Phenotypic, genomic, and transcriptomic heterogeneity in a pancreatic cancer cell line.

OBJECTIVES: To evaluate the suitability of the MIA PaCa-2 cell line for studying pancreatic cancer intratumor heterogeneity, we aim to further characterize the nature of MIA PaCa-2 cells' phenotypic, genomic, and transcriptomic heterogeneity. METHODS: MIA PaCa-2 single-cell clones were established through flow cytometry. For the phenotypic study, we quantified the cellular morphology, proliferation rate, migration potential, and drug sensitivity of the clones. The chromosome copy number and transcriptomic profiles were quantified using SNPa and RNA-seq, respectively. RESULTS: Four MIA PaCa-2 clones showed distinctive phenotypes, with differences in cellular morphology, proliferation rate, migration potential, and drug sensitivity. We also observed a degree of genomic variations between these clones in form of chromosome copy number alterations and single nucleotide variations, suggesting the genomic heterogeneity of the population, and the intrinsic genomic instability of MIA PaCa-2 cells. Lastly, transcriptomic analysis of the clones also revealed gene expression profile differences between the clones, including the uniquely regulated ITGAV, which dictates the morphology of MIA PaCa-2 clones. CONCLUSIONS: MIA PaCa-2 is comprised of cells with distinctive phenotypes, heterogeneous genomes, and differential transcriptomic profiles, suggesting its suitability as a model to study the underlying mechanisms behind pancreatic cancer heterogeneity.

Tumor­suppressive effects of Smad­ubiquitination regulator 2 in papillary thyroid carcinoma.

Smad-ubiquitination regulator 2 (SMURF2) functions as a homolog of E6AP carboxyl terminus-type E3 ubiquitin ligase to regulate cell cycle progression and tumor growth factor expression. SMURF2 has been revealed to function as a tumor suppressor in a number of cancers; however, its function in papillary thyroid carcinoma (PTC) remains largely unknown. Therefore, the aim of the present study was to investigate the function of SMURF2 in PTC. Reverse transcription-quantitative PCR and western blotting were used to detect cellular expression of SMURF2 in vitro. After increasing or inhibiting the expression of SMURF2, MTT was used to detect the effect on tumor cell proliferation and Transwell assays were used to detect the effect on tumor cell migration and invasion. Finally, ELISA was used to detect the effects on glucose and glutamine metabolism in tumor cells and the findings revealed that SMURF2 was downregulated in PTC tissues. Moreover, SMURF2 inhibited the proliferation, invasion and migration of PTC cells, and promoted their apoptosis. Finally, SMURF2 inhibited cell glycolysis and glutaminolysis and affected metabolism in the PTC cell line, TPC-1. Thus, the findings of the present study suggest that SMURF2 may be a potential target in the treatment of PTC.

RNF31 alleviates liver steatosis by promoting p53/BNIP3-related mitophagy in hepatocytes.

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) is one of the liver illnesses that may be affected by mitophagy, which is the selective removal of damaged mitochondria. RNF31, an E3 ubiquitin ligase, is carcinogenic in many malignancies. However, the influence of RNF31 on mitochondrial homeostasis and NAFLD development remains unknown. METHODS: Oleic-palmitic acid treated hepatocytes and high-fat diet (HFD)-fed mice were established to observe the effect of RNF31 on hepatocyte mitophagy and steatosis. Mitophagy processes were comprehensively assessed by mt-Keima fluorescence imaging, while global changes in hepatic gene expression were measured by RNA-seq. RESULTS: The present study discovered a reduction in RNF31 expression in lipotoxic hepatocytes with mitochondrial dysfunction. The observed decrease in RNF31 expression was associated with reduced mitochondrial membrane potential, disturbed mitophagy, and increased steatosis. Additionally, the findings indicated that RNF31 is a pivotal factor in the initiation of mitophagy and the facilitation of mitochondrial homeostasis, resulting in a decrease in steatosis in lipotoxic hepatocytes. Mechanistically, RNF31 enhanced p53 ubiquitination and subsequent proteasomal degradation. Down-regulation of p53 led to increased expression of the mitophagy receptor protein BCL2 and adenovirus E1B 19 kDa-interacting protein 3 (BNIP3), thereby promoting mitophagy in hepatocytes. Furthermore, it was demonstrated that the transportation of RNF31 via small extracellular vesicles derived from mesenchymal stem cells (referred to as sEV) had a substantial influence on reducing hepatic steatosis and restoring liver function in HFD-fed mice. CONCLUSIONS: The findings highlight RNF31's essential role in the regulation of mitochondrial homeostasis in hepatocytes, emphasizing its potential as a therapeutic target for NAFLD.

