4,163 results match your criteria isoforms targeted

Probing RAS Function with Monobodies.

Methods Mol Biol 2021 ;2262:281-302

Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA.

RAS is frequently mutated in human cancers with nearly 20% of all cancers harboring mutations in one of three RAS isoforms (KRAS, HRAS, or NRAS). Furthermore, RAS proteins are critical oncogenic drivers of tumorigenesis. As such, RAS has been a prime focus for development of targeted cancer therapeutics. Read More

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January 2021

Immune and barrier characterization of atopic dermatitis skin phenotype in Tanzanian patients.

Ann Allergy Asthma Immunol 2021 May 8. Epub 2021 May 8.

Laboratory of Inflammatory Skin Diseases, Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, New York, USA. Electronic address:

Background: Atopic dermatitis/AD is a common disease, with particularly high prevalence seen in Africa. It is increasingly recognized that AD patients of different ethnic backgrounds have unique molecular signatures in skin, potentially accounting for treatment response variations. However, the skin profile of AD patients from Africa is unknown, hindering development of new treatments targeted to this patient population. Read More

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Prostate cancer racial, socioeconomic, geographic disparities: targeting the genomic landscape and splicing events in search for diagnostic, prognostic and therapeutic targets.

Am J Cancer Res 2021 15;11(4):1012-1030. Epub 2021 Apr 15.

SAMRC/UP Precision Prevention and Novel Drug Targets for HIV-Associated Cancers Extramural Unit, Pan African Cancer Research Institute (PACRI), University of Pretoria Hatfield 0028, South Africa.

Prostate cancer (PCa) is one of the leading causes of deaths in men globally. This is a heterogeneous and complex disease that urgently warrants further insight into its pathology. Developed countries have thus far the highest PCa incidence rates, with comparatively low mortality rates. Read More

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Many Voices in a Choir: Tumor-Induced Neurogenesis and Neuronal Driven Alternative Splicing Sound Like Suspects in Tumor Growth and Dissemination.

Cancers (Basel) 2021 Apr 29;13(9). Epub 2021 Apr 29.

SAMRC Precision Prevention and Novel Drug Targets for HIV-Associated Cancers (PPNDTHAC) Unit, Pan African Cancer Research Institute (PACRI), University of Pretoria, Hatfield 0028, South Africa.

During development, as tissues expand and grow, they require circulatory, lymphatic, and nervous system expansion for proper function and support. Similarly, as tumors arise and develop, they also require the expansion of these systems to support them. While the contribution of blood and lymphatic systems to the development and progression of cancer is well known and is targeted with anticancer drugs, the contribution of the nervous system is less well studied and understood. Read More

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Personalizing Medicine With Germline and Somatic Sequencing in Advanced Pancreatic Cancer: Current Treatments and Novel Opportunities.

Am Soc Clin Oncol Educ Book 2021 Mar;41:1-13

Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX.

Performing germline and somatic sequencing in locally advanced and metastatic pancreatic cancer can identify potentially targetable genomic aberrations that impact current standard treatment options or eligibility for biomarker-targeted clinical trials. Testing for deleterious germline mutations in impacts patient selection for platinum-based chemotherapy regimens and selection of patients who are candidates to receive maintenance therapy with olaparib. Additional germline mutations also similarly introduce potential vulnerabilities to the cancers that arise and may be targeted by clinical trials. Read More

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Targeting Post-Translational Modifications of the p73 Protein: A Promising Therapeutic Strategy for Tumors.

Cancers (Basel) 2021 Apr 15;13(8). Epub 2021 Apr 15.

King Fahd Medical Research Center, Cancer and Mutagenesis Unit, Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia.

The tumor suppressor p73 is a member of the p53 family and is expressed as different isoforms with opposing properties. The TAp73 isoforms act as tumor suppressors and have pro-apoptotic effects, whereas the ΔNp73 isoforms lack the N-terminus transactivation domain and behave as oncogenes. The TAp73 protein has a high degree of similarity with both p53 function and structure, and it induces the regulation of various genes involved in the cell cycle and apoptosis. Read More

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Cardiovasc Res 2021 Apr 26. Epub 2021 Apr 26.

Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center (MUMC), Maastricht, Netherlands.

Aims: Atherosclerotic plaque hypoxia is detrimental for macrophage function. Prolyl hydroxylases (PHDs) initiate cellular hypoxic responses, possibly influencing macrophage function in plaque hypoxia. Thus, we aimed to elucidate the role of myeloid PHDs in atherosclerosis. Read More

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Targeted transcriptome analysis using synthetic long read sequencing uncovers isoform reprograming in the progression of colon cancer.

Commun Biol 2021 Apr 27;4(1):506. Epub 2021 Apr 27.

Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15261, USA.

The characterization of human gene expression is limited by short read lengths, high error rates and large input requirements. Here, we used a synthetic long read (SLR) sequencing approach, LoopSeq, to generate accurate sequencing reads that span full length transcripts using standard short read data. LoopSeq identified isoforms from control samples with 99. Read More

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The transcription factor Slug uncouples pancreatic cancer progression from the Raf-Mek1/2-Erk1/2 pathway.

Cancer Res 2021 Apr 26. Epub 2021 Apr 26.

Preclinical Research Program, Vall d'Hebron Institute of Oncology

Activating mutations in some isoforms of Ras or Raf are drivers of a substantial proportion of cancers. The main Raf effector, Mek1/2, can be targeted with several highly specific inhibitors. The clinical activity of these inhibitors seems to be mixed, showing efficacy against mutant BRAF-driven tumors but not K-Ras-driven tumors, such as pancreatic adenocarcinomas. Read More

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IDH1/IDH2 Inhibition in Acute Myeloid Leukemia.

Front Oncol 2021 29;11:639387. Epub 2021 Mar 29.

Hematology and Clinical Immunology, University of Perugia, Perugia, Italy.

Recently, the discovery of biological and clinical properties of mutated isoforms 1 and 2 mutations of isocitrate dehydrogenases (IDH) 1 and 2, affecting approximately 20% of patients with acute myeloid leukemia (AML), lead to the development of an individualized treatment strategy. Promoting differentiation and maturation of the malignant clone targeting IDH is an emerging strategy to promote clinical responses in AML. Phase I/II trials have shown evidence of safety, tolerability, and encouraging evidence of efficacy of two small molecule inhibitors targeting IDH2 and IDH1 gene mutations, respectively enasidenib and ivosidenib. Read More

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Metabolic-associated fatty liver disease and lipoprotein metabolism.

Mol Metab 2021 Apr 20:101238. Epub 2021 Apr 20.

Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Electronic address:

Background: Non-alcoholic fatty liver disease, or as recently proposed 'metabolic-associated fatty liver disease' (MAFLD), is characterized by pathological accumulation of triglycerides and other lipids in hepatocytes. This common disease can progress from simple steatosis to steatohepatitis, and eventually end-stage liver diseases. MAFLD is closely related to disturbances in systemic energy metabolism, including insulin resistance and atherogenic dyslipidemia. Read More

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Promising drug discovery strategies for sirtuin modulators: what lessons have we learnt?

Expert Opin Drug Discov 2021 Apr 21:1-13. Epub 2021 Apr 21.

Department of Biochemistry, University of Allahabad, Allahabad, India.

Introduction: Sirtuins, NAD-dependent protein deacetylases, require NAD for enzymatic activity. Recent research has indicated that sirtuins have a key role in the regulation of gene expression, the cell cycle, apoptosis, neurodegeneration and several age-related diseases. In mammals, there are seven sirtuin isoforms (SIRT-1-7) that catalyze specific lysine substrate deacetylation. Read More

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Connexin 46 and connexin 50 gap junction channel properties are shaped by structural and dynamic features of their N-terminal domains.

J Physiol 2021 Apr 20. Epub 2021 Apr 20.

Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada.

Key Points: Gap junctions formed by different connexins are expressed throughout the body and harbor unique channel properties that have not been fully defined mechanistically. Recent structural studies by Cryo-EM have produced high-resolution models of the related but functionally distinct lens connexins (Cx50 and Cx46) captured in a stable open state, opening the door for structure-function comparison. Here, we conducted comparative MD simulation and electrophysiology studies to dissect the isoform-specific differences in Cx46 and Cx50 intercellular channel function. Read More

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PPARγ and Diabetes: Beyond the Genome and Towards Personalized Medicine.

