The application of high-resolution vessel wall imaging in the in situ bypass surgeries for complex anterior cerebral artery aneurysms.

OBJECTIVE: Complex anterior cerebral artery (ACA) aneurysms are still technically challenging to treat. Bypass surgery is needed to achieve aneurysm obliteration and ACA territory revascularization. Severe atherosclerosis of aneurysm walls can cause clip slippage, intraoperative rupture, postoperative ischemic events. How to assess the atherosclerotic changes in vascular walls by high-resolution vessel wall magnitude resonance imaging (VWI) is the key question in complex ACA aneurysm surgical management. METHODS: This retrospective single-center study included eight patients diagnosed with complex anterior cerebral arteries admitted to our hospital for bypass surgery from January 2019 to April 2022. We discussed the application of VWI in aneurysms treated with in situ bypass and reviewed previous experience of revascularization strategies for complex ACA aneurysms. RESULTS: In this study, we treated 8 cases of complex ACA aneurysms (3 communicating aneurysms/5 postcommunicating aneurysms) over the prior one year. In situ side-to-side anastomosis (1 A2-to-A2/6 A3-to-A3) was performed in seven cases, and trapping combined with excision was performed in another case. Following bypass, complete trapping was performed in 4 cases, and proximal clipping was performed in 3 cases. No surgery-related neurological dysfunctions were observed. The final modified Rankin scale was 0 in seven of the eight cases and 2 in one case. CONCLUSION: High-resolution VWI, as a favorable preoperative assessment tool, provides insight into patient-specific anatomy and microsurgical options before operations, which can help neurosurgeons develop individualized and valuable surgical plans.

Finite Element Modeling of Residual Hearing after Cochlear Implant Surgery in Chinchillas.

Cochlear implant (CI) surgery is one of the most utilized treatments for severe hearing loss. However, the effects of a successful scala tympani insertion on the mechanics of hearing are not yet fully understood. This paper presents a finite element (FE) model of the chinchilla inner ear for studying the interrelationship between the mechanical function and the insertion angle of a CI electrode. This FE model includes a three-chambered cochlea and full vestibular system, accomplished using µ-MRI and µ-CT scanning technologies. This model's first application found minimal loss of residual hearing due to insertion angle after CI surgery, and this indicates that it is a reliable and helpful tool for future applications in CI design, surgical planning, and stimuli setup.

Discovery of Potent, Selective, and Orally Bioavailable Small-Molecule Inhibitors of CDK8 for the Treatment of Cancer.

Cyclin-dependent kinase 8 (CDK8), as a kinase subunit of the Mediator complex, is involved in the regulation of RNA polymerase II-mediated transcription, thereby modulating multiple signaling pathways and multiple transcription factors involved in oncogenic control. CDK8 deregulation has been implicated in human diseases, particularly in acute myeloid leukemia (AML) and advanced solid tumors, where it has been reported as a putative oncogene. Here, we report the successful optimization of an azaindole series of CDK8 inhibitors that were identified and further progressed through a structure-based generative chemistry approach. In several optimization cycles, we improved in vitro microsomal stability, kinase selectivity, and in vivo pharmacokinetic profile cross-species, leading to the discovery of compound 23, which demonstrated robust tumor growth inhibition in multiple in vivo efficacy models after oral administration.

AlphaFold accelerates artificial intelligence powered drug discovery: efficient discovery of a novel CDK20 small molecule inhibitor.