From Hit to Lead: Structure-Based Optimization of Novel Selective Inhibitors of Receptor-Interacting Protein Kinase 1 (RIPK1) for the Treatment of Inflammatory Diseases.

Receptor-interacting protein kinase 1 (RIPK1) is a key regulator of cellular necroptosis, which is considered as an important therapeutic target for necroptosis-related indications. Herein, we report the structural optimization and structure-activity relationship investigations of a series of eutectic 5-substituted-indole-3-carboxamide derivatives. The prioritized compound 10b exhibited low nanomolar IC50 values against RIPK1 and showed good kinase selectivity. Based on its eutectic structure, 10b occupied both the allosteric and ATP binding pockets of RIPK1, making it a potent dual-mode inhibitor of RIPK1. In vitro, 10b had a potent protective effect against necroptosis in cells. Compound 10b also provided robust protection in a TNFα-induced systemic inflammatory response syndrome (SIRS) model and imiquimod (IMQ)-induced psoriasis model. It also showed good pharmacokinetic properties and low toxicity. Overall, 10b is a promising lead compound for drug discovery targeting RIPK1 and warrants further study.

Integrating SNVs and CNAs on a phylogenetic tree from single-cell DNA sequencing data.

Single-cell DNA sequencing enables the construction of evolutionary trees that can reveal how tumors gain mutations and grow. Different whole-genome amplification procedures render genomic materials of different characteristics, often suitable for the detection of either single-nucleotide variation or copy number aberration, but not ideally for both. Consequently, this hinders the inference of a comprehensive phylogenetic tree and limits opportunities to investigate the interplay of SNVs and CNAs. Existing methods such as SCARLET and COMPASS require that the SNVs and CNAs are detected from the same sets of cells, which is technically challenging. Here we present a novel computational tool, SCsnvcna, that places SNVs on a tree inferred from CNA signals, whereas the sets of cells rendering the SNVs and CNAs are independent, offering a more practical solution in terms of the technical challenges. SCsnvcna is a Bayesian probabilistic model using both the genotype constraints on the tree and the cellular prevalence to search the optimal solution. Comprehensive simulations and comparison with seven state-of-the-art methods show that SCsnvcna is robust and accurate in a variety of circumstances. Particularly, SCsnvcna most frequently produces the lowest error rates, with ability to scale to a wide range of numerical values for leaf nodes in the tree, SNVs, and SNV cells. The application of SCsnvcna to two published colorectal cancer data sets shows highly consistent placement of SNV cells and SNVs with the original study while also supporting a refined placement of ATP7B, illustrating SCsnvcna's value in analyzing complex multitumor samples.

Association of prothrombin complexe concentrate with venous thrombosis after cardiac surgery: a case-control study.

Background: Prothrombin complex concentrate (PCC) enhances coagulation and controls bleeding. We aimed to assess whether perioperative infusion of PCC is associated with venous thrombosis after cardiac surgery. Methods: We conducted a case-control study of patients undergoing cardiac surgery at our hospital in 2021. Multivariate logistic regression was used to assess the correlation between perioperative PCC infusion and postoperative venous thrombosis in cardiac surgery. Stratified analysis was also performed by age, hospitalization days, and whether warfarin, warfarin combined with heparin, warfarin combined with antiplatelet drugs were used postoperatively. Results: Data from 161 patients undergoing cardiac surgery were included in the analysis. Of these, 37 (23.0%) patients in the case group developed venous thrombosis, and 124 (77.0%) patients in the control group did not develop venous thrombosis. In the analysis without adjustment for confounders (model 1), perioperative PCC infusion significantly increased the risk of postoperative venous thrombosis (OR: 3.10, 95% CI: 1.26-7.59, P = 0.0135). In the model analysis adjusted for sex, age, and hospitalization days (model 2), perioperative PCC infusion was no longer significantly associated with the risk of postoperative venous thrombosis (OR: 1.76, 95% CI: 0.56-7.59, P = 0.3317). In the fully adjusted model (model 3), there was a marginally significant association between perioperative infusion of PCC and the risk of postoperative venous thrombosis (OR: 0.03, 95% CI: 0.00-1.23, P = 0.0637). Conclusions: Our findings show no significant association between perioperative PCC infusion in cardiac surgery and the development of postoperative venous thrombosis. Randomized controlled trials are needed to determine the causal relationship between perioperative PCC infusion and venous thrombosis in cardiac surgery.

