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1.
Anat Cell Biol ; 2024 May 09.
Article in English | MEDLINE | ID: mdl-38720631

ABSTRACT

Present case report describes a case of bifid ureter arising directly from separate calyces and renal pelvis of the kidney. Incomplete ureter duplication on the left side in a 78-year-old male cadaver was found during an anatomy class. These ureters converged in a Y-shaped pattern just above the level of the anterior superior iliac spine. In the coronal section of the kidney, the anterior ureter arose from a renal pelvis that was divided into two major calyces in the lower two-thirds of the kidney. On the other hand, the posterior ureter was directly connected to a major calyx in the upper third of the kidney, without the formation of a renal pelvis. This anatomical variation has implications for diagnostic approaches, especially in the use of imaging techniques by urologists for the insertion of stents in the treatment of phyelonephritis.

2.
Leukemia ; 2024 Mar 21.
Article in English | MEDLINE | ID: mdl-38514771

ABSTRACT

DEAD box helicase 41 (DDX41) mutations are the most prevalent predisposition to familial myelodysplastic syndrome (MDS). However, the precise roles of these variants in the pathogenesis of MDS have yet to be elucidated. Here, we discovered a novel mechanism by which DDX41 contributes to R-loop-induced DNA damage responses (DDR) in cooperation with the m6A-METTL complex (MAC) and YTHDC1 using DDX41 knockout (KO) and DDX41 knock-in (KI, R525H, Y259C) cell lines as well as primary samples from MDS patients. Compared to wild type (WT), DDX41 KO and KI led to increased levels of m6A RNA methylated R-loop. Interestingly, we found that DDX41 regulates m6A/R-loop levels by interacting with MAC components. Further, DDX41 promoted the recruitment of YTHDC1 to R-loops by promoting the binding between METTL3 and YTHDC1, which was dysregulated in DDX41-deficient cells, contributing to genomic instability. Collectively, we demonstrated that DDX41 plays a key role in the physiological control of R-loops in cooperation with MAC and YTHDC1. These findings provide novel insights into how defects in DDX41 influence MDS pathogenesis and suggest potential therapeutic targets for the treatment of MDS.

3.
Nucleic Acids Res ; 52(1): 259-273, 2024 Jan 11.
Article in English | MEDLINE | ID: mdl-37994723

ABSTRACT

R-loops are three-stranded nucleic acid structures that can cause replication stress by blocking replication fork progression. However, the detailed mechanism underlying the collision of DNA replication forks and R-loops remains elusive. To investigate how R-loops induce replication stress, we use single-molecule fluorescence imaging to directly visualize the collision of replicating Phi29 DNA polymerase (Phi29 DNAp), the simplest replication system, and R-loops. We demonstrate that a single R-loop can block replication, and the blockage is more pronounced when an RNA-DNA hybrid is on the non-template strand. We show that this asymmetry results from secondary structure formation on the non-template strand, which impedes the progression of Phi29 DNAp. We also show that G-quadruplex formation on the displaced single-stranded DNA in an R-loop enhances the replication stalling. Moreover, we observe the collision between Phi29 DNAp and RNA transcripts synthesized by T7 RNA polymerase (T7 RNAp). RNA transcripts cause more stalling because of the presence of T7 RNAp. Our work provides insights into how R-loops impede DNA replication at single-molecule resolution.


Subject(s)
DNA Replication , R-Loop Structures , Single Molecule Imaging , RNA/chemistry , DNA-Directed DNA Polymerase/metabolism
4.
Hemasphere ; 7(11): e977, 2023 Nov.
Article in English | MEDLINE | ID: mdl-37908861

ABSTRACT

Aplastic anemia (AA) is a lethal hematological disorder; however, its pathogenesis is not fully understood. Although immunosuppressive therapy (IST) is a major treatment option for AA, one-third of patients do not respond to IST and its resistance mechanism remains elusive. To understand AA pathogenesis and IST resistance, we performed single-cell RNA sequencing (scRNA-seq) of bone marrow (BM) from healthy controls and patients with AA at diagnosis. We found that CD34+ early-stage erythroid precursor cells and PROM1+ hematopoietic stem cells were significantly depleted in AA, which suggests that the depletion of CD34+ early-stage erythroid precursor cells and PROM1+ hematopoietic stem cells might be one of the major mechanisms for AA pathogenesis related with BM-cell hypoplasia. More importantly, we observed the significant enrichment of CD8+ T cells and T cell-activating intercellular interactions in IST responders, indicating the association between the expansion and activation of T cells and the positive response of IST in AA. Taken together, our findings represent a valuable resource offering novel insights into the cellular heterogeneity in the BM of AA and reveal potential biomarkers for IST, building the foundation for future precision therapies in AA.