The application of artificial intelligence (AI) has been considered a revolutionary change in drug discovery and development. In 2020, the AlphaFold computer program predicted protein structures for the whole human genome, which has been considered a remarkable breakthrough in both AI applications and structural biology. Despite the varying confidence levels, these predicted structures could still significantly contribute to structure-based drug design of novel targets, especially the ones with no or limited structural information. In this work, we successfully applied AlphaFold to our end-to-end AI-powered drug discovery engines, including a biocomputational platform PandaOmics and a generative chemistry platform Chemistry42. A novel hit molecule against a novel target without an experimental structure was identified, starting from target selection towards hit identification, in a cost- and time-efficient manner. PandaOmics provided the protein of interest for the treatment of hepatocellular carcinoma (HCC) and Chemistry42 generated the molecules based on the structure predicted by AlphaFold, and the selected molecules were synthesized and tested in biological assays. Through this approach, we identified a small molecule hit compound for cyclin-dependent kinase 20 (CDK20) with a binding constant Kd value of 9.2 ± 0.5 µM (n = 3) within 30 days from target selection and after only synthesizing 7 compounds. Based on the available data, a second round of AI-powered compound generation was conducted and through this, a more potent hit molecule, ISM042-2-048, was discovered with an average Kd value of 566.7 ± 256.2 nM (n = 3). Compound ISM042-2-048 also showed good CDK20 inhibitory activity with an IC50 value of 33.4 ± 22.6 nM (n = 3). In addition, ISM042-2-048 demonstrated selective anti-proliferation activity in an HCC cell line with CDK20 overexpression, Huh7, with an IC50 of 208.7 ± 3.3 nM, compared to a counter screen cell line HEK293 (IC50 = 1706.7 ± 670.0 nM). This work is the first demonstration of applying AlphaFold to the hit identification process in drug discovery.

Funnel-Shaped Floating Vessel Oil Skimmer with Joule Heating Sorption Functionality.

Floating vessel-type oil collecting devices based on sorbent materials present potential solutions to oil spill cleanup that require a massive amount of sorbent material and manual labor. Additionally, continuous oil extraction from these devices presents opportunities for highly energy-efficient oil skimmers that use gravity as the oil/water separation mechanism. Herein, a sorbent-based oil skimmer (SOS) is developed with a novel funnel-shaped sorbent and vessel design for efficient and continuous extraction of various oils from the water surface. A carbon black (CB) embedded polydimethylsiloxane (PDMS) sponge material is characterized and used as the sorbent in the SOS. The nanocomposite sponge formulation is optimized for high reusability, hydrophobicity, and rapid oil absorption. Joule heating functionality of the sponge is also explored to rapidly absorb highly viscous oils that are a significant challenge for oil spill cleanup. The optimized sponge material with the highest porosity and 15 wt% CB loading is tested in the SOS for large-scale oil spill extraction tests and shows effective cleaning of oil spilled on the water surface. The SOS demonstrates a high maximum extraction rate of 200 mL/min for gasoline and maintains a high extraction rate performance upon reuse when the sponge funnel is cleaned and dried.

LncRNA SNHG6 inhibits autophagy of gastric carcinoma cells via PI3K/AKT/mTOR signaling pathway.

OBJECTIVE: To investigate the role of lncRNA SNHG6 (SNHG6) in gastric carcinoma (GC) and its relationship with the PI3K/AKT/mTOR signaling pathway in order to provide more comprehensive and reliable reference for the diagnosis and treatment of GC. METHODS: GC patients admitted to our hospital from May 2017 to August 2018 as well as healthy individuals who underwent physical examinations during the same time period were enrolled in this study. The serum SNHG6 level was quantified. Patients were followed up for 3 years to analyze the significance of SNHG6 in the diagnosis and treatment of GC. Finally, in vitro assays were performed to determine the influences of SNHG6 and PI3K/AKT/mTOR signaling pathway on biological behaviors and autophagy ability of GC cells. RESULTS: SNHG6 showed high expression in patients with GC and its expression decreased after therapy. SNHG6 also demonstrated a favorable predictive value for the development of GC and the death of patients. The survival curve suggested that increased SNHG6 indicated a higher risk of death. Additionally, mRNA of PI3K/AKT/mTOR pathway related molecules was highly expressed in GC patients. In in vitro assays, GC cells showed stronger viability and invasion activity and weaker apoptosis and autophagy ability after targeted up-regulation of SNHG6. According to the rescue assay, the effect of up-regulating SNHG6 on GC cells could be completely reversed by suppressing the PI3K/AKT/mTOR pathway. CONCLUSION: With high expression in patients with GC, SNHG6 can promote the development of GC by activating the PI3K/AKT/mTOR signaling pathway and suppressing the autophagy of cells. Therefore, it is a potential breakthrough in the diagnosis and treatment of GC in the future.

