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Profiling Oncogenic Germline Mutations in Unselected Chinese Lung Cancer Patients.

Front Oncol 2021 7;11:647598. Epub 2021 Apr 7.

Department of Thoracic Surgery, Affiliated Hospital of Hebei University, Baoding, China.

Introduction: Emerging evidence has suggested that inherited factors are also involved in lung cancer development. However, most studies focused on well-elucidated cancer predisposition genes, the majority of which are tumor suppressor genes. The profile of germline mutations in oncogenic driver genes remains unrevealed, which might also provide potential clinical implications for lung cancer management. Read More

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Association Mapping and Transcriptome Analysis Reveal the Genetic Architecture of Maize Kernel Size.

Front Plant Sci 2021 18;12:632788. Epub 2021 Mar 18.

Institute of Cereal Crops, Henan Academy of Agricultural Sciences, Zhengzhou, China.

Kernel length, kernel width, and kernel thickness are important traits affecting grain yield and product quality. Here, the genetic architecture of the three kernel size traits was dissected in an association panel of 309 maize inbred lines using four statistical methods. Forty-two significant single nucleotide polymorphisms (SNPs; < 1. Read More

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Identification of susceptibility loci for cardiovascular disease in adults with hypertension, diabetes, and dyslipidemia.

J Transl Med 2021 02 25;19(1):85. Epub 2021 Feb 25.

Healthcare R&D Division, Theragen Bio Co., Ltd., Gwanggyo-ro 145, Suwon-si, Gyeonggi-do, 16229, Republic of Korea.

Background: Hypertension (HTN), diabetes mellitus (DM), and dyslipidemia (DL) are well-known risk factors of cardiovascular disease (CVD), but not all patients develop CVDs. Studies have been limited investigating genetic risk of CVDs specific to individuals with metabolic diseases. This study aimed to identify disease-specific and/or common genetic loci associated with CVD susceptibility in chronic metabolic disease patients. Read More

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February 2021

HIV-1 Nef-Induced Secretion of the Proinflammatory Protease TACE into Extracellular Vesicles Is Mediated by Raf-1 and Can Be Suppressed by Clinical Protein Kinase Inhibitors.

J Virol 2021 04 12;95(9). Epub 2021 Apr 12.

Department of Virology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland

Chronic immune activation is an important driver of human immunodeficiency virus type 1 (HIV-1) pathogenesis and has been associated with the presence of tumor necrosis factor-α converting enzyme (TACE) in extracellular vesicles (EVs) circulating in infected individuals. We have recently shown that activation of the Src-family tyrosine kinase hematopoietic cell kinase (Hck) by HIV-1 Nef can trigger the packaging of TACE into EVs via an unconventional protein secretion pathway. Using a panel of HIV-1 Nef mutants and natural HIV-2 and simian immunodeficiency virus (SIV) Nef alleles, we now show that the capacity to promote TACE secretion depends on the superior ability of HIV-1-like Nef alleles to induce Hck kinase activity, whereas other Nef effector functions are dispensable. Read More

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RIPK1 contributes to cisplatin-induced apoptosis of esophageal squamous cell carcinoma cells via activation of JNK pathway.

Life Sci 2021 Mar 15;269:119064. Epub 2021 Jan 15.

Department of VIP Clinic, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200123, China. Department of Oncology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200123, China. Electronic address:

Aims: Previous studies have uncovered the function of receptor-interacting protein kinase 1 (RIPK1) to mediate both cell survival and death. Moreover, RIPK1 modulates apoptosis and necroptosis depending on its activity, phosphorylation or ubiquitylation status. Many studies have explained the role or mechanism of RIPK1 in necroptosis. Read More

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The Kinase Chemogenomic Set (KCGS): An Open Science Resource for Kinase Vulnerability Identification.

Int J Mol Sci 2021 Jan 8;22(2). Epub 2021 Jan 8.

Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

We describe the assembly and annotation of a chemogenomic set of protein kinase inhibitors as an open science resource for studying kinase biology. The set only includes inhibitors that show potent kinase inhibition and a narrow spectrum of activity when screened across a large panel of kinase biochemical assays. Currently, the set contains 187 inhibitors that cover 215 human kinases. Read More

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January 2021

NGS-PrimerPlex: High-throughput primer design for multiplex polymerase chain reactions.

PLoS Comput Biol 2020 12 30;16(12):e1008468. Epub 2020 Dec 30.

Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia.

Multiplex polymerase chain reaction (PCR) has multiple applications in molecular biology, including developing new targeted next-generation sequencing (NGS) panels. We present NGS-PrimerPlex, an efficient and versatile command-line application that designs primers for different refined types of amplicon-based genome target enrichment. It supports nested and anchored multiplex PCR, redistribution among multiplex reactions of primers constructed earlier, and extension of existing NGS-panels. Read More

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December 2020

Omipalisib inspired macrocycles as dual PI3K/mTOR inhibitors.

Eur J Med Chem 2021 Feb 18;211:113109. Epub 2020 Dec 18.

Experimental Therapeutics Programme, Spanish National Cancer Research Centre (CNIO), C/ Melchor Fernández Almagro 3, E-28029, Madrid, Spain. Electronic address:

Activation of the phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling pathway occurs frequently in a wide range of human cancers and is a main driver of cell growth, proliferation, survival, and chemoresistance of cancer cells. Compounds targeting this pathway are under active development as anticancer therapeutics and some of them have reached advanced clinical trials or been approved by the FDA. Dual PI3K/mTOR inhibitors combine multiple therapeutic efficacies in a single molecule by inhibiting the pathway both upstream and downstream of AKT. Read More

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February 2021

Liposomes Targeting P21 Activated Kinase-1 (PAK-1) and Selective for Secretory Phospholipase A (sPLA) Decrease Cell Viability and Induce Apoptosis in Metastatic Triple-Negative Breast Cancer Cells.

Int J Mol Sci 2020 Dec 10;21(24). Epub 2020 Dec 10.

Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, GA 30602, USA.

P21 activated kinases (or group I PAKs) are serine/threonine kinases whose expression is altered in prostate and breast cancers. PAK-1 activity is inhibited by the small molecule "Inhibitor targeting PAK-1 activation-3" (IPA-3), which has selectivity for PAK-1 but is metabolically unstable. Secretory Group IIA phospholipase A (sPLA) expression correlates to increased metastasis and decreased survival in many cancers. Read More

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December 2020

Identification of "regulation of RhoA activity panel" as a prognostic and predictive biomarker for gastric cancer.

Aging (Albany NY) 2020 12 3;13(1):714-734. Epub 2020 Dec 3.

Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing), Peking University Cancer Hospital and Institute, Beijing 100142, China.

RhoA is a member of the RHO family GTPases and is associated with essential functions in gastric cancer. In this study, we identified a gastric cancer biomarker, termed the "regulation of RhoA activity panel" (RRAP). Patients with gastric cancer from The Cancer Genome Atlas database were divided into training (N=160) and validation (N=155) cohorts. Read More

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December 2020

Mir-139 Regulates Autophagy in Prostate Cancer Cells Through Beclin-1 and mTOR Signaling Proteins.

Anticancer Res 2020 Dec 7;40(12):6649-6663. Epub 2020 Dec 7.

Platform Biological Sciences, Sunnybrook Research Institute, University of Toronto, Toronto, ON, Canada;

Background/aim: We previously identified a panel of five miRNAs (including miR-139) associated with biochemical recurrence and metastasis in prostate cancer patients.

Materials And Methods: We examined miR-139 transfected PC3, DU145 and LNCaP cells by morphology as well as by cell-based assays, confocal microscopy and immunoblotting.

