Combined treatment with silibinin and either sorafenib or gefitinib enhances their growth-inhibiting effects in hepatocellular carcinoma cells

Background/AimsSilibinin, the main component of silymarin, is used as a hepatoprotectant and exhibits anticancer effects against various cancer cells. This study evaluated the effects of a combination of silibinin with either gefitinib or sorafenib on hepatocellular carcinoma (HCC) cells.MethodsSeveral different human HCC cell lines were used to test the growth-inhibiting effects and cell toxicity of silibinin both alone and in combination with either gefitinib or sorafenib. The cell viability and growth inhibition were assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, trypan blue staining, and a colony-forming assay. Furthermore, changes in epidermal growth factor receptor (EGFR)-related signals were evaluated by Western blot analysis.ResultsGefitinib, sorafenib, and silibinin individually exhibited dose-dependent antiproliferative effects on HCC cells. Combined treatment with silibinin enhanced the gefitinib-induced growth-inhibiting effects in some HCC cell lines. The combination effect of gefitinib and silibinin was synergistic in the SNU761 cell line, but was only additive in the Huh-BAT cell line. The combination effect may be attributable to inhibition of EGFR-dependent Akt signaling. Enhanced growth-inhibiting effects were also observed in HCC cells treated with a combination of sorafenib and silibinin.ConclusionsCombined treatment with silibinin enhanced the growth-inhibiting effects of both gefitinib and sorafenib. Therefore, the combination of silibinin with either sorafenib or gefitinib could be a useful treatment approach for HCC in the future

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Inflammation-related immune proteins in maternal plasma as potential predictive biomarkers for rescue cerclage outcome in women with cervical insufficiency

© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.Problem: This study aimed to determine whether various novel plasma mediators of immune regulation associated with inflammation could independently predict the clinical outcome of rescue cerclage in patients with cervical insufficiency (CI). Method of study: A total of 41 singleton pregnant women (17–25 weeks) who underwent rescue cerclage for CI were retrospectively evaluated. Stored plasma samples were assayed for IGFBP-1, -2, -3, IL-6, latexin, LBP, lipocalin-2, M-CSF, MIP-1α, MMP-8, -9, pentraxin 3, resistin, S100A8, S100A8/A9, thrombospondin-2, TIMP-1, and TNFR2 levels. The primary outcome measures were spontaneous preterm birth (SPTB) at < 28 and < 34 weeks after cerclage placement. Results: Multivariate Firth's logistic regression analysis revealed that high levels of IGFBP-3 and S100A8/A9, and low levels of MIP-1α were significantly associated with SPTB at < 28 weeks after cerclage placement, whereas only low MIP-1α levels were significantly associated with SPTB at < 34 weeks, even after adjustment for baseline clinical covariates (e.g., cervical dilatation). For the prediction of SPTB at < 28 weeks, the area under the curves (AUC) of IGFBP-3, MIP-1α, and S100A8/A9 were of.686,.691, and.693, respectively. Similarly, the AUC of MIP-1 α was of.659 to predict SPTB at < 34 weeks. Conclusions: These findings suggest that plasma IGFBP-3, MIP-1α, and S100A8/A9 can represent noninvasive independent biomarkers for identifying women with CI at high risk for SPTB following rescue cerclage. Nonetheless, further in large, multicenter clinical studies should be performed to confirm the clinical value of these biomarkers.N

Thermoelectric characterization and fabrication of nanostructured p-type Bi0.5Sb1.5Te3 and n-type Bi2Te3 thin film thermoelectric energy generator with an in-plane planar structure

This paper presents in-plane bismuth-telluride-based thermoelectric (TE) energy generators fabricated using metal-shadow and radio-frequency sputtering methods at room temperature. The TE energy generators consist of four couples of 300-nm-thick nanostructured Bi2Te3 (n-BT) and Bi0.5Sb1.5Te3 (p-BST) thin films used as n-type and p-type materials, respectively, on a Si substrate for the p/n junctions of the TE energy generators. Furthermore, the effect of annealing treatment of both n-BT and p-BST thin films on the electrical and TE properties as well as the TE performance of the TE energy generators is discussed. By varying the temperature between the hot and cold junction legs of the n-BT/p-BST in-plane TE energy generators annealed at 200 °C, the maximum output voltage and power are determined to be ∼3.6 mV and ∼1.1 nW, respectively, at a temperature difference of 50 K. The output powers increased by ∼590% compared to that of the as-grown TE generator at a temperature difference of 90 K. This improvement in the TE performance is attributed to the enhancement of the electrical conductivity after heat treatment. From a numerical simulation conducted using a commercial software (COMSOL), we are confident that it plays a crucial role in determining the dimension (i.e., thickness of each leg) and material properties of both n-BT and p-BST materials of the in-plane TE energy generators