5.
Mol Cancer ; 22(1): 177, 2023 11 06.
Article in English | MEDLINE | ID: mdl-37932786

ABSTRACT

BACKGROUND: Although the development of BCR::ABL1 tyrosine kinase inhibitors (TKIs) rendered chronic myeloid leukemia (CML) a manageable condition, acquisition of drug resistance during blast phase (BP) progression remains a critical challenge. Here, we reposition FLT3, one of the most frequently mutated drivers of acute myeloid leukemia (AML), as a prognostic marker and therapeutic target of BP-CML. METHODS: We generated FLT3 expressing BCR::ABL1 TKI-resistant CML cells and enrolled phase-specific CML patient cohort to obtain unpaired and paired serial specimens and verify the role of FLT3 signaling in BP-CML patients. We performed multi-omics approaches in animal and patient studies to demonstrate the clinical feasibility of FLT3 as a viable target of BP-CML by establishing the (1) molecular mechanisms of FLT3-driven drug resistance, (2) diagnostic methods of FLT3 protein expression and localization, (3) association between FLT3 signaling and CML prognosis, and (4) therapeutic strategies to tackle FLT3+ CML patients. RESULTS: We reposition the significance of FLT3 in the acquisition of drug resistance in BP-CML, thereby, newly classify a FLT3+ BP-CML subgroup. Mechanistically, FLT3 expression in CML cells activated the FLT3-JAK-STAT3-TAZ-TEAD-CD36 signaling pathway, which conferred resistance to a wide range of BCR::ABL1 TKIs that was independent of recurrent BCR::ABL1 mutations. Notably, FLT3+ BP-CML patients had significantly less favorable prognosis than FLT3- patients. Remarkably, we demonstrate that repurposing FLT3 inhibitors combined with BCR::ABL1 targeted therapies or the single treatment with ponatinib alone can overcome drug resistance and promote BP-CML cell death in patient-derived FLT3+ BCR::ABL1 cells and mouse xenograft models. CONCLUSION: Here, we reposition FLT3 as a critical determinant of CML progression via FLT3-JAK-STAT3-TAZ-TEAD-CD36 signaling pathway that promotes TKI resistance and predicts worse prognosis in BP-CML patients. Our findings open novel therapeutic opportunities that exploit the undescribed link between distinct types of malignancies.


Subject(s)
Blast Crisis , Leukemia, Myelogenous, Chronic, BCR-ABL Positive , Animals , Mice , Humans , Blast Crisis/drug therapy , Blast Crisis/genetics , Blast Crisis/pathology , Fusion Proteins, bcr-abl/genetics , Drug Resistance, Neoplasm/genetics , Signal Transduction , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Protein Kinase Inhibitors/pharmacology , fms-Like Tyrosine Kinase 3/metabolism
6.
Am J Cancer Res ; 13(7): 3157-3168, 2023.
Article in English | MEDLINE | ID: mdl-37559975

ABSTRACT

Maintaining and transferring intact genomes from one generation to another plays a pivotal role in all living organisms. DNA damage caused by numerous endogenous and exogenous factors must be adequately repaired, as unrepaired and accumulated DNA mutations can cause severe deleterious effects, such as cell death and cancer. To prevent adverse consequences, cells have established DNA damage response mechanisms that address different forms of DNA damage, including DNA double-strand breaks, mismatches, nucleotide excision, and base excision. Among several sources of exogenous DNA damage, bacterial infections cause inflammation in the host, generating reactive oxygen species (ROS) and causing oxidative DNA damage. Recent studies have revealed the importance of the oral microbiome in inflammation and several systemic host diseases. Dysbiosis of oral bacteria can induce chronic inflammation, which enhances ROS-induced DNA damage, and improperly repaired damage can lead to carcinogenesis. This review describes the various DNA repair pathways that are affected by chronic inflammation and the discovery of the DNA damage response induced by oral bacteria such as Porphyromonas gingivalis and Fusobacterium nucleatum.