Results: We found that treatment of prostate cancer cells with miR-139 resulted in phenotypic changes characteristic of autophagic cells. Read More

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December 2020

Pyrido[2, 3-d]pyrimidin-7(8H)-ones as new selective orally bioavailable Threonine Tyrosine Kinase (TTK) inhibitors.

Eur J Med Chem 2021 Feb 16;211:113023. Epub 2020 Nov 16.

International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education (MOE), Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China. Electronic address:

A series of pyrido [2, 3-d]pyrimidin-7(8H)-ones were designed and synthesized as new selective orally bioavailable Threonine Tyrosine Kinase (TTK) inhibitors. One of the representative compounds, 5o, exhibited strong binding affinity with a K value of 0.15 nM, but was significantly less potent against a panel of 402 wild-type kinases at 100 nM. Read More

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February 2021

Discovery of a Selective, Covalent IRAK1 Inhibitor with Antiproliferative Activity in MYD88 Mutated B-Cell Lymphoma.

ACS Med Chem Lett 2020 Nov 9;11(11):2238-2243. Epub 2020 Oct 9.

Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, United States.

Interleukin 1 (IL-1) receptor-associated kinases (IRAKs) are serine/threonine kinases that play critical roles in initiating the innate immune response against foreign pathogens. Additionally, dysregulation of IRAK1 signaling plays a role in neoplastic disorders. For example, IRAK1 was shown to be important for survival and proliferation in many B-cell lymphomas, including Waldenström's macroglobulinemia (WM) and ABC subtype Diffused Large B-cell Lymphoma (DLBCL) cells. Read More

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November 2020

Molecular Genetic Landscape of Sclerosing Pneumocytomas.

Am J Clin Pathol 2021 02;155(3):397-404

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN.

Objectives: Sclerosing pneumocytomas are rare pulmonary neoplasms that are typically benign. However, rare patients experience progressive disease, and therapy targeting specific genetic underpinnings could be an attractive therapeutic option. Recent studies have found recurrent AKT 1 mutations in sclerosing pneumocytoma, but little is known about whether oncogenic fusion genes may also be present. Read More

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February 2021

Diagnostic Accuracy of Next Generation Sequencing Panel using Circulating Tumor DNA in Patients with Advanced Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis.

J Health Econ Outcomes Res 2020 14;7(2):158-163. Epub 2020 Sep 14.

Roche Diagnostics, São Paulo, Brazil.

Background/objectives: Until now, no meta-analysis has been published to evaluate the diagnostic performance of next-generation sequencing (NGS) panel using circulating tumor (ctDNA) in patients with advanced non-small cell lung cancer (aNSCLC). The aim of the study was to carry out a systematic review and a meta-analysis in order to determine the accuracy of NGS of ctDNA to detect six oncogenic driver alterations: epidermal growth factor receptor (EGFR); anaplastic lymphoma kinase (ALK); ROS proto-oncogene 1, receptor tyrosine kinase (ROS-1); serine/threonine-protein kinase B-RAF (BRAF); RET proto-oncogene (RET); and MET proto-oncogene, receptor tyrosine kinase (MET) exon 14 in patients with aNSCLC.

Methods: MEDLINE/PubMed, Cochrane Library, Latin American and Caribbean Health Sciences Literature (LILACS), and Centre for Reviews and Dissemination databases and articles obtained from other sources were searched for relevant studies that evaluate the accuracy (sensitivity and specificity) of NGS using ctDNA in patients with aNSCLC. Read More

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September 2020

Characterization of a PERK Kinase Inhibitor with Anti-Myeloma Activity.

Cancers (Basel) 2020 Oct 5;12(10). Epub 2020 Oct 5.

Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, 11528 Athens, Greece.

Due to increased immunoglobulin production and uncontrolled proliferation, multiple myeloma (MM) plasma cells develop a phenotype of deregulated unfolded protein response (UPR). The eIF2-alpha kinase 3 [EIF2αK3, protein kinase R (PKR)-like ER kinase (PERK)], the third known sensor of endoplasmic reticulum (ER) stress, is a serine-threonine kinase and, like the other two UPR-related proteins, i.e. Read More

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October 2020

PKIS deep dive yields a chemical starting point for dark kinases and a cell active BRSK2 inhibitor.

