Novel inhibitors of lysine (K)-specific Demethylase 4A with anticancer activity

Summary

Lysine (K)-specific demethylase 4A (KDM4A) is a histone demethylase that removes methyl residues from trimethylated or dimethylated histone 3 at lysines 9 and 36. Overexpression of KDM4A is found in various cancer types. To identify KDM4A inhibitors with anti-tumor functions, screening with an in vitro KDM4A enzyme activity assay was carried out. The benzylidenehydrazine analogue LDD2269 was selected, with an IC₅₀ of 6.56 μM of KDM4A enzyme inhibition, and the binding mode was investigated using in silico molecular docking. Demethylation inhibition by LDD2269 was confirmed with a cell-based assay using antibodies against methylated histone at lysines 9 and 36. HCT-116 colon cancer cell line proliferation was suppressed by LDD2269, which also interfered with soft-agar growth and migration of HCT-116 cells. AnnexinV staining and PARP cleavage experiments showed apoptosis induction by LDD2269. Derivatives of LDD2269 were synthesized and the structure–activity relationship was explored. LDD2269 is reported here as a strong inhibitor of KDM4A in in vitro and cell-based systems, with anti-tumor functions.

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Glaucoma and intraocular pressure in EPIC-Norfolk Eye Study: cross sectional study

Objectives To report the distribution of intraocular pressure (IOP) by age and sex and the prevalence of glaucoma.Design Community based cross sectional observational study.Setting EPIC-Norfolk...

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PD-1 status in CD8+ T cells associates with survival and anti-PD-1 therapeutic outcomes in head and neck cancer

Improved understanding of expression of immune checkpoint receptors (ICR) on tumor-infiltrating lymphocytes (TIL) may facilitate more effective immunotherapy in head and neck cancer (HNC) patients. A higher frequency of PD-1+ TIL has been reported in human papillomavirus (HPV)+ HNC patients, despite the role of PD-1 in T cell exhaustion. This discordance led us to hypothesize that the extent of PD-1 expression more accurately defines T cell function and prognostic impact, since PD-1high T cells may be more exhausted than PD-1low T cells and may influence clinical outcome and response to anti-PD-1 immunotherapy. In this study, PD-1 expression was indeed upregulated on HNC patient TIL, and the frequency of these PD-1+ TIL was higher in HPV+ patients (p = 0.006), who nonetheless experienced significantly better clinical outcome. However, PD-1high CD8+ TIL were more frequent in HPV- patients and represented a more dysfunctional subset with compromised IFN-γ secretion. Moreover, HNC patients with higher frequencies of PD-1high CD8+ TIL showed significantly worse disease free survival (DFS) and higher hazard ratio for recurrence (p<0.001), while higher fractions of PD-1low T cells associated with HPV positivity and better outcome. In a murine HPV+ HNC model, anti-PD-1 mAb therapy differentially modulated PD-1high/low populations, and tumor rejection associated with loss of dysfunctional PD-1high CD8+ T cells and a significant increase in PD-1low TIL. Thus, the extent of PD-1 expression on CD8+ TIL provides a potential biomarker for anti-PD-1 based immunotherapy.

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ANGPTL1 interacts with integrin {alpha}1{beta}1 to suppress HCC angiogenesis and metastasis by inhibiting JAK2/STAT3 signaling

Downregulation of tumor suppressor signaling plays an important role in the pathogenesis of hepatocellular carcinoma (HCC). Here we report that downregulation of the angiopoietin-like protein ANGPTL1 is associated with vascular invasion, tumor thrombus, metastasis and poor prognosis in HCC. Ectopic expression of ANGPTL1 in HCC cells effectively decreased their in vitro and in vivo tumorigenicity, cell motility and angiogenesis. shRNA-mediated depletion of ANGPTL1 exerted opposing effects. ANGPTL1 promoted apoptosis via inhibition of the STAT3/Bcl-2 mediated anti-apoptotic pathway and decreased cell migration and invasion via downregulation of transcription factors SNAIL and SLUG. Furthermore, ANGPTL1 inhibited angiogenesis by attenuating ERK and AKT signaling and interacted with integrin α1β1 receptor to suppress the downstream FAK/Src-JAK-STAT3 signaling pathway. Taken together, these results suggest ANGPTL1 as a prognostic biomarker and novel therapeutic agent in HCC.