7.
Exp Mol Med ; 55(8): 1720-1733, 2023 08.
Article in English | MEDLINE | ID: mdl-37524868

ABSTRACT

Autophagy functions in cellular quality control and metabolic regulation. Dysregulation of autophagy is one of the major pathogenic factors contributing to the progression of nonalcoholic fatty liver disease (NAFLD). Autophagy is involved in the breakdown of intracellular lipids and the maintenance of healthy mitochondria in NAFLD. However, the mechanisms underlying autophagy dysregulation in NAFLD remain unclear. Here, we demonstrate that the hepatic expression level of Thrap3 was significantly increased in NAFLD conditions. Liver-specific Thrap3 knockout improved lipid accumulation and metabolic properties in a high-fat diet (HFD)-induced NAFLD model. Furthermore, Thrap3 deficiency enhanced autophagy and mitochondrial function. Interestingly, Thrap3 knockout increased the cytosolic translocation of AMPK from the nucleus and enhanced its activation through physical interaction. The translocation of AMPK was regulated by direct binding with AMPK and the C-terminal domain of Thrap3. Our results indicate a role for Thrap3 in NAFLD progression and suggest that Thrap3 is a potential target for NAFLD treatment.


Subject(s)
Non-alcoholic Fatty Liver Disease , Animals , Mice , AMP-Activated Protein Kinases/metabolism , Autophagy/genetics , Diet, High-Fat/adverse effects , Lipid Metabolism , Liver/metabolism , Mice, Inbred C57BL , Mitochondria/metabolism , Non-alcoholic Fatty Liver Disease/metabolism , Transcription Factors/metabolism , Humans , Hep G2 Cells
8.
Nucleic Acids Res ; 51(15): 7936-7950, 2023 08 25.
Article in English | MEDLINE | ID: mdl-37378431

ABSTRACT

Replication protein A (RPA), a eukaryotic single-stranded DNA (ssDNA) binding protein, dynamically interacts with ssDNA in different binding modes and plays essential roles in DNA metabolism such as replication, repair, and recombination. RPA accumulation on ssDNA due to replication stress triggers the DNA damage response (DDR) by activating the ataxia telangiectasia and RAD3-related (ATR) kinase, which phosphorylates itself and downstream DDR factors, including RPA. We recently reported that the N-methyl-D-aspartate receptor synaptonuclear signaling and neuronal migration factor (NSMF), a neuronal protein associated with Kallmann syndrome, promotes RPA32 phosphorylation via ATR upon replication stress. However, how NSMF enhances ATR-mediated RPA32 phosphorylation remains elusive. Here, we demonstrate that NSMF colocalizes and physically interacts with RPA at DNA damage sites in vivo and in vitro. Using purified RPA and NSMF in biochemical and single-molecule assays, we find that NSMF selectively displaces RPA in the more weakly bound 8- and 20-nucleotide binding modes from ssDNA, allowing the retention of more stable RPA molecules in the 30-nt binding mode. The 30-nt binding mode of RPA enhances RPA32 phosphorylation by ATR, and phosphorylated RPA becomes stabilized on ssDNA. Our findings provide new mechanistic insight into how NSMF facilitates the role of RPA in the ATR pathway.