Sci Rep 2020 09 28;10(1):15826. Epub 2020 Sep 28.

Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

The Published Kinase Inhibitor Set (PKIS) is a publicly-available chemogenomic library distributed to more than 300 laboratories by GlaxoSmithKline (GSK) between 2011 and 2015 and by SGC-UNC from 2015 to 2017. Screening this library of well-annotated, published kinase inhibitors has yielded a plethora of data in diverse therapeutic and scientific areas, funded applications, publications, and provided impactful pre-clinical results. GW296115 is a compound that was included in PKIS based on its promising selectivity following profiling against 260 human kinases. Read More

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September 2020

Design and Development of Small-Molecule Arylaldoxime/5-Nitroimidazole Hybrids as Potent Inhibitors of MARK4: A Promising Approach for Target-Based Cancer Therapy.

ACS Omega 2020 Sep 1;5(36):22759-22771. Epub 2020 Sep 1.

Medicinal Chemistry Research Laboratory, Department of Chemistry, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India.

Microtubule affinity-regulating kinase 4 (MARK4), a member of the serine/threonine kinase family, is an emerging therapeutic target in anticancer drug discovery paradigm due to its involvement in regulation of microtubule dynamics, cell cycle regulation, and cancer progression. Therefore, to identify the novel chemical architecture for the design and development of novel MARK4 inhibitors with concomitant radical scavenging property, a series of small-molecule arylaldoxime/5-nitroimidazole conjugates were designed and synthesized via multistep chemical reactions following the pharmacophoric hybridization approach. Compound was identified as a promising MARK4 inhibitor with high selectivity toward MARK4 inhibition as compared to the panel of screened kinases pertaining to the serine/threonine family, which was validated by molecular docking and fluorescence binding studies. Read More

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September 2020

Genetic characterization identifies bottom-of-sulcus dysplasia as an mTORopathy.

Neurology 2020 11 26;95(18):e2542-e2551. Epub 2020 Aug 26.

From the Bruce Lefroy Centre (W.S.L., S.E.M.S., K.P., G.G., P.J.L.), Murdoch Children's Research Institute (W.M., A.S.H., R.J.L.); Department of Paediatrics (W.S.L., S.E.M.S., W.M., E.M.-L., A.S.H., R.J.L., P.J.L.), The University of Melbourne; Departments of Neurosurgery (W.M.), Neurology (E.M.-L., A.S.H., R.J.L.), and Anatomical Pathology (D.M., C.D.), The Royal Children's Hospital, Parkville; and Melbourne Brain Centre (G.J.), The Florey Institute of Neuroscience and Mental Health, Heidelberg, Australia.

Objective: To determine the genetic basis of bottom-of-sulcus dysplasia (BOSD), which is a highly focal and epileptogenic cortical malformation in which the imaging, electrophysiologic, and pathologic abnormalities are maximal at the bottom of sulcus, tapering to a normal gyral crown.

Methods: Targeted panel deep sequencing (>500×) was performed on paired blood and brain-derived genomic DNA from 20 operated patients with drug-resistant focal epilepsy and BOSD. Histopathology was assessed using immunohistochemistry. Read More

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November 2020

Inhibition of the mitotic kinase PLK1 overcomes therapeutic resistance to BET inhibitors in triple negative breast cancer.

Cancer Lett 2020 10 28;491:50-59. Epub 2020 Jul 28.