Multi-residue analysis of 206 pesticides in grass forage by the one-step quick, easy, cheap, effective, rugged, and safe method combined with ultrahigh-performance liquid chromatography quadrupole orbitrap mass spectrometry.

A novel method for detecting pesticide multi-residue in grass forage (alfalfa and oat) was established based on the one-step automatic extraction and purification technology of quick, easy, cheap, effective, rugged, and safe combined with ultrahigh-performance liquid chromatography quadrupole Orbitrap high-resolution mass spectrometry. The crushed sample was extracted with acetonitrile with 1% acetate, followed by a cleanup step with a primary-secondary amine, octadecylsilane, and graphitized carbon black. The extraction and purification were carried out using the one-step automatic pretreatment equipment. The target pesticides were acquired in positive ion electrospray ionization mode and full scan/data dependent secondary scan mode. The calibration curve shows good linearity over the corresponding concentration range, with the coefficient of determination greater than 0.99. The screening detection limits were 0.5-50 µg/kg, and the limit of quantification for the 206 pesticides was set at 1-50 µg/kg. At the spiking levels of one, two, and 10 times of limit of quantification, more than 95% of pesticides had recovery between 70-120%, with a relative standard deviation ≤20%. The method was proved to be simple, rapid, high-sensitivity, and could be routinely used for the high throughput screening and quantitative analysis of pesticide residues in alfalfa and oat.

The Role of lncRNA PVT1 and hsa-miR-30a-3p in the Development of Gastric Cancer.

OBJECTIVE: Aberrantly expressed lncRNAs have been detected in gastric cancer (GC). LncRNA PVT1 is involved in numerous types of human malignant tumor. In this project, we demonstrated the relationship between PVT1 and Myc and tested the function of PVT1 and hsa-miR-30a-3p in the tumorigenesis of GC. METHODS: For experimental study, RNA-Seq datasets and equivalent clinical data for 367 samples were achieved from The Cancer Genome Atlas (TCGA)-STAD datasets. The online software clusterProfiler was used to perform Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway functional enrichment. The co-expression of YY1, PVT1, and Myc genes was evaluated by determining the Pearson correlation coefficients. Potential competing endogenous RNAs of PVT1-miRNA-Myc were predicted by the Cytoscape tool and Kaplan- Meier curves were generated for YY1, PVT1, and Myc genes. For clinical study, Human GC samples were taken from 26 pairs of GC tissue (GCT) and para-tumor tissue (PT, 5 cm from the edge of the tumor) in which no patient had previously undergone preoperative adjuvant chemotherapy or radiotherapy. RESULTS: For experimental study, a total of 1144 differential expression genes (DEGs) were identified consisting of 731 up-regulated genes and 413 down-regulated genes. DEGs were Myc, YY1, and PVT1 and PVT1 was significantly different (adj. P=1.11E-11). The correlation coefficient between PVT1 and Myc was 0.42. A ceRNA network model suggested the hsa-miR-30a-3p was interacted between PVT1 and Myc, playing the role of information transmission. Survival analysis of these genes suggested that lncRNA PVT1 might influence the GC case survival (p=0.06). PVT1 expression was upregulated in human gastric cancer tissues and its relative PVT1 expression of PT was increased two fold compared to GCT. The expressions of PVT1 from the tumor tissues were significantly upregulated in GCT. CONCLUSION: These discoveries imply that lncRNA PVT1 and hsa-miR-30a-3p has a responsibility in the GC development. Therefore, targeting PVT1 or/and hsa-miR-30a-3p as a strategy for gastric cancer should be explored.

Enzyme and microwave co-assisted extraction, structural characterization and antioxidant activity of polysaccharides from Purple-heart Radish.