Association between metabolic syndrome and early-stage colorectal cancer.

BACKGROUND: Accumulating studies have suggested metabolic syndrome (MetS) contributed to colorectal cancer (CRC) development. However, advanced CRC might decrease the detection proportion of MetS due to chronic malnutrition, we included patients with early-stage CRC to examine the associations among MetS, onset age, and different tumorigenesis pathways of CRC. METHODS: We conducted a retrospective study that included 638 patients with early-stage CRC from January 2014 to December 2018. Patient information was collected from the medical record system and further refined during the follow-up. Stratified analyses of the associations between MetS and different stratification factors were determined by the Cochran‒Mantel‒Haenszel test. RESULTS: There were 16 (13.3%) and 111 (21.4%) cases suffering from MetS in the early-onset and late-onset CRC groups, respectively. MetS coexisted in early-stage CRC patients ≥ 50 years of age more frequently than patients < 50 years of age (OR 1.77; 95% CI 1.01 to 3.12), but not for women patients (OR 0.84; 95% CI 0.79 to 0.90). MetS patients were associated with a higher risk of advanced serrated lesions than that of conventional adenomas (OR 1.585; 95% CI 1.02 to 2.45), especially in patients ≥ 50 years (OR 1.78; 95% CI 1.11 to 2.85). CONCLUSIONS: Metabolic dysregulation might partly contribute to the incidence of colorectal serrated lesions. Prevention of MetS should be highly appreciated in the early diagnosis and early treatment of the colorectal cancer system, especially in patients ≥ 50 years.

Upregulation of ubiquitin carboxy­terminal hydrolase 47 (USP47) in papillary thyroid carcinoma ex vivo and reduction of tumor cell malignant behaviors after USP47 knockdown by stabilizing SATB1 expression in vitro.

Aberrant ubiquitination contributes to cancer development, including thyroid carcinoma. The present study assessed the expression of ubiquitin carboxy-terminal hydrolase 47 (USP47) and underlying molecular events in the development of papillary thyroid carcinoma (PTC). The effects of USP47 on PTC cell invasion and migration were analyzed by Transwell assays, while. the effects of USP47 and SATB1on PTC cell gene expression and changes in tumor cell metabolism were assayed by reverse transcription-quantitative PCR, western bolt, or ELISA, respectively. The expression of USP47 mRNA and protein was upregulated in PTC tissue and associated with the PTC tumor size. Knockdown of USP47 expression in PTC cell lines (TPC-1 and K1), decreased the cell proliferation mobility and invasion capacities, whereas USP47 overexpression in these cell lines showed an inverse effect and promoted cell glycolysis and glutamine metabolism. Moreover, expression of special AT-rich sequence-binding protein-1 (SATB1) was high in PTC tissue and was associated with USP47 expression. SATB1 expression promoted tumor cell glycolysis and glutamine metabolism, while USP47 protein bound to and deubiquitinated SATB1 to increase its intracellular levels, thus promoting glycolysis and glutamine metabolism. USP47 promotion of PTC development may be due to its stabilization of SATB1 protein, suggesting that targeting the USP47/SATB1 signaling axis may serve as a therapeutic intervention for PTC.

STING is a cell-intrinsic metabolic checkpoint restricting aerobic glycolysis by targeting HK2.

Evasion of antitumour immunity is a hallmark of cancer. STING, a putative innate immune signalling adaptor, has a pivotal role in mounting antitumour immunity by coordinating innate sensing and adaptive immune surveillance in myeloid cells. STING is markedly silenced in various human malignancies and acts as a cell-intrinsic tumour suppressor. How STING exerts intrinsic antitumour activity remains unclear. Here, we report that STING restricts aerobic glycolysis independent of its innate immune function. Mechanistically, STING targets hexokinase II (HK2) to block its hexokinase activity. As such, STING inhibits HK2 to restrict tumour aerobic glycolysis and promote antitumour immunity in vivo. In human colorectal carcinoma samples, lactate, which can be used as a surrogate for aerobic glycolysis, is negatively correlated with STING expression level and antitumour immunity. Taken together, this study reveals that STING functions as a cell-intrinsic metabolic checkpoint that restricts aerobic glycolysis to promote antitumour immunity. These findings have important implications for the development of STING-based therapeutic modalities to improve antitumour immunotherapy.