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Structurally novel antiestrogens elicit differential responses from constitutively active mutant estrogen receptors in breast cancer cells and tumors

Many ERα-positive breast cancers develop resistance to endocrine therapy via mutation of estrogen receptors (ER) whose constitutive activation is associated with shorter patient survival. Because there is now a clinical need for new antiestrogens (AE) against these mutant ER, we describe here our development and characterization of three chemically novel AE that effectively suppress proliferation of breast cancer cells and tumors. Our AE are effective against wild type and Y537S and D538G ER, the two most commonly occurring constitutively active ER. The 3 new AE suppressed proliferation and estrogen target gene expression in WT and mutant ER-containing cells and were more effective in D538G than in Y537S cells and tumors. Compared to WT ER, mutants exhibited ~10 to 20-fold lower binding affinity for AE and a reduced ability to be blocked in coactivator interaction, likely contributing to their relative resistance to inhibition by AE. Comparisons between mutant ER-containing MCF7 and T47D cells revealed that AE responses were compound, cell-type and ERα-mutant dependent. These new ligands have favorable pharmacokinetic properties and effectively suppressed growth of WT and mutant ER-expressing tumor xenografts in NOD/SCID-gamma mice after oral or subcutaneous administration; D538G tumors were more potently inhibited by AE than Y537S tumors. These studies highlight the differential responsiveness of the mutant ER to different AE and make clear the value of having a toolkit of AE for treatment of endocrine therapy-resistant tumors driven by different constitutively active ER.

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Anti-Jagged immunotherapy inhibits MDSCs and overcomes tumor-induced tolerance.

Myeloid-derived suppressor cells (MDSCs) are a major obstacle to promising forms of cancer immunotherapy, but tools to broadly limit their immunoregulatory effects remain lacking. In this study, we assessed the therapeutic effect of the humanized anti-Jagged1/2 blocking antibody CTX014 on MDSC-mediated T cell suppression in tumor-bearing mice. CTX014 decreased tumor growth, impacted the accumulation and tolerogenic activity of MDSCs in tumors, and inhibited the expression of immunosuppressive factors arginase I and iNOS. Consequently, anti-Jagged therapy overcame tumor-induced T cell tolerance, increased the infiltration of reactive CD8+ T-cells into tumors, and enhanced the efficacy of T cell-based immunotherapy. Depletion of MDSC-like cells restored tumor growth in mice treated with anti-Jagged, whereas co-injection of MDSC-like cells from anti-Jagged-treated mice with cancer cells delayed tumor growth. Jagged1/2 was induced in MDSCs by tumor-derived factors via NFkB-p65 signaling, and conditional deletion of NFkB-p65 blocked MDSC function. Collectively, our results offer a preclinical proof of concept for the use of anti-Jagged1/2 to reprogram MDSC-mediated T cell suppression in tumors, with implications to broadly improve the efficacy of cancer therapy.

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Optical coherence tomography detects necrotic regions and volumetrically quantifies multicellular tumor spheroids

Three-dimensional (3D) tumor spheroid models have gained increased recognition as important tools in cancer research and anti-cancer drug development. However, currently available imaging approaches employed in high-throughput screening drug discovery platforms e.g. bright field, phase contrast, and fluorescence microscopies, are unable to resolve 3D structures deep inside (>50 μm) tumor spheroids. In this study, we established a label-free, non-invasive optical coherence tomography (OCT) imaging platform to characterize 3D morphological and physiological information of multicellular tumor spheroids (MCTS) growing from ~250 μm up to ~600 μm in height over 21 days. In particular, tumor spheroids of two cell lines glioblastoma (U-87 MG) and colorectal carcinoma (HCT 116) exhibited distinctive evolutions in their geometric shapes at late growth stages. Volumes of MCTS were accurately quantified using a voxel-based approach without presumptions of their geometries. In contrast, conventional diameter-based volume calculations assuming perfect spherical shape resulted in large quantification errors. Furthermore, we successfully detected necrotic regions within these tumor spheroids based on increased intrinsic optical attenuation, suggesting a promising alternative of label-free viability tests in tumor spheroids. Therefore, OCT can serve as a promising imaging modality to characterize morphological and physiological features of MCTS, showing great potential for high-throughput drug screening.

