Design and Synthesis of c-Met and HDAC Dual Inhibitors for the Treatment of Breast Cancer.

In recent years, it has been proposed that c-mesenchymal-to-epithelial transition factor (c-Met) and histone deacetylase (HDAC) dual inhibition is a promising cancer treatment strategy. Herein, a series of c-Met/HDAC dual inhibitors were designed and synthesized given their synergistic anticancer effect in breast cancer cells. Compound 12d exhibited excellent inhibitory activity against c-Met (IC50 = 28.92 nM) and HDAC (85.68%@1000 nM) and inhibited the proliferation of all three breast cancer cell lines. Moreover, a mechanism investigation demonstrated that 12d could simultaneously induce cell cycle arrest in the G0/G1 phase and cell apoptosis in MDA-MB-231 cells, which was endorsed by c-Met and HDAC pathway blockade. It could also suppress cell invasion. Our results suggest that developing promising c-Met/HDAC dual inhibitors is a novel strategy for breast cancer therapy.

Dual inhibitors of DNMT and HDAC induce viral mimicry to induce antitumour immunity in breast cancer.

The existing conventional treatments for breast cancer, including immune checkpoint blockade, exhibit limited effects in some cancers, particularly triple-negative breast cancer. Epigenetic alterations, specifically DNMT and HDAC alterations, are implicated in breast cancer pathogenesis. We demonstrated that DNMTs and HDACs are overexpressed and positively correlated in breast cancer. The combination of DNMT and HDAC inhibitors has shown synergistic antitumour effects, and our previously designed dual DNMT and HDAC inhibitor (termed DNMT/HDACi) 15a potently inhibits breast cancer cell proliferation, migration, and invasion and induces apoptosis in vitro and in vivo. Mechanistically, 15a induces a viral mimicry response by promoting the expression of endogenous retroviral elements in breast cancer cells, thus increasing the intracellular level of double-stranded RNA to activate the RIG-I-MAVS pathway. This in turn promotes the production of interferons and chemokines and augments the expression of interferon-stimulated genes and PD-L1. The combination of 15a and an anti-PD-L1 antibody had an additive effect in vivo. These findings indicate that this DNMT/HDACi has immunomodulatory functions and enhances the effectiveness of immune checkpoint blockade therapy. A novel dual DNMT and HDAC inhibitor induces viral mimicry, which induces the accumulation of dsRNA to activate tumoral IFN signalling and cytokine production to enhance the immune response in breast cancer.

Design, synthesis, and evaluation of VHL-based EZH2 degraders for breast cancer.

EZH2 (enhancer of zeste homolog 2) is one of the most important histone methyltransferases (HMTs), and overexpression of EZH2 can lead to proliferation, migration and angiogenesis of tumor cells. But most of EZH2 inhibitors are only effective against some hematologic malignancies and have poor efficacy against solid tumors. Here, we report the design, synthesis, and evaluation of highly potent proteolysis targeting chimeric (PROTACs) small molecules targeting EZH2. We developed a potent and effective EZH2 degrader P4, which effectively induced EZH2 protein degradation and inhibited breast cancer cell growth. Further studies showed that P4 can significantly decrease the degree of H3K27me3 in MDA-MB-231 cell line, induce apoptosis and G0/G1 phase arrest in Pfeiffer and MDA-MB-231 cell lines. Therefore, P4 is a potential anticancer molecule for breast cancer treatment.

Design, optimization, and characterization of an XY nanopositioning stage with multi-level spatial flexure hinges for high-precision large-stroke motion guidance.