A novel method of simultaneous extraction and separation of diverse polysaccharides from Purple-heart Radish was developed by integrating EAE with MAATPE. The effects of different enzymes, the ATPS composition, extraction temperature, time etc. were investigated by single-factor experiments and RSM. Under the optimum conditions, the extraction yields of PTP, PBP and total polysaccharides were 9.107 ± 0.391%, 32.506 ± 0.046% and 41.613 ± 0.437%, respectively. By means of HPGPC and PMP-HPLC, Mw of PTP and Mw of PBP were 15935 Da and 27962 Da, respectively. PTP and PBP were mainly composed of mannose, glucuronic acid, aminogalactose, glucose, galactose and arabinose. Moreover, both polysaccharides exhibited stronger antioxidant activities for scavenging multiple radicals and anti-lipid peroxidation. Compared to the conventional extraction methods, EAE-MAATPE achieved higher extraction efficiency due to the synergistic effect between EAE and MAATPE leading to rupture and enzymolysis of cell. Thus, EAE-MAATPE provided an efficient alternative to simultaneous extraction of different polysaccharides from natural products.

Discovery of Highly Potent and Selective IRAK1 Degraders to Probe Scaffolding Functions of IRAK1 in ABC DLBCL.

MyD88 gene mutation has been identified as one of the most prevalent driver mutations in the activated B-cell-like diffuse large B-cell lymphoma (ABC DLBCL). The published literature suggests that interleukin-1 receptor-associated kinase 1 (IRAK1) is an essential gene for ABC DLBCL harboring MyD88 mutation. Importantly, the scaffolding function of IRAK1, rather than its kinase activity, is required for tumor cell survival. Herein, we present our design, synthesis, and biological evaluation of a novel series of potent and selective IRAK1 degraders. One of the most potent compounds, Degrader-3 (JNJ-1013), effectively degraded cellular IRAK1 protein with a DC50 of 3 nM in HBL-1 cells. Furthermore, JNJ-1013 potently inhibited IRAK1 downstream signaling pathways and demonstrated strong anti-proliferative effects in ABC DLBCL cells with MyD88 mutation. This work suggests that IRAK1 degraders have the potential for treating cancers that are dependent on the IRAK1 scaffolding function.

Assessing IRAK4 Functions in ABC DLBCL by IRAK4 Kinase Inhibition and Protein Degradation.

The interleukin-1 receptor-activated kinase 4 (IRAK4) belongs to the IRAK family of serine/threonine kinases and plays a central role in the innate immune response. However, the function of IRAK4 in tumor growth and progression remains elusive. Here we sought to determine the enzymatic and scaffolding functions of IRAK4 in activated B-cell-like diffuse large B cell lymphoma (ABC DLBCL). We chose a highly selective IRAK4 kinase inhibitor to probe the biological effects of kinase inhibition and developed a series of IRAK4 degraders to evaluate the effects of protein degradation in ABC DLBCL cells. Interestingly, the results demonstrated that neither IRAK4 kinase inhibition nor protein degradation led to cell death or growth inhibition, suggesting a redundant role for IRAK4 in ABC DLBCL cell survival. IRAK4 degraders characterized in this study provide useful tools for understanding IRAK4 protein scaffolding function, which was previously unachievable using pharmacological perturbation.

Theoretical insights on type I/II photoreactions of potential Zn(II) polypyridyl photosensitizers for two-photon photodynamic therapy.

