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1.
Ann Geriatr Med Res ; 26(2): 94-124, 2022 Jun.
Article in English | MEDLINE | ID: mdl-35527033

ABSTRACT

BACKGROUND: Dysphagia is a geriatric syndrome. Changes in the whole body that occur with aging also affect swallowing functions and cause presbyphagia. This condition may progress to oropharyngeal and/or esophageal dysphagia in the presence of secondary causes that increase in incidence with aging. However, no study has been published that provides recommendations for use in clinical practice that addresses in detail all aspects of the management of dysphagia in geriatric individuals. This study aimed to answer almost all potential questions and problems in the management of geriatric dysphagia in clinical practice. METHODS: A multidisciplinary team created this recommendation guide using the seven-step and three-round modified Delphi method via e-mail. The study included 39 experts from 29 centers in 14 cities. RESULTS: Based on the 5W and 1H method, we developed 216 detailed recommendations for older adults from the perspective of different disciplines dealing with older people. CONCLUSION: This consensus-based recommendation is a useful guide to address practical clinical questions in the diagnosis, rehabilitation, and follow-up for the management of geriatric dysphagia and also contains detailed commentary on these issues.

2.
Proc Natl Acad Sci U S A ; 115(40): 10076-10081, 2018 10 02.
Article in English | MEDLINE | ID: mdl-30213852

ABSTRACT

Chromosomal rearrangements, including translocations, are early and essential events in the formation of many tumors. Previous studies that defined the genetic requirements for rearrangement formation have identified differences between murine and human cells, most notably in the role of classic and alternative nonhomologous end-joining (NHEJ) factors. We reported that poly(ADP)ribose polymerase 3 (PARP3) promotes chromosomal rearrangements induced by endonucleases in multiple human cell types. We show here that in contrast to classic (c-NHEJ) factors, Parp3 also promotes rearrangements in murine cells, including translocations in murine embryonic stem cells (mESCs), class-switch recombination in primary B cells, and inversions in tail fibroblasts that generate Eml4-Alk fusions. In mESCs, Parp3-deficient cells had shorter deletion lengths at translocation junctions. This was corroborated using next-generation sequencing of Eml4-Alk junctions in tail fibroblasts and is consistent with a role for Parp3 in promoting the processing of DNA double-strand breaks. We confirmed a previous report that Parp1 also promotes rearrangement formation. In contrast with Parp3, rearrangement junctions in the absence of Parp1 had longer deletion lengths, suggesting that Parp1 may suppress double-strand break processing. Together, these data indicate that Parp3 and Parp1 promote rearrangements with distinct phenotypes.


Subject(s)
B-Lymphocytes/metabolism , DNA End-Joining Repair/physiology , Immunoglobulin Class Switching/physiology , Mouse Embryonic Stem Cells/metabolism , Poly(ADP-ribose) Polymerases/metabolism , Anaplastic Lymphoma Kinase , Animals , Fibroblasts/metabolism , Mice , Oncogene Proteins, Fusion/genetics , Oncogene Proteins, Fusion/metabolism , Poly (ADP-Ribose) Polymerase-1/genetics , Poly (ADP-Ribose) Polymerase-1/metabolism , Poly(ADP-ribose) Polymerases/genetics , Receptor Protein-Tyrosine Kinases/genetics , Receptor Protein-Tyrosine Kinases/metabolism
3.
Nature ; 542(7642): 489-493, 2017 02 23.
Article in English | MEDLINE | ID: mdl-28199309

