182,789 results match your criteria specific mutations


Timely upstream events regulating nucleotide excision repair by ubiquitin-proteasome system: ubiquitin guides the way.

DNA Repair (Amst) 2021 May 12;103:103128. Epub 2021 May 12.

Department of Radiology, The Ohio State University, Columbus, OH, 43210, United States; Department of Molecular and Cellular Biochemistry, The Ohio State University, Columbus, OH, 43210, United States; James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, OH, 43210, United States. Electronic address:

The ubiquitin-proteasome system (UPS) plays crucial roles in regulation of multiple DNA repair pathways, including nucleotide excision repair (NER), which eliminates a broad variety of helix-distorting DNA lesions that can otherwise cause deleterious mutations and genomic instability. In mammalian NER, DNA damage sensors, DDB and XPC acting in global genomic NER (GG-NER), and, CSB and RNAPII acting in transcription-coupled NER (TC-NER) sub-pathways, undergo an array of post-translational ubiquitination at the DNA lesion sites. Accumulating evidence indicates that ubiquitination orchestrates the productive assembly of NER preincision complex by driving well-timed compositional changes in DNA damage-assembled sensor complexes. Read More

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A novel GSK-3 inhibitor binds to GSK-3β via a reversible, time and Cys-199-dependent mechanism.

Bioorg Med Chem 2021 Apr 27;40:116179. Epub 2021 Apr 27.

Department of Chemical and Biomolecular Engineering, Ohio University, Athens, OH 45701, United States; Biomedical Engineering Program, Ohio University, Athens, OH 45701, United States. Electronic address:

Glycogen synthase kinase-3 (GSK-3) has been implicated in numerous pathologies making GSK-3 an attractive therapeutic target. Our group has identified a compound termed COB-187 that is a potent and selective inhibitor of GSK-3. In this study, we probed the mechanism by which COB-187 inhibits GSK-3β. Read More

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Identification of the core promoter of ZNFO, an oocyte-specific maternal effect gene in cattle.

Gene 2021 May 12:145717. Epub 2021 May 12.

Laboratory of Animal Biotechnology and Genomics, Division of Animal and Nutritional Sciences, West Virginia University, Morgantown, WV 26506, USA. Electronic address:

ZNFO is a Krüppel-associated box (KRAB) containing zinc finger transcription factor, which is exclusively expressed in bovine oocytes. Previous studies have demonstrated that ZNFO possesses an intrinsic transcriptional repressive activity and is essential for early embryonic development in cattle. However, the mechanisms regulating ZNFO transcription remain elusive. Read More

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Parallel Rap1>RalGEF>Ral and Ras signals sculpt the C. elegans nervous system.

Dev Biol 2021 May 12. Epub 2021 May 12.

Department of Translational Medical Science, College of Medicine, USA; Institute of Biosciences and Technology, Texas A&M Health Science Center, Texas A&M University, Houston, TX, USA. Electronic address:

Ras is the most commonly mutated oncogene in humans and uses three oncogenic effectors: Raf, PI3K, and RalGEF activation of Ral. Understanding the importance of RalGEF > Ral signaling in cancer is hampered by the paucity of knowledge about their function in animal development, particularly in cell movements. We found that mutations that disrupt function of RalGEF or Ral enhance migration phenotypes of mutations in genes with established roles in cell migration. Read More

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H3F3A-mutated Giant Cell Tumour of Bone without Giant Cells - Clinical Presentation, Radiology, and Histology of Three Cases.

Histopathology 2021 May 15. Epub 2021 May 15.

Bone Tumour Reference Center at the Institute of Pathology, University Hospital Basel, Basel, Switzerland.

Aims: Giant cell tumour of bone (GCTB) is histologically defined as a lesion containing reactive giant cells and a neoplastic mononuclear cell population; in up to 92% GCTB is characterized by a specific mutation of the histone gene H3F3A. The cellular composition ranges from giant cell-rich to giant cell-poor tumours. The diagnosis of GCTB can be challenging and several other lesions need to be excluded, e. Read More

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Pluripotent Stem Cell Derived Neurons as In Vitro Models for Studying Autosomal Recessive Parkinson's Disease (ARPD): PLA2G6 and Other Gene Loci.

Adv Exp Med Biol 2021 May 15. Epub 2021 May 15.

National Centre for Biological Sciences, Tata Institute of Fundamental Research, Bengaluru, India.