Large two-photon absorption cross-sections are vital to photosensitizers (PSs) in TP-PDT, which can be used to develop in-depth treatment for diseased cells and minimize the harm to surrounding cells. Here, we conduct a study about photophysical properties of one Ru(II) polypyridyl complex and two designed Zn(II) polypyridyl complexes by means of DFT and TD-DFT methods. The main results are as follows: firstly, the two-photon absorption spectrum of two designed complexes Zn-OMe and Zn-OCOOCH3 are all within the phototherapeutic window (550-900 nm). Secondly, large SOC values and small energy gaps ΔES-T of these complexes guarantee the efficiency of ISC process. Thirdly, their T1 energy is greater than that required for generating 1O2 (0.98 eV) via Type II photoreaction. In addition, the calculated results of vertical electron affinities (VEA) and vertical ionization potentials (VIP) show that these complexes are able to form superoxide ions O2(-) via Type I photoreaction. Specifically, both of two designed Zn-centric complexes have larger TPA cross-sections than that of Ru-centric complex. In a word, we are pleased to report two potential photosensitizers with excellent performance and reasonable price for Type I/II photoreactions. We expect our study will offer some theoretical guidance and help in TP-PDT.

Sequential extraction and enrichment of pesticide residues in Longan fruit by ultrasonic-assisted aqueous two-phase extraction linked to vortex-assisted dispersive liquid-liquid microextraction prior to high performance liquid chromatography analysis.

A simple, green and efficient method for extraction, purification and enrichment of pesticide residues of triazoles and pyrethroids in Longan fruit was developed by ultrasonic-assisted aqueous two-phase extraction (UAATPE) coupled to vortex-assisted dispersive liquid-liquid microextraction (VADLLME). Using an aqueous two-phase system (ATPS) of ethanol/K2HPO4 as extraction solvent, the composition of the ATPS, extraction temperature and time were investigated, respectively. Then VADLLME process also was optimized by investigating type and volume of extracting and dispersive solvents, vortex-assisted time and salt addition. The optimum conditions were as follows: the ATPS composition of ethanol concentration 30.0% (w/w) and K2HPO4 concentration 25% (w/w), extraction temperature 70 °C and extraction time 15 min for UAATPE; 1-dodecanol 200 µL as extraction solvent, ethanol 1.25 mL as dispersive solvent, vortex-assisted time 1.5 min and addition of NaCl 4% (w/v) for VADLLME. Ethanol as extraction solvent and dispersive solvent could directly connect UAATPE with VADLLME without extra steps. By means of HPLC-DAD detection, nine pesticides had good linearity ranged from 0.0200 to 13.59 µg/mL (R2 ≥ 0.9957). LODs and LOQs were in the range of 0.005576-0.01740 µg/mL and 0.01859-0.05010 µg/mL, respectively. UAATPE-VADLLME coupled to HPLC was successfully applied to simultaneous determination of multiple pesticides in Longan fruit, and mean recoveries and RSDs were between 76.95% and 98.63%, 1.2% and 9.8%, respectively. Furthermore, myclobutanil, fenpropathrin and deltamethrin were detected in pericarp and pulp of Longan samples from different districts, respectively.

CCN2 Mediates S1P-Induced Upregulation of COX2 Expression in Human Granulosa-Lutein Cells.

CCN1 and CCN2 are members of the CCN family and play essential roles in the regulation of multiple female reproductive functions, including ovulation. Cyclooxygenase-2 (COX2) is a critical mediator of ovulation and can be induced by sphingosine-1-phosphate (S1P) through the S1P1/3-mediated Yes-associated protein (YAP) signaling. However, it is unclear whether CCN1 or CCN2 can mediate S1P-induced upregulation of COX2 expression and increase in prostaglandin E2 (PGE2) production in human granulosa-lutein (hGL) cells. In the present study, we investigated the effects of S1P on the expressions of CCN1 and CCN2 in hGL cells. Additionally, we used a dual inhibition approach (siRNA-mediated silencing and small molecular inhibitors) to investigate the molecular mechanisms of S1P effects. Our results showed that S1P treatment significantly upregulated the expression of CCN1 and CCN2 in a concentration-dependent manner in hGL cells. Additionally, inhibition or silencing of S1P1, but not S1P3, completely abolished the S1P-induced upregulation of CCN2 expression. Furthermore, we demonstrated that S1P-induced nuclear translocation of YAP and inhibition or silencing of YAP completely abolished the S1P-induced upregulation of CCN1 and CCN2 expression. Notably, silencing of CCN2, but not CCN1, completely reversed the S1P-induced upregulation of COX2 expression and the increase in PGE2 production. Thus, CCN2 mediates the S1P-induced upregulation of COX2 expression through the S1P1-mediated signaling pathway in hGL cells. Our findings expand our understanding of the molecular mechanism underlying the S1P-mediated cellular activities in the human ovary.