Subject(s)
Protein Serine-Threonine Kinases , Replication Protein A , Ataxia Telangiectasia Mutated Proteins/metabolism , Checkpoint Kinase 1/metabolism , DNA Damage , DNA Replication , DNA, Single-Stranded , DNA-Binding Proteins/genetics , Phosphorylation , Protein Binding , Protein Kinases/genetics , Protein Serine-Threonine Kinases/metabolism , Replication Protein A/metabolism , Humans
9.
Nucleic Acids Res ; 51(11): 5584-5602, 2023 06 23.
Article in English | MEDLINE | ID: mdl-37140056

ABSTRACT

DNA double-strand break (DSB) repair via homologous recombination is initiated by end resection. The extent of DNA end resection determines the choice of the DSB repair pathway. Nucleases for end resection have been extensively studied. However, it is still unclear how the potential DNA structures generated by the initial short resection by MRE11-RAD50-NBS1 are recognized and recruit proteins, such as EXO1, to DSB sites to facilitate long-range resection. We found that the MSH2-MSH3 mismatch repair complex is recruited to DSB sites through interaction with the chromatin remodeling protein SMARCAD1. MSH2-MSH3 facilitates the recruitment of EXO1 for long-range resection and enhances its enzymatic activity. MSH2-MSH3 also inhibits access of POLθ, which promotes polymerase theta-mediated end-joining (TMEJ). Collectively, we present a direct role of MSH2-MSH3 in the initial stages of DSB repair by promoting end resection and influencing the DSB repair pathway by favoring homologous recombination over TMEJ.


Subject(s)
DNA Repair , Exodeoxyribonucleases , MutS Homolog 2 Protein , MutS Homolog 3 Protein , DNA/metabolism , DNA Breaks, Double-Stranded , DNA End-Joining Repair , Exodeoxyribonucleases/metabolism , Homologous Recombination , MutS Homolog 2 Protein/metabolism , Humans , Cell Line , DNA Helicases/metabolism , MutS Homolog 3 Protein/metabolism
10.
Surg Radiol Anat ; 45(4): 461-468, 2023 Apr.
Article in English | MEDLINE | ID: mdl-36792669

ABSTRACT

PURPOSE: The aim of this study was to determine the width of the fibers that extend from the orbicularis oculi muscle (OOc) to the upper lip, and the lateral and inferior lengths of the OOc at the lateral canthus level. METHODS: The OOc was investigated in the 40 hemifaces of 20 Korean cadavers. The lateral fibers of the OOc (OOc lat) were traced to determine whether or not these fibers extended to the upper lip. RESULTS: The OOc lat extended to the upper lip at the lateral canthus level in 31 of the 40 specimens (77.5%), whereas some inferolateral fibers of the OOc that extended to the upper lip were observed near the level of the lower margin of the OOc in the other 9 specimens (22.5%). The mean ± SD and maximum widths of the OOc lat that extended to the upper lip at the lateral canthus level were 6.9 ± 3.3 mm and 14.3 mm, respectively. CONCLUSION: The obtained data will be helpful to distinguish the muscles that underly the wrinkles around the lateral canthus for safer and more-efficient BoNT-A treatments for crow's feet.


Subject(s)
Botulinum Toxins, Type A , Lacrimal Apparatus , Skin Aging , Humans , Lip , Facial Muscles
11.
Nucleic Acids Res ; 51(2): 631-649, 2023 01 25.
Article in English | MEDLINE | ID: mdl-36594163

ABSTRACT

TRAIP is a key factor involved in the DNA damage response (DDR), homologous recombination (HR) and DNA interstrand crosslink (ICL) repair. However, the exact functions of TRAIP in these processes in mammalian cells are not fully understood. Here we identify the zinc finger protein 212, ZNF212, as a novel binding partner for TRAIP and find that ZNF212 colocalizes with sites of DNA damage. The recruitment of TRAIP or ZNF212 to sites of DNA damage is mutually interdependent. We show that depletion of ZNF212 causes defects in the DDR and HR-mediated repair in a manner epistatic to TRAIP. In addition, an epistatic analysis of Zfp212, the mouse homolog of human ZNF212, in mouse embryonic stem cells (mESCs), shows that it appears to act upstream of both the Neil3 and Fanconi anemia (FA) pathways of ICLs repair. We find that human ZNF212 interacted directly with NEIL3 and promotes its recruitment to ICL lesions. Collectively, our findings identify ZNF212 as a new factor involved in the DDR, HR-mediated repair and ICL repair though direct interaction with TRAIP.