Parkinson's disease (PD) is a neurodegenerative motor disorder which is largely sporadic; however, some familial forms have been identified. Genetic PD can be inherited by autosomal, dominant or recessive mutations. While the dominant mutations mirror the prototype of PD with adult-onset and L-dopa-responsive cases, autosomal recessive PD (ARPD) exhibit atypical phenotypes with additional clinical manifestations. Read More

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Myeloid/lymphoid neoplasms with FLT3 rearrangement.

Mod Pathol 2021 May 14. Epub 2021 May 14.

Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Myeloid/lymphoid neoplasms (M/LN) with 13q12/FLT3 rearrangement have been suggested as candidates for possible inclusion in the World Health Organization classification group of M/LN with eosinophilia (M/LN-eo). We report 12 patients with confirmed FLT3 rearrangement, six with t(12;13)/ETV6-FLT3; one with ins(13;22)/BCR-FLT3; and five with an unconfirmed partner gene located on chromosome bands 2p16, 3q27, 5q15, 5q35, and 7q36. Disease presentations were heterogeneous, including lymphoblastic leukemia/lymphoma, myeloid sarcoma, chronic eosinophilic leukemia, chronic myelomonocytic leukemia, and myelodysplastic syndrome. Read More

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Oxygen tension modulates the mitochondrial genetic bottleneck and influences the segregation of a heteroplasmic mtDNA variant in vitro.

Commun Biol 2021 May 14;4(1):584. Epub 2021 May 14.

Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK.

Most humans carry a mixed population of mitochondrial DNA (mtDNA heteroplasmy) affecting ~1-2% of molecules, but rapid percentage shifts occur over one generation leading to severe mitochondrial diseases. A decrease in the amount of mtDNA within the developing female germ line appears to play a role, but other sub-cellular mechanisms have been implicated. Establishing an in vitro model of early mammalian germ cell development from embryonic stem cells, here we show that the reduction of mtDNA content is modulated by oxygen and reaches a nadir immediately before germ cell specification. Read More

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Analysis of Mycobacterium africanum in the last 17 years in Aragon identifies a specific location of IS6110 in Lineage 6.

Sci Rep 2021 May 14;11(1):10359. Epub 2021 May 14.

Fundación IIS Aragón, Zaragoza, Spain.

The purpose of this study was to increase our knowledge about Mycobacterium africanum and report the incidence and characteristics of tuberculosis (TB) due to their lineages in Aragon, Spain, over the period 2003-2019. The study includes all the cases in our region, where all the M. tuberculosis complex isolates are systematically characterised. Read More

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Context-specific action of macrolide antibiotics on the eukaryotic ribosome.

Nat Commun 2021 May 14;12(1):2803. Epub 2021 May 14.

Center for Biomolecular Sciences, University of Illinois at Chicago, Chicago, IL, USA.

Macrolide antibiotics bind in the nascent peptide exit tunnel of the bacterial ribosome and prevent polymerization of specific amino acid sequences, selectively inhibiting translation of a subset of proteins. Because preventing translation of individual proteins could be beneficial for the treatment of human diseases, we asked whether macrolides, if bound to the eukaryotic ribosome, would retain their context- and protein-specific action. By introducing a single mutation in rRNA, we rendered yeast Saccharomyces cerevisiae cells sensitive to macrolides. Read More

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Decreased Tumoral Expression of Colon-Specific Water Channel Aquaporin 8 Is Associated With Reduced Overall Survival in Colon Adenocarcinoma.

Dis Colon Rectum 2021 May 13. Epub 2021 May 13.

Price Institute of Surgical Research, Hiram C. Polk, Jr. MD Department of Surgery, University of Louisville School of Medicine, Louisville, KY, 40202, USA Department of Veterinary Science, Gluck Equine Research Center, University of Kentucky, Lexington, KY Department of Bioinformatics and Biostatistics, University of Louisville, Louisville, Kentucky, USA Centre for Agricultural Bioinformatics, ICAR-Indian Agricultural Statistics Research Institute, New Delhi, India Department of Pathology, Northeast Ohio Medical University, Rootstown, Ohio Department of Pathology, University of Louisville, Louisville, KY.

Background: Colon cancer survival is dependent upon metastatic potential and treatment. Large RNA-sequencing datasets may assist in identifying colon cancer-specific biomarkers to improve patient outcomes.

Objective: To identify a highly specific biomarker for overall survival in colon adenocarcinoma using an RNA-sequencing data set. Read More

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Comprehensive analysis of clinical, pathological, and genomic characteristics of follicular helper T-cell derived lymphomas.

Exp Hematol Oncol 2021 May 14;10(1):33. Epub 2021 May 14.

Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81, Irwon-ro, Gangnam-Gu, Seoul, 06351, Korea.