Theoretical insight into the photophysical properties of long-lifetime Ir(iii) and Rh(iii) complexes for two-photon photodynamic therapy.

Two-photon photodynamic therapy (TP-PDT) plays crucial roles in curing tumors because it involves deep penetration of drugs into the tissue and has minimal damage to the surrounding cells. Our theoretical study was aimed at providing fresh insights into photosensitizers, such as [Ir(N^C)2(N^N)]+ (N^C = 2-phenylpyridine, N^N = bis-benzimidazole) and [Rh(N^C)2(N^N)]+, to treat cancer via the TP-PDT route. To better understand the properties of the complexes [Ir(N^C)2(N^N)]+ and [Rh(N^C)2(N^N)]+, the one-photon and two-photon absorption electronic spectra, energy gap (ΔES-T), strength of two-photon absorption cross-section (δ), spin-orbit matrix element (S1|HSO|Tj), and phosphorescence lifetimes (τ) were calculated by DFT and TD-DFT. The calculation results suggested that both complexes met the criteria (i.e. an efficient ISC process, enough energy to produce 1O2 and phototherapeutic window of the absorption wavelength) of photosensitizers; importantly, the designed complex [Rh(N^C)2(N^N)]+ had better performance than [Ir(N^C)2(N^N)]+, especially in the long-lived triplet excited state. It is expected that our research can make quite a few contributions to the development of photosensitizers and establish some guidelines for experiments based on TP-PDT.

The carboxyl-terminal helical domain of the ATP synthase γ subunit is involved in ε subunit conformation and energy coupling.

The γ subunit located at the center of ATP synthase (FOF1) plays critical roles in catalysis. Escherichia coli mutant with Pro substitution of the γ subunit residue γLeu218, which are located the rotor shaft near the c subunit ring, decreased NADH-driven ATP synthesis activity and ATP hydrolysis-dependent H+ transport of membranes to ~60% and ~40% of the wild type, respectively, without affecting FOF1 assembly. Consistently, the mutant was defective in growth by oxidative phosphorylation, indicating that energy coupling is impaired by the mutation. The ε subunit conformations in the γLeu218Pro mutant enzyme were investigated by cross-linking between cysteine residues introduced into both the ε subunit (εCys118 and εCys134, in the second helix and the hook segment, respectively) and the γ subunit (γCys99 and γCys260, located in the globular domain and the carboxyl-terminal helix, respectively). In the presence of ADP, the two γ260 and ε134 cysteine residues formed a disulfide bond in both the γLeu218Pro mutant and the wild type, indicating that the hook segment of ε subunit penetrates into the α3ß3-ring along with the γ subunits in both enzymes. However, γ260/ε134 cross-linking in the γLeu218Pro mutant decreased significantly in the presence of ATP, whereas this effect was small in the wild type. These results suggested that the γ subunit carboxyl-terminal helix containing γLeu218 is involved in the conformation of the ε subunit hook region during ATP hydrolysis and, therefore, is required for energy coupling in FOF1.

Discovery of an Orally Bioavailable Dual PI3K/mTOR Inhibitor Based on Sulfonyl-Substituted Morpholinopyrimidines.

The discovery and optimization of a series of 2-morpholino-pyrimidine derivatives containing various sulfonyl side chains at the C4 position led to the identification of compound 26 as a potent dual PI3K/mTOR inhibitor. It exhibited high inhibitory activity against PI3Kα/ß/γ/δ (IC50 = 20/376/204/46 nM) and mTOR (IC50 = 189 nM), potent functional suppression of AKT phosphorylation (IC50 = 196 nM), and excellent antiproliferative effects on a panel of cancer cells. Enzymic data and modeling simulation indicate that a cyclopropyl ring on the C4 sulfone chain and a fluorine on the C6 aminopyridyl moiety are responsible for its maintained PI3K activity and enhanced mTOR potency, respectively. Furthermore, compound 26 exhibited higher efficiency in the HT-29 colorectal carcinoma xenograft model at the daily dose of 3.75 and 7.5 mg/kg relative to BKM120 at the dose of 15 and 30 mg/kg.