Subject(s)
DNA Repair , Fanconi Anemia , Animals , Mice , Humans , DNA Repair/genetics , DNA Damage , DNA Replication , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Genomics , Fanconi Anemia/genetics , Mammals/metabolism , Ubiquitin-Protein Ligases/metabolism , Nerve Tissue Proteins/genetics
12.
PLoS One ; 17(10): e0276121, 2022.
Article in English | MEDLINE | ID: mdl-36228011

ABSTRACT

OBJECTIVES: The aim of this study was to elucidate the positional relationship between the courses of the angular veins and the facial muscles, and the possible roles of the latter as alternative venous valves. METHODS: The angular veins of 44 specimens of embalmed Korean adult cadavers were examined. Facial muscles were studied to establish their relationships with the angular vein, including the orbicularis oculi (OOc), depressor supercilii (DS), zygomaticus minor (Zmi), zygomaticus major (Zmj), and levator labii superioris (LLS). RESULTS: In the upper face of all specimens, the angular vein passed through the DS and descended to the medial palpebral ligament. In the midface, it passed between the origin of the levator labii superioris alaeque nasi (LLSAN) and the inferior OOc fibers. The vein coursed along the deep surface of the inferior margin of the OOc in all specimens. At the level of the nasal ala, the course of the angular vein was classified into three types: in type I it passed between the LLS and Zmi (38.6%), in type II it passed between the superficial and deep fibers of the Zmi (47.7%), and in type III it passed between the Zmi and Zmj (13.6%). In the lower face of all specimens, the angular or facial vein passed through the anterior lobe of the buccal fat pad. CONCLUSION: This study found that the angular vein coursed along the sites where facial muscle contractions are assumed to efficiently compress the veins, likely controlling venous flow as valves. The observations made and analysis performed in this study will improve the understanding of the physiological function of the facial muscles as alternative venous valves.


Subject(s)
Eyelids , Facial Muscles , Adult , Cadaver , Cheek , Humans , Nose
13.
Anat Cell Biol ; 55(4): 497-500, 2022 Dec 31.
Article in English | MEDLINE | ID: mdl-36044997

ABSTRACT

The orbicularis oculi (OOc) is a sphincteric muscle of the eyelids, whereas contraction of the orbicularis oris (OOr), another sphincteric muscle, causes narrowing of the lips. Facial muscle fibers normally blend with adjacent muscles. However, muscle fibers connecting the various facial muscles that have different actions and that are located at distant sites, such as the OOc and the OOr have been rarely reported. Herein, we report a rare case of connecting fibers between the inferior margin of the OOc and the OOr. These connecting fibers were blended with the OOr between the inserting fibers of the levator labii superioris and levator anguli oris. Contraction of such variant muscles might affect typical facial expressions.

14.
Cell Death Differ ; 29(12): 2381-2398, 2022 12.
Article in English | MEDLINE | ID: mdl-35637285

ABSTRACT

BRCA1-associated protein-1 (BAP1) is a ubiquitin C-terminal hydrolase domain-containing deubiquitinase with tumor suppressor activity. The gene encoding BAP1 is mutated in various human cancers, with particularly high frequency in kidney and skin cancers, and BAP1 is involved in many cancer-related cellular functions, such as DNA repair and genome stability. Although BAP1 stimulates DNA double-strand break repair, whether it functions in nucleotide excision repair (NER) is unknown. Here, we show that BAP1 promotes the repair of ultraviolet (UV)-induced DNA damage via its deubiquitination activity in various cell types, including primary melanocytes. Poly(ADP-ribose) polymerase 1 (PARP1) interacts with and recruits BAP1 to damage sites, with BAP1 recruitment peaking after the DDB2 and XPC damage sensors. BAP1 recruitment also requires histone H2A monoubiquitinated at Lys119, which accumulates at damage sites. PARP1 transiently poly(ADP-ribosyl)ates (PARylates) BAP1 at multiple sites after UV damage and stimulates the deubiquitination activity of BAP1 both intrinsically and via PARylation. PARP1 also promotes BAP1 stability via crosstalk between PARylation and ubiquitination. Many PARylation sites in BAP1 are mutated in various human cancers, among which the glutamic acid (Glu) residue at position 31, with particularly frequent mutation in kidney cancer, plays a critical role in BAP1 stabilization and promotes UV-induced DNA damage repair. Glu31 also participates in reducing the viability of kidney cancer cells. This study therefore reveals that BAP1 functions in the NER pathway and that PARP1 plays a role as a novel factor that regulates BAP1 enzymatic activity, protein stability, and recruitment to damage sites. This activity of BAP1 in NER, along with its cancer cell viability-reducing activity, may account for its tumor suppressor function.