Translational Research Unit, Albacete University Hospital, Albacete, Spain; Centro Regional de Investigaciones Biomédicas (CRIB), Universidad de Castilla La Mancha, Albacete, Spain; Hospital Clínico Universitario San Carlos, IDISSC and CIBERONC, Madrid, Spain. Electronic address:

The inhibition of bromo- and extraterminal domains (BET) has shown an anti-proliferative effect in triple negative breast cancer (TNBC). In this article we explore mechanisms of resistance to BET inhibitors (BETi) in TNBC, with the aim of identifying novel ways to overcome such resistance. Two cellular models of acquired resistance to the BET inhibitor JQ1 were generated using a pulsed treatment strategy. Read More

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October 2020

Use of De Novo mTOR Inhibitors in Hypersensitized Kidney Transplant Recipients: Experience From Clinical Practice.

Transplantation 2020 08;104(8):1686-1694

Nephrology and Renal Transplant Department, Hospital Clínic, Barcelona, Spain.

Background: It is commonly believed that mTOR inhibitors (mTORi) should not be used in high-immunological risk kidney transplant recipients due to a perceived increased risk of rejection. However, almost all trials that examined the association of optimal-dose mTORi with calcineurin inhibitor (CNI) have excluded hypersensitized recipients from enrollment.

Methods: To shed light on this issue, we examined 71 consecutive patients with a baseline calculated panel reactive antibody (cPRA) ≥50% that underwent kidney transplantation from June 2013 to December 2016 in our unit. Read More

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Silence of Hippo Pathway Associates with Pro-Tumoral Immunosuppression: Potential Therapeutic Target of Glioblastomas.

Cells 2020 07 23;9(8). Epub 2020 Jul 23.

Department of Systems Biology, Division of Cancer Medicine, Unit 950, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.

The critical role of the Hippo pathway has been recently investigated in various cancers, but little is known about its role in glioblastoma (GBM). In order to evaluate the clinical relevance of the Hippo pathway in GBM, we generated a core gene expression signature from four different previously-established silence of Hippo pathway (SOH) signatures. Based on a newly generated core SOH signature, a SOH and active Hippo pathway (AH) was predicted in GBM samples from The Cancer Genome Atlas (TCGA) and validated in a separate cohort. Read More

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Multi-layered proteomic analyses decode compositional and functional effects of cancer mutations on kinase complexes.

Nat Commun 2020 07 16;11(1):3563. Epub 2020 Jul 16.

Department of Biology, Institute of Molecular Systems Biology, ETH Zurich, Switzerland.

Rapidly increasing availability of genomic data and ensuing identification of disease associated mutations allows for an unbiased insight into genetic drivers of disease development. However, determination of molecular mechanisms by which individual genomic changes affect biochemical processes remains a major challenge. Here, we develop a multilayered proteomic workflow to explore how genetic lesions modulate the proteome and are translated into molecular phenotypes. Read More

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A large-scale genomic association analysis identifies the candidate causal genes conferring stripe rust resistance under multiple field environments.

Plant Biotechnol J 2021 01 3;19(1):177-191. Epub 2020 Sep 3.

State Key Laboratory of Crop Stress Biology for Arid Areas, College of Plant Protection, Northwest A&F University, Yangling, Shaanxi, China.

The incorporation of resistance genes into wheat commercial varieties is the ideal strategy to combat stripe or yellow rust (YR). In a search for novel resistance genes, we performed a large-scale genomic association analysis with high-density 660K single nucleotide polymorphism (SNP) arrays to determine the genetic components of YR resistance in 411 spring wheat lines. Following quality control, 371 972 SNPs were screened, covering over 50% of the high-confidence annotated gene space. Read More

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January 2021

TGF-β Promotes Metabolic Reprogramming in Lung Fibroblasts via mTORC1-dependent ATF4 Activation.

Am J Respir Cell Mol Biol 2020 11;63(5):601-612

Section of Pulmonary and Critical Care Medicine, Department of Medicine, The University of Chicago, Chicago, Illinois.