Establishing a novel design and accurate analytical models for XY nanopositioning stages based on voice coil motor (VCM) actuators is critical to achieving an optimal working performance. To overcome the existing design challenges of 2-degree-of-freedom guiding mechanisms, a four-layer structure composed of L-shaped spatial double parallelogram flexure mechanisms was proposed for the magnetic stage, which exhibits light weight and inhibits parasitic and decoupled motions. The guiding mechanisms were modeled by the compliance matrix method. Thereafter, by combining an electromagnetic model for the VCMs with the equivalent magnetic network method, an electromagnetic-mechanical coupling optimization method with multiple constraints was proposed for the stage to achieve a millimeter-range motion with a maximized natural frequency. The mechanical and electromagnetic performances were then verified by finite element analysis software. The optimized prototype was tested with a stroke of ±3.41 and ±3.08 mm for X axis and Y axis, respectively, a closed-loop resolution of 100 nm for X axis and 150 nm for Y axis, and a resonant frequency of 11.75 Hz for both axes. The tracking of a 0.1 Hz spiral of Archimedes achieved a maximum tracking error of 2.9%.

Efficacy and safety of low dose aspirin plus clopidogrel in the treatment of elderly patients with symptomatic intracranial artery stenosis.

Background: As one of the most common causes of stroke, symptomatic intracranial artery stenosis (sICAS) is a great threat to public health, and its financial burden is substantial, with annual direct high medical costs particularly in China. Currently, the long-term use of conventional dual antiplatelet therapy (DAPT) as the primary modality of treatment for sICAS decreases the risk of stroke recurrence but increases the risk of bleeding. We aimed to evaluate the efficacy and safety of low dose aspirin plus clopidogrel for the treatment of sICAS in the elderly population. Methods: This randomized, controlled study included 181 older patients with transient ischemic attack (TIA) or ischemic stroke (IS) attributed to sICAS, who were recruited between April 2015 and November 2020. The 90 patients assigned to the low dose therapy group included aspirin, 75 mg, plus clopidogrel, 50 mg, daily for 90 and 91 patients assigned to the conventional group included aspirin, 100 mg, plus clopidogrel, 75 mg, daily for 90 days (aspirin or clopidogrel alone daily thereafter) were included in this intention-to-treat analysis. Efficacy and safety analyses were done in this trial. Results: One hundred eighty-one eligible elderly patients with sICAS were enrolled in this trial. The median age was 70 years ranged 60-83 years. Seventy-five participants were with TIA and 106 with IS. The median time of follow-up was 30 months ranged 1-36 months. Ninety patients were assigned randomly to the low dose group and 91 patients to the conventional group. The rate of primary, secondary and composite efficacy were not significantly different between the low dose and conventional group (P > 0.05). The rate of composite safety outcome was 7.8% (7/90) in the low dose group, which was lower than 17.6% (16/91) in the conventional group (χ2 = 3.921, P = 0.048). At the time of last follow-up, 17 (9.4%) of 181 patients developed GI injuries, which occurred in four (4.4%) of 90 patients in the low dose group and in 13 (14.3%) of 91 patients in the conventional group (χ2 = 4.058, P = 0.044). The primary efficacy outcome occurred in six (18.2%) of 33 patients with severe sICAS and in 22 (38.6%) of 57 patients with moderate sICAS (χ2 = 4.064, P = 0.044) in the low dose group. Conclusion: In this study, the safety of low dose aspirin combined with clopidogrel proved to be equally efficient and significantly safer than those of conventional dose within 24 months in elderly patients with sICAS. However, the small size of this study limits the validity of the results. Further larger longitudinal and randomized controlled trials are necessary to evaluate the role of low dose DAPT in the patients with sICAS.

Computational mining of GeH-based Janus III-VI van der Waals heterostructures for solar cell applications.

The asymmetrical group III-VI monolayer Janus M2XY (M = Al, Ga, In; X ≠ Y = S, Se, Te) have attracted widespread attention due to their significant optical absorption properties, which are the potential building blocks for van der Waals (vdW) heterostructure solar cells. In this study, we unraveled an In2STe/GeH vdW heterostructure as a candidate for solar cells by screening the Janus M2XY and GeH monolayers on lattice mismatches and electronic band structures based on first-principles calculations. The results highlight that the In2STe/GeH vdW heterostructure exhibits a type-II band gap of 1.25 eV. The optical absorption curve of the In2STe/GeH vdW heterostructure indicates that it possesses significant optical absorption properties in the visible and ultraviolet light areas. In addition, we demonstrate that the In2STe/GeH vdW heterostructure shows high and directionally anisotropic carrier mobility and good stability. Furthermore, strain engineering improves the theoretical power conversion efficiency of the In2STe/GeH vdW heterostructure up to 19.71%. Our present study will provide an idea for designing Janus M2XY and GeH monolayer-based vdW heterostructures for solar cell applications.