An adjusted Asia-Pacific colorectal screening score system to predict advanced colorectal neoplasia in asymptomatic Chinese patients.

PURPOSE: The Asia-Pacific Colorectal Screening (APCS) score and its derivatives have been used to predict advanced colorectal neoplasia (ACN). However, it remains unknown whether they apply to the current Chinese population in general clinical practice. Therefore, we aimed to update the APCS score system by applying data from two independent asymptomatic populations to predict the risk of ACN in China. METHODS: We developed an adjusted APCS (A-APCS) score by using the data of asymptomatic Chinese patients undergoing colonoscopies from January 2014 to December 2018. Furthermore, we validated this system in another cohort of 812 patients who underwent screening colonoscopy between January and December 2021. The discriminative calibration ability of the A-APCS and APCS scores was comparatively evaluated. RESULTS: Univariate and multivariate logistic regression were applied to assess the risk factors for ACN, and an adjusted scoring system of 0 to 6.5 points was schemed according to the results. Utilizing the developed score, 20.2%, 41.2%, and 38.6% of patients in the validation cohort were classified as average, moderate, and high risk, respectively. The corresponding ACN incidence rates were 1.2%, 6.0%, and 11.1%, respectively. In addition, the A-APCS score (c-statistics: 0.68 for the derivation and 0.80 for the validation cohort) showed better discriminative power than using predictors of APCS alone. CONCLUSIONS: The A-APCS score may be simple and useful in clinical applications for predicting ACN risk in China.

Oncolytic herpes simplex virus armed with a bacterial GBP1 degrader improves antitumor activity.

Oncolytic viruses (OVs) encoding various transgenes are being evaluated for cancer immunotherapy. Diverse factors such as cytokines, immune checkpoint inhibitors, tumor-associated antigens, and T cell engagers have been exploited as transgenes. These modifications are primarily aimed to reverse the immunosuppressive tumor microenvironment. By contrast, antiviral restriction factors that inhibit the replication of OVs and result in suboptimal oncolytic activity have received far less attention. Here, we report that guanylate-binding protein 1 (GBP1) is potently induced during HSV-1 infection and restricts HSV-1 replication. Mechanistically, GBP1 remodels cytoskeletal organization to impede nuclear entry of HSV-1 genome. Previous studies have established that IpaH9.8, a bacterial E3 ubiquitin ligase, targets GBPs for proteasomal degradation. We therefore engineered an oncolytic HSV-1 to express IpaH9.8 and found that the modified OV effectively antagonized GBP1, replicated to a higher titer in vitro and showed superior antitumor activity in vivo. Our study features a strategy for improving the replication of OVs via targeting a restriction factor and achieving promising therapeutic efficacy.

Delayed PCI is not beneficial for STEMI patients with impaired renal function: a retrospective cohort study.

BACKGROUND: Preexisting impaired renal function (IRF) and contrast-induced nephropathy (CIN) after percutaneous coronary intervention (PCI) in patients with ST-segment elevation myocardial infarction (STEMI) are important prognostic parameters, but it is unknown whether delayed PCI is still beneficial for STEMI patients with IRF. METHODS: A retrospective single-center cohort study was performed in 164 patients who presented at least 12 h after symptom onset, and were diagnosed with STEMI and IRF. They were assigned to two groups to receive PCI plus optimal medical therapy (OMT) and OMT alone respectively. Clinical outcomes at 30 days and 1 year were compared between two groups, and hazard ratio for survival was analyzed using Cox regression model. A power analysis demanded 34 patients in each group to produce a power of 90% and a P value of 0.05. RESULTS: The 30-day mortality was significantly lower in PCI group (n = 126) than in non-PCI group (n = 38) (11.1% versus 28.9%, P = 0.018), while there was no significant difference in the 1-year mortality and incidence of cardiovascular comorbidities between the two groups. Cox regression analysis showed that patients with IRF didn't benefit from receiving PCI on survival rate (P = 0.267). CONCLUSIONS: Delayed PCI is not beneficial on one-year clinical outcomes for STEMI patients with IRF.