Background: The 2016 World Health Organization (WHO) classification introduced nodal lymphomas of T follicular helper (Tfh) cell origin, such as angioimmunoblastic T-cell lymphoma (AITL), follicular peripheral T-cell lymphoma (F-PTCL), and nodal peripheral T-cell lymphoma with T follicular helper phenotype (nodal PTCL with TFH phenotype). However, the accurate incidence rate and clinical characteristics of F-PTCL and nodal PTCL with TFH are unstudied.

Methods: Between February 2012 to June 2020, a total of 207 cases diagnosed with nodal lymphomas of T follicular helper (Tfh) cell origin and PTCL-NOS were reviewed for clinical and histopathologic data. Read More

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Role of surface-exposed charged basic amino acids (Lys, Arg) and guanidination in insulin on the interaction and stability of insulin-insulin receptor complex.

Comput Biol Chem 2021 Apr 24;92:107501. Epub 2021 Apr 24.

Department of Biomedical Science, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia. Electronic address:

Naturally occurring proteins are emerging as novel therapeutics in the protein-based biopharmaceutical industry for the treatment of diabetes and obesity. However, proteins are not suitable for oral delivery due to short half-life, reduced physical and chemical stability and low permeability across the membrane. Chemical modification has been identified as a formulation strategy to enhance the stability and bioavailability of protein drugs. Read More

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CD56 expression in basaloid anal squamous cell carcinoma - A potential diagnostic pitfall.

Ann Diagn Pathol 2021 May 8;53:151758. Epub 2021 May 8.

Department of Pathology, University of Massachusetts, UMass Memorial Medical Center, 1 Innovation Dr., Biotech 3 Bldg., 2nd Floor, Worcester, MA, USA. Electronic address:

Anal squamous cell carcinoma (SqCC) is a morphologically heterogeneous entity. Basaloid and non-keratinizing anal SqCC may be confused with other tumors including neuroendocrine carcinoma due to morphologic overlap, and expression of neuroendocrine markers is not well-studied in anal SqCC. Prompted by a case of anal SqCC that was initially misdiagnosed as neuroendocrine carcinoma on the basis of morphology and CD56 expression, we retrospectively examined the expression of neuroendocrine markers CD56, synaptophysin, and chromogranin in 48 cases of basaloid anal SqCC, with clinicopathologic correlation. Read More

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Human iPSC-based neurodevelopmental models of globoid cell leukodystrophy uncover patient- and cell type-specific disease phenotypes.

Stem Cell Reports 2021 May 4. Epub 2021 May 4.

San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italy. Electronic address:

Globoid cell leukodystrophy (GLD) is a rare neurodegenerative lysosomal storage disease caused by an inherited deficiency of β-galactocerebrosidase (GALC). GLD pathogenesis and therapeutic correction have been poorly studied in patient neural cells. Here, we investigated the impact of GALC deficiency and lentiviral vector-mediated GALC rescue/overexpression in induced pluripotent stem cell (iPSC)-derived neural progenitors and neuronal/glial progeny obtained from two GLD patients. Read More

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Tropomyosin receptor kinases in sarcomas - of joy and despair.

Curr Opin Oncol 2021 May 14. Epub 2021 May 14.

Department of Medical Oncology, Sarcoma Center, West German Cancer Center, University Duisburg-Essen, Medical School, Essen DKTK partner site Essen, German Cancer Consortium (DKTK), Heidelberg Institute of Pathology, University Duisburg-Essen, Medical School, Essen, Germany.

Purpose: The relatively recent discovery of neurotrophic tropomyosin receptor kinase (NTRK) gene arrangements as pan-tumor predictive biomarkers has led to impressive novel treatments for patients with TRK fusions. Although the number of patients who qualify for treatment is vanishingly small for cancer patients in general, a few histological subsets of sarcomas exhibit NTRK fusions more commonly leading to large expectations within the sarcoma community.

Recent Findings: Larotrectenib and entrectenib have recently been approved based on durable responses in TRK positive cancers with nonresectable or metastatic disease, including many sarcomas. Read More

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Pulsed Hydrogen-Deuterium Exchange Reveals Altered Structures and Mechanisms in the Aggregation of Familial Alzheimer's Disease Mutants.

ACS Chem Neurosci 2021 May 14. Epub 2021 May 14.

Washington University in St. Louis, Department of Chemistry, St. Louis, Missouri 63130, United States.

Mutations of the Amyloid Precursor Protein, from which the amyloid β peptide Aβ42 is cleaved, are associated with familial Alzheimer's disease. The disease-relevant familial mutations include the Arctic (E22G), Iowa (D23N), Italian (E22K), Dutch (E22Q), Japanese (D7N), English (D6R), and Flemish (A21G) variants. A detailed mechanistic understanding of the aggregation behavior of the mutant peptides at the residue level is, however, still lacking. Read More

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A participant-derived xenograft model of HIV enables long-term evaluation of autologous immunotherapies.

