Loss of PTEN tumor suppressor enhances metastatic risk in breast cancer, although the underlying mechanisms are poorly defined. We report that homozygous deletion of PTEN in mammary epithelial cells ...induces tubulin-based microtentacles (McTNs) that facilitate cell reattachment and homotypic aggregation. Treatment with contractility-modulating drugs showed that McTNs in PTEN(-/-) cells are suppressible by controlling the actin cytoskeleton. Because outward microtubule extension is counteracted by actin cortical contraction, increased activity of actin-severing proteins could release constraints on McTN formation in PTEN(-/-) cells. One such actin-severing protein, cofilin, is activated in detached PTEN(-/-) cells that could weaken the actin cortex to promote McTNs. Expression of wild-type cofilin, an activated mutant (S3A), and an inactive mutant (S3E) demonstrated that altering cofilin phosphorylation directly affects McTNs formation. Chemical inhibition of PI3K did not reduce McTNs or inactivate cofilin in PTEN(-/-) cells. Additionally, knock-in expression of the two most common PI3K-activating mutations observed in human cancer patients did not increase McTNs or activate cofilin. PTEN loss and PI3K activation also caused differential activation of the cofilin regulators, LIM-kinase1 (LIMK) and Slingshot-1L (SSH). Furthermore, McTNs were suppressed and cofilin was inactivated by restoration of PTEN in the PTEN(-/-) cells, indicating that both the elevation of McTNs and the activation of cofilin are specific results arising from PTEN loss. These data identify a novel mechanism by which PTEN loss could remodel the cortical actin network to facilitate McTNs that promote tumor cell reattachment and aggregation. Using isogenic MCF-10A PTEN(-/-) and PIK3CA mutants, we have further demonstrated that there are clear differences in activation of cofilin, LIMK and SSH between PTEN loss and PI3K activation, providing a new evidence that these mutations yield distinct cytoskeletal phenotypes, which could have an impact on tumor biology.
Fertilin, a member of the ADAM family, is found on the plasma membrane of mammalian sperm. Sperm from mice lacking fertilin β were shown to be deficient in sperm-egg membrane adhesion, sperm-egg ...fusion, migration from the uterus into the oviduct, and binding to the egg zona pellucida. Egg activation was unaffected. The results are consistent with a direct role of fertilin in sperm-egg plasma membrane interaction. Fertilin could also have a direct role in spermzona binding or oviduct migration; alternatively, the effects on these functions could result from the absence of fertilin activity during spermatogenesis.
De novo variants in the gene encoding cyclin‐dependent kinase 13 (CDK13) have been associated with congenital heart defects and intellectual disability (ID). Here, we present the clinical assessment ...of 15 individuals and report novel de novo missense variants within the kinase domain of CDK13. Furthermore, we describe 2 nonsense variants and a recurrent frame‐shift variant. We demonstrate the synthesis of 2 aberrant CDK13 transcripts in lymphoblastoid cells from an individual with a splice‐site variant. Clinical characteristics of the individuals include mild to severe ID, developmental delay, behavioral problems, (neonatal) hypotonia and a variety of facial dysmorphism. Congenital heart defects were present in 2 individuals of the current cohort, but in at least 42% of all known individuals. An overview of all published cases is provided and does not demonstrate an obvious genotype‐phenotype correlation, although 2 individuals harboring a stop codons at the end of the kinase domain might have a milder phenotype. Overall, there seems not to be a clinically recognizable facial appearance. The variability in the phenotypes impedes an à vue diagnosis of this syndrome and therefore genome‐wide or gene‐panel driven genetic testing is needed. Based on this overview, we provide suggestions for clinical work‐up and management of this recently described ID syndrome.
De novo CDK13 variants.