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Whole-Genome Sequencing Reveals Breast Cancers with Mismatch Repair Deficiency

Mismatch repair (MMR)–deficient cancers have been discovered to be highly responsive to immune therapies such as PD-1 checkpoint blockade, making their definition in patients, where they may be relatively rare, paramount for treatment decisions. In this study, we utilized patterns of mutagenesis known as mutational signatures, which are imprints of the mutagenic processes associated with MMR deficiency, to identify MMR-deficient breast tumors from a whole-genome sequencing dataset comprising a cohort of 640 patients. We identified 11 of 640 tumors as MMR deficient, but only 2 of 11 exhibited germline mutations in MMR genes or Lynch Syndrome. Two additional tumors had a substantially reduced proportion of mutations attributed to MMR deficiency, where the predominant mutational signatures were related to APOBEC enzymatic activity. Overall, 6 of 11 of the MMR-deficient cases in this cohort were confirmed genetically or epigenetically as having abrogation of MMR genes. However, IHC analysis of MMR-related proteins revealed all but one of 10 samples available for testing as MMR deficient. Thus, the mutational signatures more faithfully reported MMR deficiency than sequencing of MMR genes, because they represent a direct pathophysiologic readout of repair pathway abnormalities. As whole-genome sequencing continues to become more affordable, it could be used to expose individually abnormal tumors in tissue types where MMR deficiency has been rarely detected, but also rarely sought. Cancer Res; 77(18); 1–8. ©2017 AACR.

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A consensus-based approach to evidence-based clinical practice

Publication date: Available online 12 September 2017
Source:Dental Materials
Author(s): Jean-François Roulet




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Academy of Dental Materials guidance—Resin composites: Part II—Technique sensitivity (handling, polymerization, dimensional changes)

Publication date: Available online 13 September 2017
Source:Dental Materials
Author(s): J.L. Ferracane, T.J. Hilton, J.W. Stansbury, D.C. Watts, N. Silikas, N. Ilie, S. Heintze, M. Cadenaro, R. Hickel
ObjectiveThe objective of this work, commissioned by the Academy of Dental Materials, was to review and critically appraise test methods to characterize properties related to critical issues for dental resin composites, including technique sensitivity and handling, polymerization, and dimensional stability, in order to provide specific guidance to investigators planning studies of these properties.MethodsThe properties that relate to each of the main clinical issues identified were ranked in terms of their priority for testing, and the specific test methods within each property were ranked. An attempt was made to focus on the tests and methods likely to be the most useful, applicable, and supported by the literature, and where possible, those showing a correlation with clinical outcomes. Certain methods are only briefly mentioned to be all-inclusive. When a standard test method exists, whether from dentistry or another field, this test has been identified. Specific examples from the literature are included for each test method.ResultsThe properties for evaluating resin composites were ranked in the priority of measurement as follows: (1) porosity, radiopacity, sensitivity to ambient light, degree of conversion, polymerization kinetics, depth of cure, polymerization shrinkage and rate, polymerization stress, and hygroscopic expansion; (2) stickiness, slump resistance, and viscosity; and (3) thermal expansion.SignificanceThe following guidance is meant to aid the researcher in choosing the most appropriate test methods when planning studies designed to assess certain key properties and characteristics of dental resin composites, specifically technique sensitivity and handling during placement, polymerization, and dimensional stability.



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FOXP3 Is a HCC suppressor gene and Acts through regulating the TGF-β/Smad2/3 signaling pathway

FOXP3 has been discovered to be expressed in tumor cells and participate in the regulation of tumor behavior. Herein, we investigated the clinical relevance and biological significance of FOXP3 expression in h...

