome-wide association studies (GWAs) optimizing discriminatory accuracy of colorectal cancer (CRC) in Chinese remains unclear. In the present validation study, we assessed 75 recently identified variants from GWAs. A risk predictive model combining 19 variants using the least absolute shrinkage and selection operator (LASSO) statistics offered certain clinical advantages. This model demonstrated an area under the receiver operating characteristic (AUC) of 0.61 during training analysis and yielded robust AUCs from 0.59 to 0.61 during validation analysis in three independent centers. The individuals carrying the highest quartile of risk score revealed over 2-fold risks of CRC (ranging from 2.12 to 2.90) compared with those who presented the lowest quartile of risk score. This genetic model offered the possibility of partitioning risk within the average risk population, which might serve as a first step toward developing individualized CRC prevention strategies in China.

Contrast-enhanced ultrasound in the assessment of Crohn's disease activity: comparison with computed tomography enterography.

BACKGROUND AND OBJECTIVE: Continuous assessment of disease activity remains a huge challenge during the follow-ups of patients with Crohn's disease (CD). In this paper, we aimed to evaluate the performance of contrast-enhanced ultrasound (CEUS) by comparing with computed tomography enterography (CTE) in the assessment of disease activity in CD. MATERIALS AND METHODS: Fifty-two patients diagnosed with CD were included in this study, using the CEUS and CTE as imaging methods for comparison. The selected parameters included the location and thickness of the thickest part of the intestinal wall, mesenteric fat proliferation, mesenteric vessels change, enhancement pattern and the presence of complications. Patients were clinically assessed using the Crohn's disease activity index (CDAI), C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). Simple endoscopic score for Crohn's disease (SES-CD) was regarded as the reference standard. RESULTS: The location of the thickest part of the intestinal wall (κ = 0.653), bowel wall thickness (ICC = 0.795), mesenteric vessels change (κ = 0.692) and complications (κ = 0.796) displayed substantial agreement (0.61-0.80) between CEUS and CTE, while the detection of mesenteric fat proliferation (κ = 0.395) and enhancement pattern (κ = 0.288) showed fair consistency (0.21-0.40) for comparison. In CEUS, bowel wall thickness, mesenteric fat proliferation, enhancement pattern and mesenteric vessels change were statistically significant in assessing CD activity, while bowel wall thickness, mesenteric fat proliferation and mesenteric vessels change in CTE. Bowel wall thickness showed the best diagnostic performance in the assessment of CD activity at CEUS and CTE. CONCLUSION: CEUS provides a radiation-free and effective way to assess the CD activity in comparison with CTE, which also avoids frequent colonoscopy examinations, improves tolerance of patients, and reduces the cost of medical care, thereby serving as a useful tool for CD follow-up.

Design, synthesis and anticancer evaluation of 3-methyl-1H-indazole derivatives as novel selective bromodomain-containing protein 4 inhibitors.

Bromodomain-containing Protein 4 (BRD4), an 'epigenetic reader', regulates chromatin structure and gene expression via recognizing and binding acetylated lysine in histones. BRD4 has become a therapeutic target for cancers because it promotes the expression of the tumor genes, such as c-Myc, NF-κB, and Bcl-2. In this study, a new series of 3-methyl-1H-indazole derivatives were designed via virtual screening and structure-based optimization. All compounds were synthesized and evaluated for their inhibitory activities to BRD4-BD1 and their antiproliferative effects in cancer cell lines. Among them, several compounds (such as 9d, 9u and 9w) exhibited strong BRD4-BD1 affinities and inhibition activities, and potently suppressed MV4;11 cancer cell line proliferation. Among them, compound 9d showed excellent selectivity for BRD4 and effectively suppressed c-Myc, the downstream protein of BRD4. This study provided new lead compounds for further biological evaluation on BRD4.

Discovery of 4-amino-1H-pyrazolo[3,4-d]pyrimidin derivatives as novel discoidin domain receptor 1 (DDR1) inhibitors.

DDR1 is a receptor tyrosine kinase that is activated by triple-helical collagens and has become an attractive target for anticancer therapy given its involvement in tumor growth, metastasis development, and tumor dormancy. Several drugs on the market, such as dasatinib and nilotinib, were reported to potently suppress the function of DDR1 and show significant therapeutic benefits in a variety of preclinical tumor models. Whereas only a few selective DDR1 inhibitors were disclosed in recent years. A series of 4-amino-1H-pyrazolo[3,4-d]pyrimidin derivatives were designed and synthesized. All compounds were evaluated via DDR1 kinase inhibition assay and cell anti-proliferative assay. One of the representative compounds, 6c, suppressed DDR1 kinase activity with an IC50 value of 44 nM and potently inhibited cell proliferation in DDR1-overexpressing cell lines HCT-116 and MDA-MB-231 with IC50 value of 4.00 and 3.36 µM respectively. Further molecular docking study revealed that 6c fitted ideally into DDR1 binding pocket and maintained the crucial hydrogen bonds with DDR1 kinase domain. Overall, these results suggest that the compound 6c is a potential DDR1 inhibitor deserving further investigation for cancer treatment.

Transcriptome analysis reveals differing response and tolerance mechanism of EPSPS and GAT genes among transgenic soybeans.