Idiopathic pulmonary fibrosis is a fatal interstitial lung disease characterized by the TGF-β (transforming growth factor-β)-dependent differentiation of lung fibroblasts into myofibroblasts, which leads to excessive deposition of collagen proteins and progressive scarring. We have previously shown that synthesis of collagen by myofibroblasts requires synthesis of glycine, the most abundant amino acid found in collagen protein. TGF-β upregulates the expression of the enzymes of the serine-glycine synthesis pathway in lung fibroblasts; however, the transcriptional and signaling regulators of this pathway remain incompletely understood. Read More

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November 2020

Inhibition of PI3K by copanlisib exerts potent antitumor effects on Merkel cell carcinoma cell lines and mouse xenografts.

Sci Rep 2020 06 1;10(1):8867. Epub 2020 Jun 1.

Department of Dermatology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA.

Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine skin cancer with steadily increasing incidence and poor prognosis. Despite recent success with immunotherapy, 50% of patients still succumb to their diseases. To date, there is no Food and Drug Administration-approved targeted therapy for advanced MCC. Read More

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IRE1α and IGF signaling predict resistance to an endoplasmic reticulum stress-inducing drug in glioblastoma cells.

Sci Rep 2020 05 20;10(1):8348. Epub 2020 May 20.

The Laboratory of Immunology, Department of Medicine and Moores Cancer Center, University of California, San Diego 9500 Gilman Drive, La Jolla, CA, 92093-0815, USA.

To date current therapies of glioblastoma multiforme (GBM) are largely ineffective. The induction of apoptosis by an unresolvable unfolded protein response (UPR) represents a potential new therapeutic strategy. Here we tested 12ADT, a sarcoendoplasmic reticulum Ca ATPase (SERCA) inhibitor, on a panel of unselected patient-derived neurosphere-forming cells and found that GBM cells can be distinguished into "responder" and "non-responder". Read More

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HSV1 VP1-2 deubiquitinates STING to block type I interferon expression and promote brain infection.

J Exp Med 2020 07;217(7)

Department of Biomedicine, Aarhus University, Aarhus, Denmark.

Herpes simplex virus (HSV) is the main cause of viral encephalitis in the Western world, and the type I interferon (IFN) system is important for antiviral control in the brain. Here, we have compared Ifnb induction in mixed murine brain cell cultures by a panel of HSV1 mutants, each devoid of one mechanism to counteract the IFN-stimulating cGAS-STING pathway. We found that a mutant lacking the deubiquitinase (DUB) activity of the VP1-2 protein induced particularly strong expression of Ifnb and IFN-stimulated genes. Read More

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Design, synthesis and biological activity of novel 2,3,4,5-tetra-substituted thiophene derivatives as PI3Kα inhibitors with potent antitumor activity.

Eur J Med Chem 2020 Jul 19;197:112309. Epub 2020 Apr 19.

Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, 103 Wenhua Road, Shenhe District, Shenyang, 110016, PR China. Electronic address:

Using a rational design strategy for isoform-selective inhibition of PI3Kα, two series of novel 2,3,4,5-tetra-substituted thiophene derivatives containing either diaryl urea or N-Acylarylhydrazone scaffold were designed and synthesized. The most promising compound 12k was demonstrated to bear nanomolar PI3Kα inhibitory potency with 12, 28, 30, 196-fold selectivity against isoforms β, γ, δ and mTOR. Besides, it also showed good developability profiles in cell-based proliferation against a panel of human tumor cells as well as ADME assays. Read More

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CHK1/2 Inhibitor Prexasertib Suppresses NOTCH Signaling and Enhances Cytotoxicity of Cisplatin and Radiation in Head and Neck Squamous Cell Carcinoma.

Mol Cancer Ther 2020 06 5;19(6):1279-1288. Epub 2020 May 5.

Department of Radiation Oncology, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama.

Platinum-based chemoradiotherapy is a mainstay of organ-preserving therapy for patients with head and neck squamous cell carcinoma cancer (HNSCC). However, the disease eventually becomes resistant to treatment necessitating new therapies. Checkpoint kinase 1 and 2 (CHK1/2) are serine/threonine kinases that activate cell-cycle checkpoints and serve a critical role in the DNA-damage response (DDR). Read More

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