ABSTRACT

Activation-induced cytidine deaminase (AID) is a B-cell-specific enzyme that targets immunoglobulin genes to initiate class switch recombination and somatic hypermutation. In addition, through off-target activity, AID has a much broader effect on genomic instability by initiating oncogenic chromosomal translocations and mutations involved in the development and progression of lymphoma. AID expression is tightly regulated in B cells and its overexpression leads to enhanced genomic instability and lymphoma formation. The phosphatidylinositol 3-kinase δ (PI3Kδ) pathway regulates AID by suppressing its expression in B cells. Drugs for leukaemia or lymphoma therapy such as idelalisib, duvelisib and ibrutinib block PI3Kδ activity directly or indirectly, potentially affecting AID expression and, consequently, genomic stability in B cells. Here we show that treatment of primary mouse B cells with idelalisib or duvelisib, and to a lesser extent ibrutinib, enhanced the expression of AID and increased somatic hypermutation and chromosomal translocation frequency to the Igh locus and to several AID off-target sites. Both of these effects were completely abrogated in AID-deficient B cells. PI3Kδ inhibitors or ibrutinib increased the formation of AID-dependent tumours in pristane-treated mice. Consistently, PI3Kδ inhibitors enhanced AID expression and translocation frequency to IGH and AID off-target sites in human chronic lymphocytic leukaemia and mantle cell lymphoma cell lines, and patients treated with idelalisib, but not ibrutinib, showed increased somatic hypermutation in AID off-targets. In summary, we show that PI3Kδ or Bruton's tyrosine kinase inhibitors increase genomic instability in normal and neoplastic B cells by an AID-dependent mechanism. This effect should be carefully considered, as such inhibitors can be administered to patients for years.


Subject(s)
B-Lymphocytes/drug effects , B-Lymphocytes/metabolism , Class I Phosphatidylinositol 3-Kinases/antagonists & inhibitors , Genomic Instability/drug effects , Phosphoinositide-3 Kinase Inhibitors , Adenine/analogs & derivatives , Agammaglobulinaemia Tyrosine Kinase , Animals , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacology , B-Lymphocytes/enzymology , B-Lymphocytes/pathology , Cell Line, Tumor , Class I Phosphatidylinositol 3-Kinases/metabolism , Cytidine Deaminase/metabolism , Enzyme Inhibitors/adverse effects , Enzyme Inhibitors/pharmacology , Female , Humans , Immunoglobulin Class Switching/drug effects , Immunoglobulin Heavy Chains/genetics , Isoquinolines/adverse effects , Isoquinolines/pharmacology , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/pathology , Lymphoma, Mantle-Cell/genetics , Lymphoma, Mantle-Cell/pathology , Mice , Phosphatidylinositol 3-Kinases/metabolism , Piperidines , Protein-Tyrosine Kinases/antagonists & inhibitors , Purines/adverse effects , Purines/pharmacology , Pyrazoles/adverse effects , Pyrazoles/pharmacology , Pyrimidines/adverse effects , Pyrimidines/pharmacology , Quinazolinones/adverse effects , Quinazolinones/pharmacology , Recombination, Genetic/drug effects , Somatic Hypermutation, Immunoglobulin/drug effects , Translocation, Genetic/drug effects
4.
Cell Rep ; 9(4): 1219-27, 2014 Nov 20.
Article in English | MEDLINE | ID: mdl-25456124

ABSTRACT

Generation of genetically engineered mouse models (GEMMs) for chromosomal translocations in the endogenous loci by a knockin strategy is lengthy and costly. The CRISPR/Cas9 system provides an innovative and flexible approach for genome engineering of genomic loci in vitro and in vivo. Here, we report the use of the CRISPR/Cas9 system for engineering a specific chromosomal translocation in adult mice in vivo. We designed CRISPR/Cas9 lentiviral vectors to induce cleavage of the murine endogenous Eml4 and Alk loci in order to generate the Eml4-Alk gene rearrangement recurrently found in non-small-cell lung cancers (NSCLCs). Intratracheal or intrapulmonary inoculation of lentiviruses induced Eml4-Alk gene rearrangement in lung cells in vivo. Genomic and mRNA sequencing confirmed the genome editing and the production of the Eml4-Alk fusion transcript. All mice developed Eml4-Alk-rearranged lung tumors 2 months after the inoculation, demonstrating that the CRISPR/Cas9 system is a feasible and simple method for the generation of chromosomal rearrangements in vivo.