Curr Diab Rep 2021 Apr 18;21(6):18. Epub 2021 Apr 18.

Institute of Genetics and Biophysics "Adriano Buzzati-Traverso", CNR, Via P. Castellino 111, 80131, Naples, Italy.

Purpose Of Review: Full and partial synthetic agonists targeting the transcription factor PPARγ are contained in FDA-approved insulin-sensitizing drugs and used for the treatment of metabolic syndrome-related dysfunctions. Here, we discuss the association between PPARG genetic variants and drug efficacy, as well as the role of alternative splicing and post-translational modifications as contributors to the complexity of PPARγ signaling and to the effects of synthetic PPARγ ligands.

Recent Findings: PPARγ regulates the transcription of several target genes governing adipocyte differentiation and glucose and lipid metabolism, as well as insulin sensitivity and inflammatory pathways. Read More

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A Review of Small-Molecule Inhibitors of One-Carbon Enzymes: SHMT2 and MTHFD2 in the Spotlight.

ACS Pharmacol Transl Sci 2021 Apr 1;4(2):624-646. Epub 2021 Mar 1.

Department of Medicinal Chemistry, College of Pharmacy and the Rogel Cancer Center, University of Michigan, North Campus Research Complex, 1600 Huron Parkway, Ann Arbor, Michigan 48109, United States.

Metabolic reprogramming is a key hallmark of cancer and shifts cellular metabolism to meet the demands of biomass production necessary for abnormal cell reproduction. One-carbon metabolism (1CM) contributes to many biosynthetic pathways that fuel growth and is comprised of a complex network of enzymes. Methotrexate and 5-fluorouracil were pioneering drugs in this field and are still widely used today as anticancer agents as well as for other diseases such as arthritis. Read More

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Simultaneous Detection of Six Isoforms of Tau Protein in Human Cerebrospinal Fluid by Multidimensional Mass Spectrometry-Based Targeted Proteomics.

J Proteome Res 2021 May 12;20(5):2299-2307. Epub 2021 Apr 12.

School of Pharmacy, Nanjing Medical University, Nanjing 211166, China.

Abnormal expression of Tau protein can cause the development of Alzheimer's disease (AD). So far, much evidence has demonstrated that Tau has multiple isoforms. These isoforms are suggested to have distinct physiological roles and contribute unequally to the progress of AD. Read More

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CCN Family Proteins in Cancer: Insight Into Their Structures and Coordination Role in Tumor Microenvironment.

Front Genet 2021 23;12:649387. Epub 2021 Mar 23.

Department of Nutrition, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.

The crosstalk between tumor cells and the tumor microenvironment (TME), triggers a variety of critical signaling pathways and promotes the malignant progression of cancer. The success rate of cancer therapy through targeting single molecule of this crosstalk may be extremely low, whereas co-targeting multiple components could be complicated design and likely to have more side effects. The six members of cellular communication network (CCN) family proteins are scaffolding proteins that may govern the TME, and several studies have shown targeted therapy of CCN family proteins may be effective for the treatment of cancer. Read More

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Assessing acquired resistance to IDH1 inhibitor therapy by full-exon sequencing and structural modeling.

Cold Spring Harb Mol Case Stud 2021 Apr 8;7(2). Epub 2021 Apr 8.

Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota 55455, USA.

Somatic mutations in hotspot regions of the cytosolic or mitochondrial isoforms of the isocitrate dehydrogenase gene ( and , respectively) contribute to the pathogenesis of acute myeloid leukemia (AML) by producing the oncometabolite 2-hydroxyglutarate (2-HG). The allosteric IDH1 inhibitor, ivosidenib, suppresses 2-HG production and induces clinical responses in relapsed/refractory -mutant AML. Herein, we describe a clinical case of AML in which we detected the neomorphic p. Read More

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JMJD6 Is a Druggable Oxygenase That Regulates AR-V7 Expression in Prostate Cancer.

Cancer Res 2021 02;81(4):1087-1100

Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Oxford, United Kingdom.