Responses of Bacterial Community Structure, Diversity, and Chemical Properties in the Rhizosphere Soil on Fruiting-Body Formation of Suillus luteus.

Mycorrhiza helper bacteria (MHB) play an important role in driving mycorrhizal formation. There are few reports on the relationship between bacteria and fruiting growths. Taking mycorrhizal rhizosphere soil from sporocarps of the S. luteus and non-mycorrhizal rhizosphere soil of the host plant (Larix gmelinii), we measured the bacterial community structure and diversity and chemical properties to clarify the effect of bacteria on fruiting-body formation. The bacterial diversity was significantly higher in mycorrhizal rhizosphere soil (p < 0.05) than that in non-mycorrhizal rhizosphere soil. The relative abundance of Burkholderia, Bradyrhizobium, Pseudomonas, and Rhizobium was significantly higher (p < 0.05) in mycorrhizal rhizosphere soil than in non-mycorrhizal rhizosphere soil. The soil organic matter (SOM), total nitrogen (TN), total phosphorus (TP), total potassium (TK), ammonium nitrogen (AN), available phosphorus (AP), available potassium (AK), and the activity of catalase, urease, and phosphatase in mycorrhizal rhizosphere soil were significantly higher (p < 0.05) than those in non-mycorrhizal rhizosphere soil. A redundancy analysis (RDA) showed that dominant bacteria are closely related to soil enzyme activity and physicochemical properties (p < 0.05). The boletus recruits a large number of bacteria around the plant roots that speed up nutrient transformation and increase the soil nutrient content, providing an important guarantee for mycelium culture and fruiting-body formation. These findings provide ideas for the nutritional supply of boletus sporocarps and lay the theoretical foundation for the efficient artificial cultivation of boletus.

Case Study of a MEMS Snap-Through Actuator: Modeling and Fabrication Considerations.

MEMS actuators rely on the deformation of silicon structures. Using dimensions smaller than dozens of micrometers reveals that the micro-electro-mechanical systems (MEMS) actuators are affected by fabrication inaccuracies, leading to hardly predictable forces and/or actuation results. In this paper, MEMS bistable buckled beam actuators are presented. A series of structures based on pre-shaped buckled beams of lengths ranging from 2 to 4 mm, constant width of 5 µm and actuation stroke ranging from 20 to 100 µm was fabricated. Experimental data show a significant difference with predictions from a conventional analytical model. The model commonly used for buckled beams design assumes a rectangular beam section, but it is not the case of the fabricated beams. Furthermore, only symmetric buckling modes (mode 1, mode 3…) are supposed to exist during snap-through. In this paper, new analytical models have been developed on the basis of the models of the literature to consider the effective beam shape. The first improved analytical model enabled prediction of the MEMS buckled beams mechanical behavior in a 30% margin on the whole range of operation. A second model has been introduced to consider both the effective shape of the beam and centro-symmetric buckling modes. This refined model exhibits the partial suppression of buckling mode 2 by a central shuttle. Therefore, mode 2 and mode 3 coexist at the beginning and the end of snap-through, while mode 3 quickly vanishes due to increasing rotation of the central shuttle to leave exclusive presence of mode 2 near the mid-stroke. With this refined model, the effective force-displacement curve can be predicted in a margin reduced to a few percentages in the center zone of the response curve, allowing the accurate prediction of the position switch force. In addition, the proposed model allows accurate results to be reached with very small calculation time.

