The pan-inhibitor of Aurora kinases danusertib induces apoptosis and autophagy and suppresses epithelial-to-mesenchymal transition in human breast cancer cells

Danusertib (Danu) is a pan-inhibitor of Aurora kinases and a third-generation breakpoint cluster region-Abelson murine leukemia viral oncogene homolog 1 (Bcr-Abl) tyrosine kinase inhibitor, but its antitumor effect and underlying mechanisms in the treatment of human breast cancer remain elusive. This study aimed to investigate the effects of Danu on the growth, apoptosis, autophagy, and epithelial-to-mesenchymal transition (EMT) and the molecular mechanisms in human breast cancer MCF7 and MDA-MB-231 cells. The results demonstrated that Danu remarkably inhibited cell proliferation, induced apoptosis and autophagy, and suppressed EMT in both breast cancer cell lines. Danu arrested MCF7 and MDA-MB-231 cells in G2/M phase, accompanied by the downregulation of cyclin-dependent kinase 1 and cyclin B1 and upregulation of p21 Waf1/Cip1, p27 Kip1, and p53. Danu significantly decreased the expression of B-cell lymphoma-extra-large (Bcl-xl) and B-cell lymphoma 2 (Bcl-2), but increased the expression of Bcl-2-associated X protein (Bax) and p53-upregulated modulator of apoptosis (PUMA), and promoted the cleavage of caspases 3 and 9. Furthermore, Danu significantly increased the expression levels of the membrane-bound microtubule-associated protein 1A/1B-light chain 3 (LC3-II) and beclin 1 in breast cancer cells, two markers for autophagy. Danu induced the activation of p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinases 1 and 2 (Erk1/2) and inhibited the activation of protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathways in breast cancer cells. Treatment with wortmannin (a phosphatidylinositol 3-kinase inhibitor) markedly inhibited Danu-induced activation of p38 MAPK and conversion of cytosolic LC3-I to membrane-bound LC3-II. Pharmacological inhibition and small interfering RNA-mediated knockdown of p38 MAPK suppressed Akt activation, resulting in LC3-II accumulation and enhanced autophagy. Pharmacological inhibition and small interfering RNA-mediated knockdown of Erk1/2 also remarkably increased the level of LC3-II in MCF7 cells. Moreover, Danu inhibited EMT in both MCF7 and MDA-MB-231 cells with upregulated E-cadherin and zona occludens protein 1 (ZO-1) but downregulated N-cadherin, zinc finger E-box-binding homeobox 1 (TCF8/ZEB1), snail, slug, vimentin, and β-catenin. Notably, Danu showed lower cytotoxicity toward normal breast epithelial MCF10A cells. These findings indicate that Danu promotes cellular apoptosis and autophagy but inhibits EMT in human breast cancer cells via modulation of p38 MAPK/Erk1/2/Akt/mTOR signaling pathways. Danu may represent a promising anticancer agent for breast cancer treatment. More studies are warranted to fully delineate the underlying mechanisms, efficacy, and safety of Danu in breast cancer therapy

Recent advances in crystalline oxidopolyborate complexes of d-block or p-block metals: structural aspects, syntheses and physical properties

Crystalline materials containing hybrid inorganic–organic metal borates (complexes with oxidoborate ligands) display a variety of novel framework building blocks. The structural aspects of these hybrid metallaoxidoborates containing Cd(II), Co(II), Cu(II), Ga(III), In(III), Mn(II), Ni(II) or Zn(II) metal centers are discussed in this review. The review describes synthetic approaches to these hybrid materials, their physical properties, their spectroscopic properties and their potential applications

Sample Enrichment via Temporary Operations on Subsequences for Sequential Recommendation

Sequential recommendation leverages interaction sequences to predict forthcoming user behaviors, crucial for crafting personalized recommendations. However, the true preferences of a user are inherently complex and high-dimensional, while the observed data is merely a simplified and low-dimensional projection of the rich preferences, which often leads to prevalent issues like data sparsity and inaccurate model training. To learn true preferences from the sparse data, most existing works endeavor to introduce some extra information or design some ingenious models. Although they have shown to be effective, extra information usually increases the cost of data collection, and complex models may result in difficulty in deployment. Innovatively, we avoid the use of extra information or alterations to the model; instead, we fill the transformation space between the observed data and the underlying preferences with randomness. Specifically, we propose a novel model-agnostic and highly generic framework for sequential recommendation called sample enrichment via temporary operations on subsequences (SETO), which temporarily and separately enriches the transformation space via sequence enhancement operations with rationality constraints in training. The transformation space not only exists in the process from input samples to preferences but also in preferences to target samples. We highlight our SETO's effectiveness and versatility over multiple representative and state-of-the-art sequential recommendation models (including six single-domain sequential models and two cross-domain sequential models) across multiple real-world datasets (including three single-domain datasets, three cross-domain datasets and a large-scale industry dataset).Comment: 12 pages, 6 figure