Subject(s)
Kidney Neoplasms , Ubiquitin Thiolesterase , Humans , Ubiquitin Thiolesterase/genetics , Ubiquitin Thiolesterase/metabolism , Poly (ADP-Ribose) Polymerase-1/genetics , Poly (ADP-Ribose) Polymerase-1/metabolism , DNA Damage , DNA Repair , DNA Breaks, Double-Stranded , Tumor Suppressor Proteins/genetics , Tumor Suppressor Proteins/metabolism
15.
EMBO Rep ; 23(7): e53492, 2022 07 05.
Article in English | MEDLINE | ID: mdl-35582821

ABSTRACT

Genome instability is one of the leading causes of gastric cancers. However, the mutational landscape of driver genes in gastric cancer is poorly understood. Here, we investigate somatic mutations in 25 Korean gastric adenocarcinoma patients using whole-exome sequencing and show that PWWP2B is one of the most frequently mutated genes. PWWP2B mutation correlates with lower cancer patient survival. We find that PWWP2B has a role in DNA double-strand break repair. As a nuclear protein, PWWP2B moves to sites of DNA damage through its interaction with UHRF1. Depletion of PWWP2B enhances cellular sensitivity to ionizing radiation (IR) and impairs IR-induced foci formation of RAD51. PWWP2B interacts with MRE11 and participates in homologous recombination via promoting DNA end-resection. Taken together, our data show that PWWP2B facilitates the recruitment of DNA repair machinery to sites of DNA damage and promotes HR-mediated DNA double-strand break repair. Impaired PWWP2B function might thus cause genome instability and promote gastric cancer development.


Subject(s)
Chromosomal Proteins, Non-Histone/metabolism , Stomach Neoplasms , CCAAT-Enhancer-Binding Proteins/metabolism , DNA Breaks, Double-Stranded , DNA Damage , DNA Repair , Genomic Instability , Homologous Recombination , Humans , Rad51 Recombinase/metabolism , Recombinational DNA Repair , Stomach Neoplasms/genetics , Ubiquitin-Protein Ligases/metabolism
16.
Cancer Med ; 11(21): 4005-4020, 2022 11.
Article in English | MEDLINE | ID: mdl-35352878

ABSTRACT

Cobll1 affects blast crisis (BC) progression and tyrosine kinase inhibitor (TKI) resistance in chronic myeloid leukemia (CML). PACSIN2, a novel Cobll1 binding protein, activates TKI-induced apoptosis in K562 cells, and this activation is suppressed by Cobll1 through the interaction between PACSIN2 and Cobll1. PACSIN2 also binds and inhibits SH3BP1 which activates the downstream Rac1 pathway and induces TKI resistance. PACSIN2 competitively interacts with Cobll1 or SH3BP1 with a higher affinity for Cobll1. Cobll1 preferentially binds to PACSIN2, releasing SH3BP1 to promote the SH3BP1/Rac1 pathway and suppress TKI-mediated apoptosis and eventually leading to TKI resistance. Similar interactions among Cobll1, PACSIN2, and SH3BP1 control hematopoiesis during vertebrate embryogenesis. Clinical analysis showed that most patients with CML have Cobll1 and SH3BP1 expression at the BC phase and BC patients with Cobll1 and SH3BP1 expression showed severe progression with a higher blast percentage than those without any Cobll1, PACSIN2, or SH3BP1 expression. Our study details the molecular mechanism of the Cobll1/PACSIN2/SH3BP1 pathway in regulating drug resistance and BC progression in CML.