Tripartite motif-containing protein 31 confers protection against nonalcoholic steatohepatitis by deactivating mitogen-activated protein kinase kinase kinase 7.

BACKGROUND AIMS: As a global health threat, NASH has been confirmed to be a chronic progressive liver disease that is strongly associated with obesity. However, no approved drugs or efficient therapeutic strategies are valid, mainly because its complicated pathological processes is underestimated. APPROACH RESULTS: We identified the RING-type E3 ubiquitin transferase-tripartite motif-containing protein 31 (TRIM31), a member of the E3 ubiquitin ligases family, as an efficient endogenous inhibitor of transforming growth factor-beta-activated kinase 1 (mitogen-activated protein kinase kinase kinase 7; MAP3K7), and we further confirmed that TRIM31 is an MAP3K7-interacting protein and promotes MAP3K7 degradation by enhancing ubiquitination of K48 linkage in hepatocytes. Hepatocyte-specific Trim31 deletion blocks hepatic metabolism homeostasis, concomitant with glucose metabolic syndrome, lipid accumulation, up-regulated inflammation, and dramatically facilitates NASH progression. Inversely, transgenic overexpression, lentivirus, or adeno-associated virus-mediated Trim31 gene therapy restrain NASH in three dietary mice models. Mechanistically, in response to metabolic insults, TRIM31 interacts with MAP3K7 and conjugates K48-linked ubiquitination chains to promote MAP3K7 degradation, thus blocking MAP3K7 abundance and its downstream signaling cascade activation in hepatocytes. CONCLUSIONS: TRIM31 may serve as a promising therapeutic target for NASH treatment and associated metabolic disorders.

Comparison of pregnancy outcomes between GnRH antagonist protocol with freeze-all strategy and long-acting GnRH agonist protocol in women with adenomyosis undergoing IVF/ICSI: a propensity-score matching analysis.

BACKGROUND: Plenty of studies explored the most optimal treatment protocol for infertile women with adenomyosis in in-vitro fertilization (IVF) /intracytoplasmic sperm injection (ICSI), however, there is still no consensus on which treatment protocol is ideal for these women at present. So, we conducted this study comparing the pregnancy outcomes in infertile women with ultrasound-diagnosed adenomyosis who underwent GnRH antagonist protocol with freeze-all strategy or long-acting GnRH agonist protocol. METHODS: This was a retrospective cohort study and a propensity-score matching (PSM) analysis including 282 women diagnosed with adenomyosis undergoing their first IVF/ICSI cycle from January 2016 to July 2021 at the Assisted Reproduction Center, Northwest Women's and Children's Hospital, China. The patients were divided into two groups: the GnRH antagonist protocol with freeze-all strategy (n = 168) and the long-acting GnRH agonist protocol with fresh embryo transfer (n = 114) according their treatment protocols. The primary outcome was live birth rate. Cumulative live birth rate was also calculated. RESULTS: After adjusting for confounders, clinical pregnancy rate (49.40% vs 64.04%; odds ratio (OR) 1.33; 95% confidence interval (CI) 0.70 to 2.37; P = 0.358), live birth rate (36.90% vs 45.61%; OR 1.10; 95% CI 0.61 to 2.00, P = 0.753) and cumulative live birth rate (51.79% vs 64.04%; OR 1.01; 95% CI 0.49 to 1.74, P = 0.796) were not significantly different between the GnRH antagonist protocol with freeze-all strategy and long-acting GnRH agonist protocol. Similar results were conducted in PSM analysis with clinical pregnancy rate (46.48% vs 60.56%; OR 1.33; 95% CI 0.76 to 2.34; P = 0.321), live birth rate (32.39% vs 45.07%; OR 1.31; 95% CI 0.63 to 2.72, P = 0.463) and cumulative live birth rate (54.90% vs 60.60%; OR 1.01; 95% CI 0.59 to 1.74, P = 0.958). CONCLUSIONS: For infertile women with adenomyosis, these two treatment protocols resulted in similar pregnancy outcomes. Larger, prospective studies are needed in the future.

Genomic heterogeneity in pancreatic cancer organoids and its stability with culture.