J Exp Med 2021 Jul 14;218(7). Epub 2021 May 14.

Infectious Diseases Division, Department of Medicine, Weill Cornell Medical College, New York, NY.

HIV-specific CD8+ T cells partially control viral replication and delay disease progression, but they rarely provide lasting protection, largely due to immune escape. Here, we show that engrafting mice with memory CD4+ T cells from HIV+ donors uniquely allows for the in vivo evaluation of autologous T cell responses while avoiding graft-versus-host disease and the need for human fetal tissues that limit other models. Treating HIV-infected mice with clinically relevant HIV-specific T cell products resulted in substantial reductions in viremia. Read More

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Biological nanomotors, driving forces of life.

Authors:
Anne Houdusse

C R Biol 2021 Apr 21;343(4):53-78. Epub 2021 Apr 21.

Structural Motility, Institut Curie, Université Paris Sciences et Lettres, Sorbonne Université, CNRS UMR144, 75248 Paris, France.

Life is driven by awe-inspiring coordinated movements observed in cells and tissues. In each cell, nm-size molecular motor proteins contribute to these movements as they power numerous mechanical processes with precision and complex orchestration. For the multiple functions that an eukaryotic cell accomplish, motility is essential both at molecular and cellular scales. Read More

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GCN2 Regulates ATF3-p38 MAPK Signaling Transduction in Pulmonary Veno-Occlusive Disease.

J Cardiovasc Pharmacol Ther 2021 May 14:10742484211015535. Epub 2021 May 14.

Department of Cell Biology, State Key Laboratory of Medical Molecular Biology, 12501Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Pulmonary veno-occlusive disease (PVOD) is a fatal disease of pulmonary vascular lesions leading to right heart failure. Heritable PVOD (hPVOD) is related to biallelic mutation of (encoding GCN2), but its molecular mechanism remains unclear. In this study, we aimed to investigate the pathogenesis of PVOD and to find potential drug targets for PVOD. Read More

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Real-world data on treatment outcomes in mutant non-small-cell lung cancer patients receiving osimertinib in second or further lines.

Future Oncol 2021 May 14. Epub 2021 May 14.

Oncology 2, Istituto Oncologico Veneto IOV - IRCCS, Padova, 35128, Italy.

This study describes real-world outcomes of pretreated T790M-positive (T790M) advanced non-small-cell lung cancer patients progressing after first- or second-generation tyrosine kinase inhibitors and receiving osimertinib, compared with T790M-negative (T790M) patients. We have also described progression patterns and treatment sequences. This is a retrospective multicenter Italian observational study including consecutive Caucasian patients referred between 2014 and 2018. Read More

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The role of BAG3 in health and disease: A "Magic BAG of Tricks".

J Cell Biochem 2021 May 14. Epub 2021 May 14.

Department of Anesthesiology and Perioperative Medicine, University of Rochester Medical Center, Rochester, New York, USA.

The multi-domain structure of Bcl-2-associated athanogene 3 (BAG3) facilitates its interaction with many different proteins that participate in regulating a variety of biological pathways. After revisiting the BAG3 literature published over the past ten years with Citespace software, we classified the BAG3 research into several clusters, including cancer, cardiomyopathy, neurodegeneration, and viral propagation. We then highlighted recent key findings in each cluster. Read More

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A mini-review: Bridging the gap between autism spectrum disorder and pain comorbidities.

Can J Pain 2020 Dec 30;4(4):37-44. Epub 2020 Dec 30.

Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.

Background: Pain is a complex neurobiological response with a multitude of causes; however, patients with autism spectrum disorder (ASD) often report chronic pain with no known etiology. Recent research has been aimed toward identifying the causal mechanisms of pain in mouse and human models of ASD. In recent years, efforts have been made to better document and explore secondary phenotypes observed in ASD patients in the clinic. Read More

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December 2020

Endometrial Tumor Classification by Histomorphology and Biomarkers in the Nurses' Health Study.

J Cancer Epidemiol 2021 12;2021:8884364. Epub 2021 Mar 12.

Department of Pathology, Brigham and Women's Hospital, 75 Francis Street, Boston, MA, USA 02115.