Eco-Friendly Water-Processable Polyimide Binders with High Adhesion to Silicon Anodes for Lithium-Ion Batteries

Silicon is an attractive anode material for lithium-ion batteries (LIBs) because of its natural abundance and excellent theoretical energy density. However, Si-based electrodes are difficult to commercialize because of their significant volume changes during lithiation that can result in mechanical damage. To overcome this limitation, we synthesized an eco-friendly water-soluble polyimide (W-PI) precursor, poly(amic acid) salt (W-PAmAS), as a binder for Si anodes via a simple one-step process using water as a solvent. Using the W-PAmAS binder, a composite Si electrode was achieved by low-temperature processing at 150 °C. The adhesion between the electrode components was further enhanced by introducing 3,5-diaminobenzoic acid, which contains free carboxylic acid (–COOH) groups in the W-PAmAS backbone. The –COOH of the W-PI binder chemically interacts with the surface of Si nanoparticles (SiNPs) by forming ester bonds, which efficiently bond the SiNPs, even during severe volume changes. The Si anode with W-PI binder showed improved electrochemical performance with a high capacity of 2061 mAh g−1 and excellent cyclability of 1883 mAh g−1 after 200 cycles at 1200 mA g−1. Therefore, W-PI can be used as a highly effective polymeric binder in Si-based high-capacity LIBs

Targeting FLT3-TAZ signaling to suppress drug resistance in blast phase chronic myeloid leukemia

BackgroundAlthough the development of BCR::ABL1 tyrosine kinase inhibitors (TKIs) rendered chronic myeloid leukemia (CML) a manageable condition, acquisition of drug resistance during blast phase (BP) progression remains a critical challenge. Here, we reposition FLT3, one of the most frequently mutated drivers of acute myeloid leukemia (AML), as a prognostic marker and therapeutic target of BP-CML.MethodsWe generated FLT3 expressing BCR::ABL1 TKI-resistant CML cells and enrolled phase-specific CML patient cohort to obtain unpaired and paired serial specimens and verify the role of FLT3 signaling in BP-CML patients. We performed multi-omics approaches in animal and patient studies to demonstrate the clinical feasibility of FLT3 as a viable target of BP-CML by establishing the (1) molecular mechanisms of FLT3-driven drug resistance, (2) diagnostic methods of FLT3 protein expression and localization, (3) association between FLT3 signaling and CML prognosis, and (4) therapeutic strategies to tackle FLT3+ CML patients.ResultsWe reposition the significance of FLT3 in the acquisition of drug resistance in BP-CML, thereby, newly classify a FLT3+ BP-CML subgroup. Mechanistically, FLT3 expression in CML cells activated the FLT3-JAK-STAT3-TAZ-TEAD-CD36 signaling pathway, which conferred resistance to a wide range of BCR::ABL1 TKIs that was independent of recurrent BCR::ABL1 mutations. Notably, FLT3+ BP-CML patients had significantly less favorable prognosis than FLT3- patients. Remarkably, we demonstrate that repurposing FLT3 inhibitors combined with BCR::ABL1 targeted therapies or the single treatment with ponatinib alone can overcome drug resistance and promote BP-CML cell death in patient-derived FLT3+ BCR::ABL1 cells and mouse xenograft models.ConclusionHere, we reposition FLT3 as a critical determinant of CML progression via FLT3-JAK-STAT3-TAZ-TEAD-CD36 signaling pathway that promotes TKI resistance and predicts worse prognosis in BP-CML patients. Our findings open novel therapeutic opportunities that exploit the undescribed link between distinct types of malignancies