Synthesis of α-Amino Tertiary Alkylperoxides by Lewis Acid-Catalyzed Peroxidation of 1,3,5-Triazines.

α-Substituted peroxides have been found in natural products and are widely used as anti-malarial agents. Zn(OTf)2 -catalyzed peroxidation of 1,3,5-triazines has been developed, accessing diversely substituted α-amino tertiary alkylperoxides with high efficiency. Mechanistic investigations and useful synthetic application of the products have also been presented.

Design, synthesis and anti-tumor evaluation of 1,2,4-triazol-3-one derivatives and pyridazinone derivatives as novel CXCR2 antagonists.

Chemokine receptor 2 (CXCR2) is the receptor of glutamic acid-leucine-arginine sequence-contained chemokines CXCs (ELR+ CXCs). In recent years, CXCR2-target treatment strategy has come a long way in cancer therapy. CXCR2 antagonists could block CXCLs/CXCR2 axis, and are widely used in regulating immune cell migration, tumor metastasis, apoptosis and angiogenesis. Herein, two series of new CXCR2 small-molecule inhibitors, including 1,2,4-triazol-3-one derivatives 1-11 and pyridazinone derivatives 12-22 were designed and synthesized based on the proof-to-concept. The pyridazinone derivative 18 exhibited good CXCR2 antagonistic activity (69.4 ± 10.5 %Inh at 10 µM) and demonstrated its significant anticancer metastasis activity in MDA-MB-231 cells and remarkable anti-angiogenesis activity in HUVECs. Furthermore, noteworthy was that 18 exhibited an obvious synergistic effect with Sorafenib in anti-proliferation assay in MDA-MB-231 cells. Moreover, 18 showed a distinct reduction of the phosphorylation levels of both PI3K and AKT proteins in MDA-MB-231 cells, and also affected the expression levels of other PI3K/AKT signaling pathway-associated proteins. The molecular docking studies of 18 with CXCR2 also verified the rationality of our design strategy. All of these results revealed pyridazinone derivative 18 as a promising CXCR2 antagonist for future cancer therapy.

Discovery of the PARP (poly ADP-ribose polymerase) inhibitor 2-(1-(4,4-difluorocyclohexyl)piperidin-4-yl)-1H-benzo[d]imidazole-4-carboxamide for the treatment of cancer.

In this work, two series of cyclic amine-containing benzimidazole carboxamide derivatives were designed and synthesized as potent anticancer agents. PARP1/2 inhibitory activity assays indicated that most of the compounds showed significant activity. The in vitro antiproliferative activity of these compounds was investigated against four human cancer cell lines (MDA-MB-436, MDA-MB-231, MCF-7 and CAPAN-1), and several compounds exhibited strong cytotoxicity to tumor cells. Among them, 2-(1-(4,4-difluorocyclohexyl)piperidin-4-yl)-1H-benzo[d]imidazole-4-carboxamide (17d) was found to be effective PARP1/2 inhibitors (IC50 = 4.30 and 1.58 nM, respectively). In addition, 17d possessed obvious selective antineoplastic activity and noteworthy microsomal metabolic stability. What's more, further studies revealed that 17d was endowed with an excellent ADME profile. These combined results indicated that 17d could be a promising candidate for the treatment of cancer.

Design, synthesis and evaluation of novel ErbB/HDAC multitargeted inhibitors with selectivity in EGFRT790M mutant cell lines.

Acquired resistance leads to the failure of EGFR TKIs in NSCLC treatment. A novel series of hydroxamic acid-containing 4-aminoquinazoline derivatives as irreversible ErbB/HDAC multitargeted inhibitors for NSCLC therapy had been designed and synthesized, which displayed weak anti-proliferative activity in several EGFR wild-type cancer cell lines (NCI-H838, SK-BR-3, A549, A431) yet retained moderate activity to EGFRT790M resistance mutation harboring NCI-H1975 cells. The mechanistic studies revealed that the representative compound 11e was able to inhibit the phosphorylation of EGFR, up-regulate hyperacetylation of histone H3 and even reduce the expression of EGFR and Akt in NCI-H1975 cells. In further assays, compound 11e also showed moderate anti-proliferative activity in other EGFRT790M harboring tumor cell lines (NCI-H820, Ba/F3_EGFR_Del19-T790M-C797S) and low toxicities in normal cell lines (HL-7702, FHC). This selectivity of designed multitargeted compounds could serve as a potential strategy to circumvent multiple mechanisms of acquired resistance to EGFR-targeted therapy without severe toxicities and side effects resulting from broad inhibition.