The Belle II experiment at the High Energy Accelerator Research Organization (KEK) in Japan started gathering data in Phase II in April 2018 to unravel new physics beyond the standard model by ...precisely measuring charge conjugation parity symmetry (CP) violation and rare weak decays of heavy quarks and leptons. It was performed at the SuperKEKB electron-positron collider mainly running at the <inline-formula> <tex-math notation="LaTeX">\Upsilon (4S) </tex-math></inline-formula> resonance energy with the goal to reach the maximum instantaneous luminosity of <inline-formula> <tex-math notation="LaTeX">8\times 10^{35} </tex-math></inline-formula> cm −2 s −1 . A new algorithm is needed to operate the Belle II calorimeter trigger system stably in the much higher luminosity and beam background environment of SuperKEKB compared with the KEKB collider. In order to develop an appropriate algorithm, a detailed simulation study of the Belle II calorimeter trigger system is crucial. In this article, we report the results of the simulation of the electromagnetic calorimeter (ECL) trigger using physics and beam background Monte Carlo (MC) events and compare them with the ECL trigger performance in the Phase II operation. The simulation package is developed with the Belle II Geant4-based analysis framework called Basf2.
Cancer still represents a major global health problem. All currently available anticancer agents have disadvantages like resistance or side effects. Therefore, introduction of novel anticancer agents ...is needed. Intrigued by the high success rate for natural products-based drug discovery, we designed and synthesized antiproliferative chemical entities as hybrids of two natural products; 3,5,4′-trimethoxystilbene and 5,6,7-trimethoxyflavone. To probe the spectrum of the synthesized compounds, in vitro evaluation was conducted against nine panels representing major cancer diseases. The results revealed the hybrid analogs 4f, 4h, 4k and 4q as promising broad-spectrum anticancer lead compounds eliciting high growth inhibition of several cell lines representing multiple cancers diseases. Evaluation of the promising lead compounds against normal human cell lines suggested a selective cytotoxic effect on cancer cells. Mechanistic investigation of the cytotoxic activity of compound 4f in human cervical cancer HeLa cells showed that it triggers cell death through induction of apoptosis. As a whole, this study presents the natural products hybrid analogs 4f, 4h, 4k and 4q as potential lead compounds for further development of novel anticancer therapeutics.
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•Design, synthesis and in vitro antiproliferative evaluation of 3,5,4′-trimethoxystilbene-5,6,7-trimethoxyflavone hybrids.•Compounds 4f, 4h, 4k and 4q elicited promising broad spectrum antiproliferative activity.•Compounds 4f, 4h, 4k and 4q were more selective to human cancer cells rather than normal human cells.•Compound 4f triggered cell death via induction of apoptosis in HeLa cells.•Compounds 4f, 4h, 4k and 4q might be potential leads for development of natural-products based anticancer agents.
Amongst different forms of leishmaniasis, visceral leishmaniasis caused by L. donovani is highly mortal. Identification of new hit compounds might afford new starting points to develop novel ...therapeutics. In this lieu, a rationally designed small library of bestatin analogs-4-quinolone hybrids were prepared and evaluated. Analysis of SAR unveiled distinct profiles for hybrids type 1 and type 2, which might arise from their different molecular targets. Amongst type 1 bestatin analog-4-quinolone hybrids, hybrid 1e was identified as potential hit inhibiting growth of L. donovani promastigotes by 91 and 53% at 50 and 25 μM concentrations, respectively. Meanwhile, hybrid 2j was identified amongst type 2 bestatin analog-4-quinolone hybrids as potential hit compound inhibiting growth of L. donovani promastigotes by 50 and 38% at 50 and 25 μM concentrations, respectively. Preliminary safety evaluation of the promising hit compounds showed that they are 50–100 folds safer against human derived monocytic THP-1 cells relative to the drug erufosine. In silico study was conducted to predict the possible binding of hybrid 1e with methionine aminopeptidases 1 and 2 of L. donovani. Molecular dynamic simulations verified the predicted binding modes and provide more in depth understanding of the impact of hybrid 1e on LdMetAP-1 and LdMetAP-2.
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•Design and synthesis and evaluation of bestatin analogs-4-quinolinone hybrids as antileishmanial agents.•Hybrid 1e was identified as a potential hit against of L. donovani.•Hybrid 1e was safe against used human cells.•In silico studies of hybrid 1e to get molecular insights.