BACKGROUND: Glyphosate is a broad-spectrum, non-selective systemic herbicide. Introduction of glyphosate tolerance genes such as EPSPS or detoxification genes such as GAT can confer glyphosate tolerance on plants. Our previous study revealed that co-expression of EPSPS and GAT genes conferred higher glyphosate tolerance without "yellow flashing". However, the plant response to glyphosate at the transcriptional level was not investigated. METHODS AND RESULTS: To investigate the glyphosate tolerance mechanism, RNA-seq was conducted using four soybean genotypes, including two non-transgenic (NT) soybeans, ZH10 and MD12, and two GM soybeans, HJ698 and ZH10-6. Differentially expressed genes (DEGs) were identified in these soybeans before and after glyphosate treatment. Similar response to glyphosate in the two NT soybeans and the different effects of glyphosate on the two GM soybeans were identified. As treatment time was prolonged, the expression level of some DEGs involved in shikimate biosynthetic pathway and herbicide targeted cross-pathways was increased or declined continuously in NT soybeans, and altered slightly in HJ698. However, the expression level of some DEGs was altered in ZH10-6 at 12 hpt, while similar expression level of some DEGs involved in shikimate biosynthetic pathway and herbicide targeted cross-pathways was observed in ZH10-6 at 0 hpt and 72 hpt. These observations likely explain the higher glyphosate tolerance in ZH10-6 than in HJ698 and NT soybeans. CONCLUSIONS: These results suggested that GAT and EPSPS genes together play a crucial role in response to glyphosate, the GAT gene may work at the early stage of glyphosate exposure, whereas the EPSPS gene may be activated after the uptake of glyphosate by plants. These findings will provide valuable insight for the molecular basis underlying glyphosate tolerance or glyphosate detoxication.

Expression profiles and prognostic roles of m6A writers, erasers and readers in gastric cancer.

Aim: To explore the expression profiles of N6-methyladenosine (m6A) enzymes (writers, erasers and readers) and their associations with gastric cancer (GC) prognosis. Methods: Gene expression was analyzed using the UALCAN and Oncomine web resources. The prognostic roles of these genes in GC were analyzed using data from The Cancer Genome Atlas. Results: Thirteen m6A enzymes were found to be upregulated in GC tissues. The expression of m6A writers METTL3, RBM15 and WTAP was associated with pathological stage. The m6A eraser FTO was related to tumor stage and ALKBH5 expression was related to GC prognosis. The m6A reader YTHDF3 expression was associated with tumor stage. YTHDC2 was associated with survival of GC patients. Conclusion: Abnormal changes of key genes involved in m6A RNA methylation may have an important impact on GC development and prognosis.

Lay abstract RNA N6-methyladenosine (m6A) methylation is modulated by a series of epigenetic modulator enzymes termed 'writers', 'erasers' and 'readers'. We aimed to explore the expression profiles of these m6A enzymes and their associations with gastric cancer (GC) development and prognosis. Gene expression was analyzed using the UALCAN and Oncomine web resources. Clinical data were downloaded from The Cancer Genome Atlas. Gene­gene networks and protein­protein interaction networks were built using the softwares STRING and GeneMANIA. Thirteen m6A enzymes were found to be upregulated in GC tissues. The expression of m6A writers METTL3, RBM15 and WTAP was associated with pathological stage. The m6A eraser FTO was related to tumor stage and ALKBH5 expression was related to GC prognosis. The m6A reader YTHDF3 expression was associated with tumor stage, and YTHDC2 was associated with survival of GC patients. In summary, these results suggest that abnormal changes of key genes involved in regulation and function of m6A RNA methylation may have an important impact on GC development and its clinical prognosis.

AQUEOUS HUMOR CYTOKINE LEVELS AND REBOUND MACULAR EDEMA AFTER CONBERCEPT TREATMENT IN PATIENTS WITH CENTRAL RETINAL VEIN OCCLUSION.

PURPOSE: This study aimed to investigate the effect of intravitreal conbercept (IVC) injections on the aqueous humor concentrations of angiogenic and inflammatory cytokines in patients with macular edema (ME) due to central retinal vein occlusion and to determine whether changes in cytokine levels after IVC are associated with the development of rebound ME. METHODS: Forty-nine patients with ME caused by central retinal vein occlusion were included in this retrospective study. Monthly doses of IVC were administered for three months, followed by a Pro Re Nata dosing regimen. Rebound ME was defined as ≥110% increase in the foveal thickness compared with the baseline. Whenever injections were administered, aqueous humor samples were obtained. Multiplex bead assay was used to measure seven angiogenic and inflammatory cytokines in aqueous humor samples. RESULTS: At baseline, patients with central retinal vein occlusion showed significantly higher aqueous humor concentrations of vascular endothelial growth factor, placental growth factor, monocyte chemoattractant protein-1, platelet-derived growth factor-AA, IL-6, IL-8, and IL-12. At 1-month and 2-month follow-up after IVC, significantly decreased concentrations of all cytokines were observed. During the 12-month follow-up period, 6 of the 49 eyes (12.2%) showed rebound ME after IVC. Patients with rebound ME showed significantly elevated levels of inflammatory but not angiogenic cytokines. CONCLUSION: Angiogenic and inflammatory cytokines were overexpressed in patients with ME caused by central retinal vein occlusion. Conbercept treatment influenced the concentrations of various inflammatory cytokines and reduced aqueous vascular endothelial growth factor and placental growth factor concentrations. Rebound ME may occur due to disruption of the balance between angiogenic and inflammatory cytokines and an accompanying excess of inflammatory cytokines but not angiogenic cytokines, after antivascular endothelial growth factor therapy.