The establishment of patient-derived pancreatic cancer organoid culture in recent years creates an exciting opportunity for researchers to perform a wide range of in vitro studies on a model that closely recapitulates the tumor. One of the outstanding question in pancreatic cancer biology is the causes and consequences of genomic heterogeneity observed in the disease. However, to use pancreatic cancer organoids as a model to study genomic variations, we need to first understand the degree of genomic heterogeneity and its stability within organoids. Here, we used single-cell whole-genome sequencing to investigate the genomic heterogeneity of two independent pancreatic cancer organoid lines, as well as their genomic stability with extended culture. Clonal populations with similar copy number profiles were observed within the organoids, and the proportion of these clones was shifted with extended culture, suggesting the growth advantage of some clones. However, sub-clonal genomic heterogeneity was also observed within each clonal population, indicating the genomic instability of the pancreatic cancer cells themselves. Furthermore, our transcriptomic analysis also revealed a positive correlation between copy number alterations and gene expression regulation, suggesting the "gene dosage" effect of these copy number alterations that translates to gene expression regulation.

Wenshen Yiqi Keli Mitigates the Proliferation and Migration of Cigarette Smoke Extract-Induced Human Airway Smooth Muscle Cells through miR-155/FoxO3a Axis.

Some domestic scholars revealed the effectiveness of Wenshen Yiqi Keli (WSYQKL) on chronic obstructive pulmonary disease (COPD). However, the exact mechanism of WSYQKL on COPD is fuzzy and needs further research. We adopted UPLC-Q/TOF-MS to analyze the chemical components of WSYQKL. In in vitro experiments, human airway smooth muscle cells (hASMCs) were intervened with 2.5% cigarette smoke extract (CSE), medicine serum of WSYQKL, miR-155 mimic, and FoxO3a silencing. Cell viability, proliferation, migration, and the expressions of miR-155, PCNA, Ki67, p21, p27, and FoxO3a were examined by cell counting kit-8, EdU staining, Transwell assay, scarification assay, qRT-PCR, immunol cytochemistry, and western blot, respectively. The association between miR-155 and FoxO3a was assessed by database and luciferase reporter gene analysis. We identified 47 kinds of chemical compositions of WSYQKL in ESI+ mode and 42 kinds of components of WSYQKL in ESI- mode. The medicine serum of WSYQKL strongly alleviated the proliferation and migration of hASMCs induced by CSE in a concentration-dependent manner. The medicine serum of WSYQKL enhanced the levels of p21, p27, and FoxO3a and weakened PCNA and Ki67 levels in hASMCs induced by CSE with the increase of concentration. MiR-155 mimic or FoxO3a silencing notably advanced CSE-treated HASMC viability, proliferation, migration, and the levels of PCNA and Ki67 and downregulated the levels of p21, p27, and FoxO3a in CSE-triggered hASMCs, which was reversed by WSYQKL-containing serum. Our results described that WSYQKL alleviated the proliferation and migration of hASMCs induced by CSE by modulating the miR-155/FoxO3a axis.

The novel FGFR inhibitor F1-7 induces DNA damage and cell death in colon cells.

BACKGROUND: Fibroblast growth factor receptor (FGFR) signaling influenced tumour occurrence and development. Overexpression of FGFR had been observed in many types of cancers, including colon cancer. FGFR inhibitor is considered to be effective in treating colon cancer patients. METHODS: First, the kinase inhibition rate was determined. MTT, western blotting, colony formation, EdU and comet assays were performed to evaluate the anti-tumour effects of F1-7 in vitro. RNA-seq and bioinformatics analysis were used for further verification. Additionally, a xenograft model was generated to investigate the anti-tumour effect of F1-7. RESULTS: F1-7 can inhibit the proliferation of colon cancer cells in vitro. It could significantly inhibit FGFR phosphorylation and its downstream signaling pathway. Whole-genome RNA-seq analysis found that the changed genes were not only functionally focused on MAPK signaling pathway but also related to cell apoptosis and ferroptosis. Experimental evidence demonstrated that F1-7 can directly increase the level of cellular DNA damage. The occurrence of DNA damage led to cell cycle arrest and inhibition of cell metastasis and cell apoptosis. Mouse model experiments also confirmed that F1-7 could inhibit tumour growth by inhibiting the FGFR pathway. CONCLUSIONS: F1-7 exhibits anti-tumour activity by inhibiting the FGFR pathway. It could be a novel therapeutic agent for targeting colon cancer cells.