Subject(s)
Adaptor Proteins, Signal Transducing , GTPase-Activating Proteins , Leukemia, Myelogenous, Chronic, BCR-ABL Positive , Transcription Factors , Humans , Adaptor Proteins, Signal Transducing/genetics , Apoptosis , Blast Crisis , Drug Resistance , Drug Resistance, Neoplasm , GTPase-Activating Proteins/genetics , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Protein Kinase Inhibitors/pharmacology , Transcription Factors/genetics
17.
Article in English | MEDLINE | ID: mdl-35206468

ABSTRACT

The precise location of the Master Knot of Henry (MKH) has important clinical significance, but its anatomical definition has not been agreed upon. The purpose of this study is to present a linear regression equation for predicting length variables based on foot length, by evaluating the correlation of length variables related to flexor hallucis longus (FHL) and flexor digitorum longus (FDL), with respect to the location of the MKH. A total of 95 limbs were dissected from 48 adult cadavers, and were fixed in formalin. Measurements were made for the length parameter, with reference to the landmark. The relevance between length variables was analyzed through simple correlation analysis and linear regression analysis. The foot length was 213.69 ± 17.53 mm, MKH-great toe distal phalanx was 140.16 ± 14.69 mm, MKH-FHL insertion was 124.55 ± 13.46 mm, MKH-little toe distal phalanx was 121.79 ± 13.41 mm, MKH-FDL little toe insertion was 109.07 ± 14.16 mm, and the FHL-FDL angle was 33.15 ± 5.39. The correlation coefficient between all the length variables for foot length showed a high positive correlation. We derived a regression equation that can predict the length of each variable. This regression formula is considered to be highly useful because it can estimate the positional relationship of the MKH relatively simply.


Subject(s)
Foot , Tendons , Adult , Cadaver , Humans , Muscle, Skeletal , Toes
18.
Leuk Res ; 112: 106754, 2022 01.
Article in English | MEDLINE | ID: mdl-34906861

ABSTRACT

To compare the clinical significance of 3-month cytogenetic and molecular monitoring, we analyzed 1,410 paired cytogenetic and molecular data from 705 chronic-phase chronic myeloid leukemia patients. Based on early cytogenetic response (ECyR, Ph+≤35 %) and molecular response (EMR, BCR-ABL1IS≤10 %) at 3 months, the patients were divided into four groups (group 1: ECyR + EMR, n = 560; group 2: no ECyR + EMR, n = 27; group 3: ECyR + no EMR, n = 55; group 4: no ECyR + no EMR, n = 63). By 10 years, major molecular response (MMR), deep molecular response (MR4.5), overall survival (OS), and progression-free survival (PFS) rates were significantly high in group 1 (P < 0.001). Comparing groups 2 and 3, the MMR (P = 0.096), MR4.5 (P = 0.945), OS (P = 0.832), and PFS (P = 0.627) rates tended to be higher in group 2, although not significantly. Thus, the cytogenetic assay can not only be useful but its addition may also provide a more precise prediction of MR4.5.


Subject(s)
Cytogenetic Analysis/methods , Fusion Proteins, bcr-abl/antagonists & inhibitors , Imatinib Mesylate/therapeutic use , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Leukemia, Myeloid, Chronic-Phase/drug therapy , Adolescent , Adult , Aged , Aged, 80 and over , Child , Female , Fusion Proteins, bcr-abl/genetics , Gene Expression Regulation, Leukemic/drug effects , Humans , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology , Leukemia, Myeloid, Chronic-Phase/genetics , Leukemia, Myeloid, Chronic-Phase/pathology , Male , Middle Aged , Progression-Free Survival , Protein Kinase Inhibitors/classification , Protein Kinase Inhibitors/therapeutic use , Reverse Transcriptase Polymerase Chain Reaction , Treatment Outcome , Young Adult
19.
Int. j. morphol ; 40(4): 1043-1047, 2022. ilus
Article in English | LILACS | ID: biblio-1405242