Subject(s)
CRISPR-Associated Proteins/metabolism , Clustered Regularly Interspaced Short Palindromic Repeats/genetics , Gene Rearrangement , Genetic Engineering/methods , Translocation, Genetic/genetics , Animals , Base Sequence , Carcinogenesis/genetics , Carcinogenesis/pathology , HEK293 Cells , Humans , Lung Neoplasms/genetics , Mice , Molecular Sequence Data , Oncogene Proteins, Fusion/genetics , Oncogene Proteins, Fusion/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism
5.
Tissue Eng Part A ; 20(15-16): 2088-101, 2014 Aug.
Article in English | MEDLINE | ID: mdl-24842693

ABSTRACT

Musculoskeletal tissue engineering aims at repairing and regenerating damaged tissues using biological tissue substitutes. One approach to achieve this aim is to develop osteoconductive scaffolds that facilitate the formation of functional bone tissue. We have fabricated nanoclay-enriched electrospun poly(ɛ-caprolactone) (PCL) scaffolds for osteogenic differentiation of human mesenchymal stem cells (hMSCs). A range of electrospun scaffolds is fabricated by varying the nanoclay concentrations within the PCL scaffolds. The addition of nanoclay decreases fiber diameter and increases surface roughness of electrospun fibers. The enrichment of PCL scaffold with nanoclay promotes in vitro biomineralization when subjected to simulated body fluid (SBF), indicating bioactive characteristics of the hybrid scaffolds. The degradation rate of PCL increases due to the addition of nanoclay. In addition, a significant increase in crystallization temperature of PCL is also observed due to enhanced surface interactions between PCL and nanoclay. The effect of nanoclay on the mechanical properties of electrospun fibers is also evaluated. The feasibility of using nanoclay-enriched PCL scaffolds for tissue engineering applications is investigated in vitro using hMSCs. The nanoclay-enriched electrospun PCL scaffolds support hMSCs adhesion and proliferation. The addition of nanoclay significantly enhances osteogenic differentiation of hMSCs on the electrospun scaffolds as evident by an increase in alkaline phosphates activity of hMSCs and higher deposition of mineralized extracellular matrix compared to PCL scaffolds. Given its unique bioactive characteristics, nanoclay-enriched PCL fibrous scaffold may be used for musculoskeletal tissue engineering.


Subject(s)
Cell Differentiation/drug effects , Mesenchymal Stem Cells/cytology , Nanoparticles/chemistry , Osteogenesis/drug effects , Polyesters/pharmacology , Tissue Engineering/methods , Tissue Scaffolds/chemistry , Alkaline Phosphatase/metabolism , Bone Matrix/drug effects , Bone Matrix/physiology , Calcification, Physiologic/drug effects , Cell Adhesion/drug effects , Cell Proliferation/drug effects , Humans , Mechanical Phenomena/drug effects , Mesenchymal Stem Cells/drug effects , Mesenchymal Stem Cells/enzymology , Nanofibers/chemistry , Temperature
6.
Nat Methods ; 10(4): 361-5, 2013 Apr.
Article in English | MEDLINE | ID: mdl-23503052

ABSTRACT

We present a genome-wide approach to map DNA double-strand breaks (DSBs) at nucleotide resolution by a method we termed BLESS (direct in situ breaks labeling, enrichment on streptavidin and next-generation sequencing). We validated and tested BLESS using human and mouse cells and different DSBs-inducing agents and sequencing platforms. BLESS was able to detect telomere ends, Sce endonuclease-induced DSBs and complex genome-wide DSB landscapes. As a proof of principle, we characterized the genomic landscape of sensitivity to replication stress in human cells, and we identified >2,000 nonuniformly distributed aphidicolin-sensitive regions (ASRs) overrepresented in genes and enriched in satellite repeats. ASRs were also enriched in regions rearranged in human cancers, with many cancer-associated genes exhibiting high sensitivity to replication stress. Our method is suitable for genome-wide mapping of DSBs in various cells and experimental conditions, with a specificity and resolution unachievable by current techniques.


Subject(s)
DNA Breaks, Double-Stranded , Genomics/methods , Nucleic Acid Amplification Techniques/methods , Animals , Aphidicolin , Base Sequence , Cell Line, Tumor , Cloning, Molecular , DNA Replication , Fibroblasts/metabolism , Humans , Male , Mice , Mice, Inbred C57BL , Microsatellite Repeats , Physical Chromosome Mapping/methods , Sequence Analysis, DNA , Spleen , Testis , Virus Replication
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