Endocrine resistance (EnR) in advanced prostate cancer is fatal. EnR can be mediated by androgen receptor (AR) splice variants, with AR splice variant 7 (AR-V7) arguably the most clinically important variant. In this study, we determined proteins key to generating AR-V7, validated our findings using clinical samples, and studied splicing regulatory mechanisms in prostate cancer models. Read More

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February 2021

TGF-β2 Promotes Oxidative Stress in Human Trabecular Meshwork Cells by Selectively Enhancing NADPH Oxidase 4 Expression.

Invest Ophthalmol Vis Sci 2021 Apr;62(4)

Research Service, Department of Veterans Affairs, Edward Hines Jr. VA Hospital, Hines, IL, United States.

Purpose: The multifunctional profibrotic cytokine TGF-β2 is implicated in the pathophysiology of primary open angle glaucoma (POAG). While the underlying cause of POAG remains unclear, TGF-β2 dependent remodeling of the extracellular matrix (ECM) within the trabecular meshwork (TM) microenvironment is considered an early pathologic consequence associated with impaired aqueous humor (AH) outflow and elevated IOP. Mitochondrial-targeted antioxidants have been recently shown by our group to markedly attenuate TGF-β2 profibrotic responses, strongly implicating oxidative stress as a key facilitator of TGF-β2 signaling in human TM cells. Read More

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The contrasting role of nasopharyngeal angiotensin converting enzyme 2 (ACE2) transcription in SARS-CoV-2 infection: A cross-sectional study of people tested for COVID-19 in British Columbia, Canada.

EBioMedicine 2021 Apr 2;66:103316. Epub 2021 Apr 2.

British Columbia Centre for Disease Control, Vancouver, BC V5Z 4R4, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC V6T 1Z4, Canada. Electronic address:

Background: Angiotensin converting enzyme 2 (ACE2) protein serves as the host receptor for SARS-CoV-2, with a critical role in viral infection. We aim to understand population level variation of nasopharyngeal ACE2 transcription in people tested for COVID-19 and the relationship between ACE2 transcription and SARS-CoV-2 viral load, while adjusting for expression of: (i) the complementary protease, Transmembrane serine protease 2 (TMPRSS2), (ii) soluble ACE2, (iii) age, and (iv) biological sex. The ACE2 gene was targeted to measure expression of transmembrane and soluble transcripts. Read More

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Aquaporins in platelet function.

Platelets 2021 Apr 4:1-7. Epub 2021 Apr 4.

School of Physiology, Pharmacology and Neuroscience, University of Bristol, England, UK.

Structurally, aquaporins (AQPs) are small channel proteins with monomers of ~ 30 kDa that are assembled as tetramers to form pores on cell membranes. Aquaporins mediate the conduction of water but at times also small solutes including glycerol across cell membranes and along osmotic gradients. Thirteen isoforms of AQPs have been reported in mammalian cells, and several of these are likely expressed in platelets. Read More

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Krüppel-Like Factor 6 Splice Variant 1: An Oncogenic Transcription Factor Involved in the Progression of Multiple Malignant Tumors.

Front Cell Dev Biol 2021 18;9:661731. Epub 2021 Mar 18.

Department of Oncology, Jinan Central Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.

Krüppel-like factor 6 (KLF6) is one of the most studied members of the specificity protein/Krüppel-like factor (SP/KLF) transcription factor family. It has a typical zinc finger structure and plays a pivotal role in regulating the biological processes of cells. Recently, it has been considered to play a role in combatting cancer. Read More

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GSK-3: a multifaceted player in acute leukemias.

Leukemia 2021 Apr 2. Epub 2021 Apr 2.

Department of Microbiology & Immunology, Brody School of Medicine, East Carolina University, Greenville, NC, USA.

Glycogen synthase kinase 3 (GSK-3) consists of two isoforms (α and β) that were originally linked to glucose metabolism regulation. However, GSK-3 is also involved in several signaling pathways controlling many different key functions in healthy cells. GSK-3 is a unique kinase in that its isoforms are constitutively active, while they are inactivated mainly through phosphorylation at Ser residues by a variety of upstream kinases. Read More

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Growth and Viability of Cutaneous Squamous Cell Carcinoma Cell Lines Display Different Sensitivities to Isoform-Specific Phosphoinositide 3-Kinase Inhibitors.