Cost-effectiveness analysis of etanercept plus methotrexate vs triple therapy in treating Chinese rheumatoid arthritis patients.

OBJECTIVE: This study aimed to explore the cost-effectiveness of etanercept plus methotrexate (ETN+MTX) compared to triple disease-modifying anti-rheumatic drugs (DMARDs) in treating Chinese rheumatoid arthritis (RA) patients. METHODS: The 134 Chinese RA patients who were about to initiate ETN+MTX or triple DMARDs therapy based on treat-to-target strategy were consecutively recruited and categorized into ETN+MTX group (N = 49) or triple DMARDs group (N = 85). Treatment efficacy was assessed at month 3 (M3)/M6/M9/M12 after initiation of treatment. Also, 1-year treatment cost was evaluated, and cost-effectiveness analysis and sensitivity analysis were conducted. RESULTS: RA patients in ETN+MTX group exhibited similar disease activity and quality of life at each time point while elevated 28-joint disease activity score based on erythrocyte sedimentation rate (DAS28-ESR) change (M0-M12) and low disease activity rate compared with triple DMARDs group. For 1-year treatment cost, ETN+MTX required increased drug cost, decreased other medical cost, and finally elevated total cost compared with triple DMARDs. Meanwhile, compared to triple DMARDs, ETN+MTX produced an additional quality-adjusted life year (QALY) of 0.015, resulting in an incremental cost-effectiveness ratio (ICER) of ¥2,939,506.7 per QALY that was 53.1 folds of gross domestic product (GDP) per capita in China. More interestingly, sensitivity analysis revealed that the ETN price had to be reduced at least by 71.3% before ETN+MTX became cost-effectiveness compared to triple DMARDs. CONCLUSION: ETN+MTX is less cost-effective in treating Chinese RA patients compared with triple DMARDs.

A Novel, Portable and Fast Moisture Content Measuring Method for Grains Based on an Ultra-Wideband (UWB) Radar Module and the Mode Matching Method.

To perform fast and portable grain moisture measurements under field conditions, a novel moisture sensor was designed, which consisted of a coaxial waveguide, a circular waveguide, and an isolation layer. The electromagnetic characteristics of the sensor were simulated and measured. The analytical model, which represented the relationship between the reflection coefficient of the sensor and the complex permittivity of grain, was established by using the mode matching method. The reflection coefficient of the sensor was measured by using an ultra-wideband (UWB) radar module, and the moisture content of grains was calculated from the complex permittivity by using density-independent model. To verify the performance of the proposed method, wheat, rough rice, and barley were taken as examples. The measured results in the range from 1.0% to 26.0%, wet basis, agreed well with the reference values (R2 was more than 0.99), and the maximum absolute errors for wheat, rough rice, and barley were 1.1%, 1.0%, and 1.4%, respectively. In addition, the effect of isolation layer was discussed. Both the simulation results and the experimental results showed that the isolation layer improved the stability of sensor.

Clinical efficacy and safety of gemcitabine plus nedaplatin in the treatment of advanced nasopharyngeal carcinoma.