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Can you un-ring the bell? A qualitative study of how affect influences cancer screening decisions

The belief that early detection is the best protection against cancer underlies cancer screening. Emerging research now suggests harms associated with early detection may sometimes outweigh the benefits. Gover...

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What factors are associated with reporting lacking interest in sex and how do these vary by gender? Findings from the third British national survey of sexual attitudes and lifestyles

Objectives

To investigate factors associated with reporting lacking interest in sex and how these vary by gender.

Setting

British general population.

Design

Complex survey analyses of data collected for a cross-sectional probability sample survey, undertaken 2010–2012, specifically logistic regression to calculate age-adjusted OR (AOR) to identify associated factors.

Participants

4839 men and 6669 women aged 16–74 years who reported ≥1 sexual partner (opposite-sex or same-sex) in the past year for the third National Survey of Sexual Attitudes and Lifestyles (Natsal-3).

Main outcome measure

Lacking interest in sex for ≥3 months in the past year.

Results

Overall, 15.0% (13.9–16.2) of men and 34.2% (32.8–35.5) of women reported lacking interest in sex. This was associated with age and physical and mental health for both men and women, including self-reported general health and current depression. Lacking interest in sex was more prevalent among men and women reporting sexually transmitted infection diagnoses (ever), non-volitional sex (ever) and holding sexual attitudes related to normative expectations about sex. Some gender similarities in associated relationship and family-related factors were evident, including partner having had sexual difficulties in the last year (men: AOR 1.41 (1.07–1.86); women: AOR 1.60 (1.32–1.94)), not feeling emotionally close to partner during sex (men: 3.74 (1.76–7.93); women: 4.80 (2.99–7.69) and ease of talking about sex (men: 1.53 (1.23–1.90);women: 2.06 (1.77–2.39)). Among women only, lack of interest in sex was higher among those in a relationship of >1 year in duration and those not sharing the same level of interest (4.57 (3.87–5.38)) or preferences (2.91 (2.22–3.83)) with a partner.

Conclusions

Both gender similarities and differences were found in factors associated with lacking interest in sex, with the most marked differences in relation to some relationship variables. Findings highlight the need to assess, and if appropriate, treat lacking interest in sex in a holistic and relationship-specific way.

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Impact of Rotational Twin Boundaries and Lattice Mismatch on III–V Nanowire Growth

ACS Nano

DOI: 10.1021/acsnano.7b01228

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Two-Dimensional Simulation of Flows in an Open Channel with Groin-Like Structures by iRIC Nays2DH

This study presents the results obtained from the numerical simulation on turbulent flows around a single groin for different orientations. Here iRIC Nays2DH, which is based on 2D model, is used to simulate the flows in a straight open channel with groin of 45°, 90°, and 135° angled with the approaching flow. A depth-averaged - model is used as turbulence closure model with finite differential advections as upwind scheme. The numerical results of velocity and bed shear stress profiles are compared with the available experimental data. Good agreements are found between experimental and calculated results. From the simulation, it is observed that the peak of velocity and bed shear stress is maximum at the position of head of groin when lateral distance , where l is the groin length. The position of maximum velocity and bed shear stress is found to be shifted towards downstream with increasing . The maximum velocity and bed shear stress for 135° groin are found lower than the other two cases for all the sections of .

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Insulin-Like Growth Factor Binding Protein-6 Alters Skeletal Muscle Differentiation of Human Mesenchymal Stem Cells

Insulin-like growth factor binding protein-6 (IGFBP-6), the main regulator of insulin-like growth factor-2 (IGF-2), is a component of the stem cell niche in developing muscle cells. However, its role in muscle development has not been clearly defined. In this study, we investigated the role of IGFBP-6 in muscle commitment and differentiation of human mesenchymal stem cells derived from the placenta. We showed that placental mesenchymal stem cells (PMSCs) have the ability to differentiate into muscle cells when exposed to a specific culture medium by expressing muscle markers Pax3/7, MyoD, myogenin, and myosin heavy chain in a stage-dependent manner with the ultimate formation of multinucleated fibers and losing pluripotency-associated markers, OCT4 and SOX2. The addition of IGFBP-6 significantly increased pluripotency-associated markers as well as muscle differentiation markers at earlier time points, but the latter decreased with time. On the other hand, silencing IGFBP-6 decreased both pluripotent and differentiation markers at early time points. The levels of these markers increased as IGFBP-6 levels were restored. These findings indicate that IGFBP-6 influences MSC pluripotency and myogenic differentiation, with more prominent effects observed at the beginning of the differentiation process before muscle commitment.