Theoretical study on photophysical properties of three high water solubility polypyridyl complexes for two-photon photodynamic therapy.

Two-photon photodynamic therapy (TP-PDT) is a very promising treatment that has drawn much attention in recent years due to its ability to penetrate deeper into tissues and minimize the damage to normal cells. Here, the properties of three highly water soluble Ru(ii) and Zn(ii) polypyridyl complexes as photosensitizers (PSs) were examined, including the one-photon and two-photon absorption (OPA and TPA) spectra, singlet-triplet energy gap (ΔH-L), TPA cross-section and spin-orbit coupling constant via Density Function Theory (DFT) and Time-Dependent Density Functional Theory (TD-DFT). Their potential therapeutic use as photosensitizers in TP-PDT is proposed, where the reasoning is as follows: first, they possess strong absorption in the therapeutic window; second, the vertical excitation energy is greater than 0.98 eV, which can generate a singlet oxygen species and the remarkable coupling between the S1 and T1 states. Moreover, the spin-orbit matrix elements are greater than 0.24 cm-1 for Ru-bpy and Zn-tpy, indicating that the intersystem spin crossing processes are efficient. It is expected that these complexes will be applied to PSs in TP-PDT, and we hope this research can serve as a guideline for the development of efficient two-photon PSs.

Discovery of N-aryl-N'-pyrimidin-4-yl ureas as irreversible L858R/T790M mutant selective epidermal growth factor receptor inhibitors.

A novel series of N-aryl-N'-pyrimidin-4-yl ureas has been optimized to afford potent and selective inhibitors of the EGFR L858R/T790M. The most representative compound 28 showed high activity against EGFR L858R/T790M kinase (IC50 = 4 nM) and 22-fold selectivity against wild type EGFR. Moreover, compound 28 potently inhibited EGFR L858R/T790M phosphorylation (IC50 = 41 nM) and cellular proliferation (IC50 = 37 nM) in the H1975 cell line, while being significantly less toxic to A431 cells. Further, compound 28 exhibited a great selectivity in a mini-panel of kinases.

Sprouty4 mediates amphiregulin-induced down-regulation of E-cadherin and cell invasion in human ovarian cancer cells.

Sprouty (SPRY) proteins are well-characterized factors that inhibit receptor tyrosine kinase (RTK)-mediated activation of cellular signaling pathways. The down-regulation of SPRY4 expression has been reported in human ovarian cancer. However, the specific roles and mechanisms by which SPRY4 affects ovarian cancer progression are completely unknown. Amphiregulin (AREG) binds exclusively to the epidermal growth factor receptor (EGFR) and has been considered to be a dominant autocrine/paracrine EGFR ligand in ovarian cancer. In the present study, we first examined the effects of AREG on SPRY4 expression and the possible underlying molecular mechanisms involved in this process in two human ovarian cancer cell lines. Our results demonstrated that treatment with AREG up-regulated SPRY4 expression by activating the ERK1/2 signaling pathway. In addition, we showed that small interfering RNA (siRNA)-mediated knockdown of SPRY4 attenuated the AREG-induced down-regulation of E-cadherin by inhibiting the expression of SNAIL but not SLUG. In contrast, overexpression of SPRY4 enhanced AREG-induced down-regulation of E-cadherin by increasing the expression of SNAIL. Moreover, SPRY4 knockdown attenuated AREG-induced cell migration and invasion. Overexpression of SPRY4 enhanced AREG-induced cell invasion. This study reveals that SPRY4 is involved in EGFR-mediated human ovarian cancer progression.