Objective: Endometrial cancers have historically been classified by histomorphologic appearance, which is subject to interobserver disagreement. As molecular and biomarker testing has become increasingly available, the prognostic significance and accuracy of histomorphologic diagnoses have been questioned. To address these issues for a large, prospective cohort study, we provide the results of a centralized pathology review and biomarker analysis of all incidental endometrial carcinomas occurring between 1976 and 2012 in the Nurses' Health Study. Read More

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Recent Understanding and Future Directions of Recurrent Corticotroph Tumors.

Front Endocrinol (Lausanne) 2021 26;12:657382. Epub 2021 Apr 26.

Neuroendocrinology Clinic, Department of Endocrinology and Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.

Corticotroph tumors (CTs) are pituitary neoplasms arising from the Tpit lineage, which may or not express adrenocorticotrophic hormone (ACTH). Functioning CTs cause Cushing's disease (CD), which has high morbidity and mortality due to hypercortisolemia. "Non-functioning" or silent CTs (SCT) and the Crooke's cell subtypes do not cause CD and may be asymptomatic until manifested by compressive symptoms and are more frequently found as macroadenoma. Read More

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Unbiased Label-Free Quantitative Proteomics of Cells Expressing Amyotrophic Lateral Sclerosis (ALS) Mutations in Reveals Activation of the Apoptosis Pathway: A Workflow to Screen Pathogenic Gene Mutations.

Front Mol Neurosci 2021 27;14:627740. Epub 2021 Apr 27.

Centre for Motor Neuron Disease Research, Department of Biomedical Sciences, Faculty of Medicine, Health, and Human Sciences, Macquarie University, North Ryde, NSW, Australia.

The past decade has seen a rapid acceleration in the discovery of new genetic causes of ALS, with more than 20 putative ALS-causing genes now cited. These genes encode proteins that cover a diverse range of molecular functions, including free radical scavenging (e.g. Read More

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Re-evaluating tumors of purported specialized prostatic stromal origin reveals molecular heterogeneity, including non-recurring gene fusions characteristic of uterine and soft tissue sarcoma subtypes.

Mod Pathol 2021 May 13. Epub 2021 May 13.

Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

Tumors of purported specialized prostatic stromal origin comprise prostatic stromal sarcomas (PSS) and stromal tumors of uncertain malignant potential (STUMP). Prior studies have described their clinicopathologic characteristics, but the molecular features remain incompletely understood. Moreover, these neoplasms are morphologically heterogeneous and the lack of specific adjunctive markers of prostatic stromal lineage make precise definition more difficult, leading some to question whether they represent a specific tumor type. Read More

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The landscape and driver potential of site-specific hotspots across cancer genomes.

NPJ Genom Med 2021 May 13;6(1):33. Epub 2021 May 13.

Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.

Large sets of whole cancer genomes make it possible to study mutation hotspots genome-wide. Here we detect, categorize, and characterize site-specific hotspots using 2279 whole cancer genomes from the Pan-Cancer Analysis of Whole Genomes project and provide a resource of annotated hotspots genome-wide. We investigate the excess of hotspots in both protein-coding and gene regulatory regions and develop measures of positive selection and functional impact for individual hotspots. Read More

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Myocardial Lipin 1 knockout in mice approximates cardiac effects of human LPIN1 mutations.

JCI Insight 2021 May 10;6(9). Epub 2021 May 10.

Division of Geriatrics and Nutritional Science, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.

Lipin 1 is a bifunctional protein that is a transcriptional regulator and has phosphatidic acid (PA) phosphohydrolase activity, which dephosphorylates PA to generate diacylglycerol. Human lipin 1 mutations lead to episodic rhabdomyolysis, and some affected patients exhibit cardiac abnormalities, including exercise-induced cardiac dysfunction and cardiac triglyceride accumulation. Furthermore, lipin 1 expression is deactivated in failing heart, but the effects of lipin 1 deactivation in myocardium are incompletely understood. Read More

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Updates in the molecular pathology of non-small cell lung cancer.

Semin Diagn Pathol 2021 Apr 25. Epub 2021 Apr 25.

Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, NSW, Australia; Sydney Medical School, University of Sydney, Sydney, NSW, Australia; School of Medicine, Western Sydney University, Sydney, NSW, Australia. Electronic address:

An understanding of the molecular pathology of non-small cell lung cancer (NSCLC) is important for pathologists as molecular characterization is now required for treatment decisions in advanced stage disease. While assessment for EGFR mutations, ALK and ROS1 fusions, and in some countries BRAF mutations, is now standard practice, other oncogenic mutations are also emerging that may impact routine clinical practice including alterations involving KRAS, NTRK, RET, MET and HER2. In addition, molecular pathology alterations of NSCLC are associated with responses to immune checkpoint therapy and are being increasingly investigated. Read More

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