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The Artificial Neural Networks Based on Scalarization Method for a Class of Bilevel Biobjective Programming Problem

A two-stage artificial neural network (ANN) based on scalarization method is proposed for bilevel biobjective programming problem (BLBOP). The induced set of the BLBOP is firstly expressed as the set of minimal solutions of a biobjective optimization problem by using scalar approach, and then the whole efficient set of the BLBOP is derived by the proposed two-stage ANN for exploring the induced set. In order to illustrate the proposed method, seven numerical examples are tested and compared with results in the classical literature. Finally, a practical problem is solved by the proposed algorithm.

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The Role of Nrf2 in Cardiovascular Function and Disease

Free radicals, reactive oxygen/nitrogen species (ROS/RNS), hydrogen sulphide, and hydrogen peroxide play an important role in both intracellular and intercellular signaling; however, their production and quenching need to be closely regulated to prevent cellular damage. An imbalance, due to exogenous sources of free radicals and chronic upregulation of endogenous production, contributes to many pathological conditions including cardiovascular disease and also more general processes involved in aging. Nuclear factor erythroid 2-like 2 (NFE2L2; commonly known as Nrf2) is a transcription factor that plays a major role in the dynamic regulation of a network of antioxidant and cytoprotective genes, through binding to and activating expression of promoters containing the antioxidant response element (ARE). Nrf2 activity is regulated by many mechanisms, suggesting that tight control is necessary for normal cell function and both hypoactivation and hyperactivation of Nrf2 are indicated in playing a role in different aspects of cardiovascular disease. Targeted activation of Nrf2 or downstream genes may prove to be a useful avenue in developing therapeutics to reduce the impact of cardiovascular disease. We will review the current status of Nrf2 and related signaling in cardiovascular disease and its relevance to current and potential treatment strategies.

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Optical Network Models and Their Application to Software-Defined Network Management

Software-defined networking is finding its way into optical networks. Here, it promises a simplification and unification of network management for optical networks allowing automation of operational tasks despite the highly diverse and vendor-specific commercial systems and the complexity and analog nature of optical transmission. Common abstractions and interfaces are a fundamental component for software-defined optical networking. Currently, a number of models for optical networks are available. They all claim to provide open and vendor agnostic management of optical equipment. In this work, we survey and compare the most important models and propose an intent interface for creating virtual topologies which is integrated in the existing model ecosystem.

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Modelling Risk to US Military Populations from Stopping Blanket Mandatory Polio Vaccination

Objectives. Transmission of polio poses a threat to military forces when deploying to regions where such viruses are endemic. US-born soldiers generally enter service with immunity resulting from childhood immunization against polio; moreover, new recruits are routinely vaccinated with inactivated poliovirus vaccine (IPV), supplemented based upon deployment circumstances. Given residual protection from childhood vaccination, risk-based vaccination may sufficiently protect troops from polio transmission. Methods. This analysis employed a mathematical system for polio transmission within military populations interacting with locals in a polio-endemic region to evaluate changes in vaccination policy. Results. Removal of blanket immunization had no effect on simulated polio incidence among deployed military populations when risk-based immunization was employed; however, when these individuals reintegrated with their base populations, risk of transmission to nondeployed personnel increased by 19%. In the absence of both blanket- and risk-based immunization, transmission to nondeployed populations increased by 25%. The overall number of new infections among nondeployed populations was negligible for both scenarios due to high childhood immunization rates, partial protection against transmission conferred by IPV, and low global disease incidence levels. Conclusion. Risk-based immunization driven by deployment to polio-endemic regions is sufficient to prevent transmission among both deployed and nondeployed US military populations.

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