Short Intussusception Valves Prevent Reflux After Jejunal Interposition Bilioduodenal Anastomosis

Short whole circumference and semi-circumference intussusception valves were created in interposition cholecysto-jejunal-duodenal conduits in pigs to determine which method best prevented gastrointestinal reflux into the biliary tract. Following intravenous injection of 99 mTc-HIDA the time interval for its excretion from the liver and appearance in the duodenum was not different in either whole or semi-circumference valve animals or in controls without valves. After intragastric administration of 99 mTc-DTPA the relative radioactivity of gallbladder contents (reflux) in the cohort without valves was significantly higher than in both cohorts with valves. Animals with semi-circumferential valves in turn had significantly higher levels of nuclide than those with whole circumference valves. Reflux was observed grossly in 100% of animals without valves, in 20% of those with semi-circumference valves, and in no animals with whole circumference valves. This study indicates that both Whole and semi-circumference intussusception valves placed in jejunal biliary conduits allow unimpeded flow of bile into the gastrointestinal tract. Whole circumference valves are more effective for prevention of reflux than semi-circumferential valves

On the efficacy of anthracene isomers for triplet transmission from CdSe nanocrystals

The effect of isomeric substitutions on the transmitter for triplet energy transfer (TET) between nanocrystal (NC) donor and molecular acceptor is investigated. Each isomeric acceptor is expected to bind in a unique orientation with respect to the NC donor. We see that this orbital overlap drastically affects the transmission of triplets. Here, two functional groups, the carboxylic acid and dithiocarbamate, were varied between the 1-, 2- and 9-positions of the anthracene ring to give three ACA and three ADTC isomers. These six anthracene isomers served as transmitters for triplets between CdSe NC sensitizers and 9,10-diphenylanthracene annihilators for photon upconversion. The photon upconversion quantum yield (QY) is the highest for 9-ACA (12%), lowest for 9-ADTC (0.1%), around 3% for both 1-ACA and 1-ADTC, and about 1% for the 2-isomers. These trends in QYs are reflected in the rates of TET given by ultrafast transient absorption spectroscopy where a maximum of 3.8 × 107 s−1 for 9-ACA was measured. Molecular excited state energy levels were measured both in solution and polymer hosts to correlate structure to TET. This work confirms that anthracene excited states levels are very sensitive to molecular substitution, which in combination with orbital overlap, critically affect Dexter-based TET.Instituto de Investigaciones Fisicoquímicas Teóricas y Aplicada

Real-world analysis of community colorectal neoplasia screening based on stool DNA methylation detection

This study aimed to assess the effectiveness of stool DNA methylation detection (sDNAMD) in improving colorectal neoplasia (CN) detection rates and colonoscopy compliance in a real-world community setting. Between July 1, 2023, and June 30, 2024, residents aged 50–75 from Maqiao Town, Minhang District, Shanghai, were invited to participate in a CN screening program. Participants were randomly assigned to one of three groups: high-risk questionnaire + fecal occult blood test (HRFO), high-risk questionnaire + FOBT + sDNAMD (HRFOsD), or sDNAMD only (sDNA). Colonoscopy was performed based on initial screening results, and the number of individuals undergoing colonoscopy, along with results, were recorded to calculate compliance and CN detection rates. The HRFOsD group exhibited a significantly higher colonoscopy compliance rate (93.7%) compared to the HRFO (32.6%) and sDNA (73.5%) groups (P<0.0001). Residents with negative FOBT, negative sDNA results, or those who did not undergo sDNA testing did not undergo colonoscopy. In the HRFOsD group, the CN detection rate was higher in females compared to males. Compared to the HR and FOBT+ group, the CN detection rate was significantly higher in the LR and FOBT+ and sDNA+ group. Adding sDNAMD to the high-risk questionnaire and FOBT screening led to a notable increase in both colonoscopy compliance and CN detection rates. The conclusion is that adding stool DNA methylation detection to the community FOBT screening program can significantly improve colonoscopy compliance and colorectal neoplasia detection rates among community residents