Int J Mol Sci 2021 Mar 30;22(7). Epub 2021 Mar 30.

Centre for Cell Biology and Cutaneous Research, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK.

Cutaneous squamous cell carcinomas (cSCCs) account for about 20% of keratinocyte carcinomas, the most common cancer in the UK. Therapeutic options for cSCC patients who develop metastasis are limited and a better understanding of the biochemical pathways involved in cSCC development/progression is crucial to identify novel therapeutic targets. Evidence indicates that the phosphoinositide 3-kinases (PI3Ks)/Akt pathway plays an important role, in particular in advanced cSCC. Read More

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Multifaceted Functions of Protein Kinase D in Pathological Processes and Human Diseases.

Biomolecules 2021 Mar 23;11(3). Epub 2021 Mar 23.

Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15261, USA.

Protein kinase D (PKD) is a family of serine/threonine protein kinases operating in the signaling network of the second messenger diacylglycerol. The three family members, PKD1, PKD2, and PKD3, are activated by a variety of extracellular stimuli and transduce cell signals affecting many aspects of basic cell functions including secretion, migration, proliferation, survival, angiogenesis, and immune response. Dysregulation of PKD in expression and activity has been detected in many human diseases. Read More

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Proton Transport in Cancer Cells: The Role of Carbonic Anhydrases.

Int J Mol Sci 2021 Mar 20;22(6). Epub 2021 Mar 20.

Department of Biology, University of Kaiserslautern, D-67653 Kaiserslautern, Germany.

Intra- and extracellular pH regulation is a pivotal function of all cells and tissues. Net outward transport of H is a prerequisite for normal physiological function, since a number of intracellular processes, such as metabolism and energy supply, produce acid. In tumor tissues, distorted pH regulation results in extracellular acidification and the formation of a hostile environment in which cancer cells can outcompete healthy local host cells. Read More

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Incorporation of a nucleoside analog maps genome repair sites in postmitotic human neurons.

Science 2021 04;372(6537):91-94

Laboratory of Genetics, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037-1002, USA.

Neurons are the longest-lived cells in our bodies and lack DNA replication, which makes them reliant on a limited repertoire of DNA repair mechanisms to maintain genome fidelity. These repair mechanisms decline with age, but we have limited knowledge of how genome instability emerges and what strategies neurons and other long-lived cells may have evolved to protect their genomes over the human life span. A targeted sequencing approach in human embryonic stem cell-induced neurons shows that, in neurons, DNA repair is enriched at well-defined hotspots that protect essential genes. Read More

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The expression of B7-H3 isoforms in newly diagnosed glioblastoma and recurrence and their functional role.

Acta Neuropathol Commun 2021 04 1;9(1):59. Epub 2021 Apr 1.

Laboratory of Nervous System Disorders and Therapy, GIGA-Neurosciences Research Centre, University of Liège, Avenue de L'Hôpital, 1, 4000, Liège, Belgium.

Short survival of glioblastoma (GBM) patients is due to systematic tumor recurrence. Our laboratory identified a GBM cell subpopulation able to leave the tumor mass (TM) and invade the subventricular zone (SVZ-GBM cells). SVZ-GBM cells escape treatment and appear to contribute to GBM recurrence. Read More

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Oral PI3K-δ,γ Inhibitor for the Management of People with Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma: A Narrative Review on Duvelisib.

Onco Targets Ther 2021 25;14:2109-2119. Epub 2021 Mar 25.

CLL Research and Treatment Center, Division of Hematology-Oncology, Department of Medicine at Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA.

The development of highly effective targeted therapies has led to a new treatment paradigm in patients with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL). Despite these advances, many patients will eventually require alternative treatment strategies due to the emergence of tolerability issues or resistance to these novel agents. Duvelisib is a first-in-class, potent oral agent with dual inhibitor activity against the δ and γ isoforms of phosphoinositide 3-kinase (PI3Kδ and PI3Kγ), which are specific to the hematopoietic system. Read More

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