Discovery of benzo[d]oxazol-2(3H)-one derivatives as a new class of TNIK inhibitors for the treatment of colorectal cancer.

Colorectal cancer (CRC) is one of the most commonly diagnosed cancer types and Traf2- and Nck-interacting kinase (TNIK) has been thought as a potential target for CRC treatment. Herein we report the discovery and structure-activity relationship (SAR) of benzo[d]oxazol-2(3H)-one derivatives as a new class of TNIK inhibitors. The most potent compound 8g showed an IC50 value of 0.050 µM against TNIK. It effectively suppressed proliferation and migration of colorectal cancer cells. Western blot analysis indicated that 8g could inhibit aberrant transcription activation of Wnt signaling. Collectively, this study provides a potential lead compound for subsequent drug discovery targeting TNIK.

Prognostic Value of ß1 Adrenergic Receptor Autoantibody and Soluble Suppression of Tumorigenicity-2 in Patients With Acutely Decompensated Heart Failure.

BACKGROUND: Both ß1 adrenergic receptor autoantibody (ß1-AA) and soluble suppression of tumorigenicity-2 (sST2) take a role in the pathological remodeling of heart failure. However, limited studies investigated the correlation between the expression of ß1-AA and sST2 in patients with acutely decompensated heart failure (ADHF). OBJECTIVE: To explore the correlation between ß1-AA and sST2, and evaluate their prognostic value in patients with ADHF. METHODS: Patients who were admitted for ADHF were included. The N-terminal pro-brain natriuretic peptide (NT-proBNP), sST2, and ß1-AA in blood samples were tested at hospital admission and then followed up for assessing the outcomes. Pearson correlation analysis was used to explore the correlation between ß1-AA and sST2. The effects of ß1-AA, sST2, or the combination of them on the all-cause mortality of patients with ADHF were assessed by Multivariate Cox regression analysis. RESULTS: There were 96 patients with ADHF and 96 control populations enrolled. The ß1-AA was significantly higher in ADHF than in the control group (0.321 ± 0.06 vs. 0.229 ± 0.04, P = 0.000). Pearson correlation analysis showed that ß1-AA was positively correlated with sST2 (r = 0.593), NT-proBNP (r = 0.557), Procalcitonin (r = 0.176), and left ventricular end-diastolic diameter (r = 0.315), but negatively correlated with triglycerides (r = -0.323), and left ventricular ejection fraction (r = -0.430) (all P < 0.05) in ADHF. Patients with ADHF, complicated with both high ß1-AA and sST2, showed the highest all-cause mortality during an average of 25.5 months of follow-up. Multivariate Cox regression showed the combination of both high ß1-AA and sST2 independently correlated with the all-cause mortality after adjustment for other risk factors (hazard ratio 3.348, 95% CI 1.440 to 7.784, P = 0.005). After adding with ß1-AA and sST2, the area under the curves for the prognostic all-cause mortality could increase from 0.642 to 0.748 (P = 0.011). CONCLUSION: The ß1-AA is positively correlated with sST2 in patients with ADHF. Elevated plasma ß1-AA and sST2 level in patients with ADHF are associated with poorer prognoses.

Discovery of 3,4-Dihydrobenzo[f][1,4]oxazepin-5(2H)-one Derivatives as a New Class of Selective TNIK Inhibitors and Evaluation of Their Anti-Colorectal Cancer Effects.

The Traf2- and Nck-interacting protein kinase (TNIK) is a downstream signal protein of the Wnt/ß-catenin pathway and has been thought of as a potential target for the treatment of colorectal cancer (CRC) that is often associated with dysregulation of Wnt/ß-catenin signaling pathway. Herein, we report the discovery of a series of 3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one derivatives as a new class of TNIK inhibitors. Structure-activity relationship (SAR) analyses led to the identification of a number of potent TNIK inhibitors with compound 21k being the most active one (IC50: 0.026 ± 0.008 µM). This compound also displayed excellent selectivity for TNIK against 406 other kinases. Compound 21k could efficiently suppress CRC cell proliferation and migration in in vitro assays and exhibited considerable antitumor activity in the HCT116 xenograft mouse model. It also showed favorable pharmacokinetic properties. Overall, 21k could be a promising lead compound for drug discovery targeting TNIK and deserves further studies.