OBJECTIVE: The purpose was to explore the clinical effects and safety of gemcitabine plus nedaplatin in the treatment of advanced nasopharyngeal carcinoma. MATERIALS AND METHODS: From March 2014 to August 2015, we recruited 63 advanced nasopharyngeal carcinoma patients in our hospital. Moreover, the 62 cases were randomly divided into control group (n = 31) and treatment group (n = 32). Patients in the control groups were treated with 5-fluorouracil 500 mg/m 2 + 500 ml 0.9% sodium chloride injection intervenous drop infusion in day 1-5 plus cisplatin 20 mg/m 2 + 500 ml 0.9% sodium chloride injection intervenous drop infusion in day 1-5 with 21 days per cycle for 3 cycles; Moreover, patients in the treatment group were given gemcitabine 1000 mg/m 2 + 500 ml 0.9% sodium chloride injection intervenous drop infusion in day 1 and 8 plus nedaplatin 20 mg/m 2 + 500 ml 0.9% sodium chloride injection intervenous drop infusion in day 1 with 21 days per cycle for 3 cycles. The objective response rate (ORR) and chemotherapy-associated toxicities were compared between the two groups. RESULTS: After 3 cycle chemotherapy, the ORR was 41.9% and 78.1% in the control and treatment group, respectively, with statistical difference (P < 0.05); The main chemotherapy-related toxicity were hematological toxicity and gastrointestinal reaction with no statistical difference between the two groups (P > 0.05). CONCLUSION: The ORR was relative high for gemcitabine plus nedaplatin in the treatment of advanced nasopharyngeal carcinoma with main toxicity of hematological toxicity and gastrointestinal reaction.

[CT/MRI image characteristics of iliopsoas bursitis in avascular necrosis of femoral head].

OBJECTIVE: To investigate the spectrum of CT and MR imaging and surgical operation findings in iliopsoas bursitis in patients with avascular necrosis of femoral head so as to enhance the diagnostic ability. METHODS: A total of 1,415 patients with avascular necrosis of the femoral head were analyzed retrospectively; of them, 15 patients were complicated by iliopsoas bursitis surgically or aspiration of synovial fluid between May 2005 and May 2007. Fifteen cases were all necrosis of the bilateral femoral head and 17 hips were combined with iliopsoas bursitis. There were 14 males and 1 female, aging 29-58 years. The course of disease was 1 month to 3 years. All 15 patients had limitation of ability of the hips and the "4" type sign was positive. The Harris score of hip's function was 54-78 (mean 62.7). Five patients of them can be touched a palpable cystic mass and tenderness in the inguinal area, and 3 of them associated with femoral neuropathy and 2 patients presented slight atrophy of the thigh muscle in suffering side. All these cases were taken X-ray films of positive and frog-leg lateral position, helical CT scan with 5 mm thinness, and MRI was performed in 6 patients with TlWI, T2WI, T2WI and fat-saturated inversion recovery sequence. RESULTS: The radiographs were the primary basis evidences for diagnosis and degrees of the avascular necrosis of femoral head. According to the standards of Association Research Circulation Osseuse, there were 2 hips at stage II (II C 2), 6 hips at stage III ( II B 1, III C 5 and 9 hips at stage IV. The X-ray films showed the bulging of the fat pad and soft tissue swelling in 6 patients. CT analysis disclosed that the enlarged iliopsoas bursae appeared as hypodense, well-defined, thin-walled (< 2 mm) cystic structures. The content of the examined bursae was homogeneous with a CT density of ranging from 12.7 to 41.2 Hu, showing fluid collection. They were round or oval in shape medial to the iliopsoas, exhibiting inyvrted water-drop cystic shadow just inferior to the femoral head. Slight contrast enhancement of the bursal wall was seen after contrast agent administration in 3 cases. MRI demonstrated that the iliopsoas bursitis presented as low signal on T1WI and water-like high signal on T2WI and markedly higher signal on STIR in 6 cases. The demonstration of the extent, size, mass effects and its relation and subsequent affection to surrounding anatomical structures were clearly shown by MRI, and by the communications between the il opsoas bursa and the adjacent hip joint. CONCLUSION: In the diagnosis of avascular necrosis of femoral head with imaging approaches, much attention should be paid to the abnormalities around the articular capsule to early identify iliopsoas bursitis for further management.