Zinc oxide (ZnO) nanoparticle is one of the most important materials in diverse applications, since it has UV light absorption, antimicrobial, catalytic, semi-conducting, and magnetic properties. ...However, there is little information about the toxicological effects of ZnO nanoparticles with respect to physicochemical properties. The aim of this study was, therefore, to evaluate the relationships between cytotoxicity and physicochemical properties of ZnO nanoparticle such as particle size and surface charge in human lung cells. Two different sizes of ZnO nanoparticles (20 and 70 nm) were prepared with positive (+) or negative (−) charge, and then, cytotoxicity of different ZnO nanoparticles was evaluated by measuring cell proliferation in short-term and long-term, membrane integrity, and generation of reactive oxygen species (ROS). The results demonstrated that smaller particles exhibited high cytotoxic effects compared to larger particles in terms of inhibition of cell proliferation, membrane damage, and ROS generation. In addition, positively charged ZnO showed greater ROS production than ZnO with negative charge. These findings suggest that the cytoxicity of ZnO nanoparticles are strongly affected by their particle size and surface charge, highlighting the role of the physicochemical properties of nanoparticles to understand and predict their potential adverse effects on human.
Summary
Background
Epidemiologic studies have suggested that helminth infections play a protective role against allergy; this inverse association, however, has not been consistent. Clonorchis ...sinensis, the liver fluke of human, is prevalent in the Far East. The association between C. sinensis infection and allergy has not yet been reported.
Objective
We evaluated the association between clonorchiasis and atopy or allergic diseases in adults in endemic areas of clonorchiasis.
Methods
A total of 1116 subjects (males 419, females 697; age range, 30–86; mean age=61 years) were recruited from two endemic areas of C. sinensis in Korea. Clonorchiasis was confirmed by stool examination. Allergic symptoms were evaluated with a modified ISAAC questionnaire, and atopy was defined by skin prick test for common inhalant allergens. Total serum IgE and C. sinensis‐specific IgE level was measured by ELISA and methacholine bronchial provocation test was performed to evaluate airway hyperresponsiveness (AHR).
Results
Clonorchiasis was positively associated with atopy odds ratio (OR), 1.856; 95% confidence interval (CI), 1.199–2.873 and high levels of total serum IgE (OR, 1.455; 95% CI, 1.050–2.016). Higher association with clonorchiasis was shown in subjects who showed both atopy and high total serum IgE levels (OR, 2.540; 95% CI, 1.448–4.455). Clonorchiasis had no association with wheezing, AHR, asthma or allergic rhinitis.
Conclusion and Clinical Relevance
Clonorchiasis was positively associated with atopy in adults in endemic area.
Cite this as: M‐H Choi, Y‐S Chang, M. K. Lim, Y. M. Bae, S‐T Hong, J‐K Oh, E. H. Yun, M‐J Bae, H‐S Kwon, S‐M Lee, H‐W Park, K‐U Min, Y‐Y Kim and S‐H Cho, Clinical & Experimental Allergy, 2011 (41) 697–705.
Dishevelled (Dvl) is a key regulator of Wnt signaling both in the canonical and non-canonical pathways. Here we report the identification of a regulatory domain of ubiquitination (RDU) in the ...C-terminus of Dvl. Mutations in the RDU resulted in accumulation of polyubiquitinated forms of Dvl, which were mainly K63 linked. Small interfering RNA-based screening identified Usp14 as a mediator of Dvl deubiquitination. Genetic and chemical suppression of Usp14 activity caused an increase in Dvl polyubiquitination and significantly impaired downstream Wnt signaling. These data suggest that Usp14 functions as a positive regulator of the Wnt signaling pathway. Consistently, tissue microarray analysis of colon cancer revealed a strong correlation between the levels of Usp14 and β-catenin, which suggests an oncogenic role for Usp14 via enhancement of Wnt/β-catenin signaling.
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