ABSTRACT

SUMMARY: This study aimed to determine the anatomical connections between the inferior fibers of M. orbicularis oculi (OOc inf.) and the M. levator labii superioris alaeque nasi (LLSAN), providing anatomical variations of the connecting fibers. This study examined the OOc and LLSAN of 44 specimens from 22 embalmed adult Korean cadavers. Connecting fibers between the OOc inf. and LLSAN were observed in 29.5 % of the specimens. Connecting patterns of the OOc inf. to the LLSAN were classified into three categories according to the directions of the connecting fibers; Type I (13.6 %), in which some of the OOc inf. coursed medially to blend with the lateral originating fibers of the LLSAN. Type II (11.4 %), in which some of the OOc inf. descended vertically to blend with the LLSAN. Type III (4.5 %), in which both types I and II were found simultaneously. Some of the OOc inf. coursed medially to blend with the lateral originating fibers of the LLSAN, and some of the OOc inf. descended vertically to blend with the LLSAN. These findings provide greater knowledge of the connecting fibers between the OOc inf. and LLSAN, thereby helping us understand complicated expressions, inject BoNT-A into related wrinkles, and analyze EMG activities.


RESUMEN: Este estudio tuvo como objetivo determinar las conexiones anatómicas entre las fibras inferiores del músculo orbicular del ojo (MOO inf.) y el levantador nasolabial (Musculus levator nasiolabialis; M. levator labii superioris alaeque nasi) (LNL), proporcionando variaciones anatómicas de las fibras conectoras. Se examinó el orbicularis oculi (MOO) y LNL de 44 especímenes de 22 cadáveres coreanos adultos embalsamados. Se observaron fibras conectoras entre los MOO inf. y LNL en el 29,5 % de los especímenes. Patrones de conexión del OOc inf. a LNL se clasificaron en tres categorías según las direcciones de las fibras conectoras; Tipo I (13,6 %), en el que algunos de los MOO inf. cursaban medialmente para mezclarse con las fibras de origen lateral del LNL. Tipo II (11,4 %), en el que algunos de los MOO inf. descendían verticalmente para mezclarse con el LNL. Tipo III (4,5 %), en el que se encontraron simultáneamente los tipos I y II. Algunos de los MOO inf. cursaron medialmente para mezclarse con las fibras de origen lateral de la LNL y algunas de las MOO inf. descendían verticalmente para mezclarse con el LNL. Estos hallazgos aportan un mayor conocimiento de las fibras conectoras entre los MOO inf. y LNL, lo que nos ayuda a comprender expresiones complicadas, inyectar BoNT-A en las arrugas relacionadas y analizar las actividades de EMG.


Subject(s)
Humans , Male , Female , Adult , Middle Aged , Aged , Aged, 80 and over , Facial Muscles/anatomy & histology , Oculomotor Muscles/anatomy & histology , Cadaver
20.
Elife ; 102021 12 29.
Article in English | MEDLINE | ID: mdl-34964438

ABSTRACT

Background: Non-alcoholic fatty liver disease (NAFLD) is characterized by excessive lipid accumulation and imbalances in lipid metabolism in the liver. Although nuclear receptors (NRs) play a crucial role in hepatic lipid metabolism, the underlying mechanisms of NR regulation in NAFLD remain largely unclear. Methods: Using network analysis and RNA-seq to determine the correlation between NRs and microRNA in human NAFLD patients, we revealed that MIR20B specifically targets PPARA. MIR20B mimic and anti-MIR20B were administered to human HepG2 and Huh-7 cells and mouse primary hepatocytes as well as high-fat diet (HFD)- or methionine-deficient diet (MCD)-fed mice to verify the specific function of MIR20B in NAFLD. We tested the inhibition of the therapeutic effect of a PPARα agonist, fenofibrate, by Mir20b and the synergic effect of combination of fenofibrate with anti-Mir20b in NAFLD mouse model. Results: We revealed that MIR20B specifically targets PPARA through miRNA regulatory network analysis of nuclear receptor genes in NAFLD. The expression of MIR20B was upregulated in free fatty acid (FA)-treated hepatocytes and the livers of both obesity-induced mice and NAFLD patients. Overexpression of MIR20B significantly increased hepatic lipid accumulation and triglyceride levels. Furthermore, MIR20B significantly reduced FA oxidation and mitochondrial biogenesis by targeting PPARA. In Mir20b-introduced mice, the effect of fenofibrate to ameliorate hepatic steatosis was significantly suppressed. Finally, inhibition of Mir20b significantly increased FA oxidation and uptake, resulting in improved insulin sensitivity and a decrease in NAFLD progression. Moreover, combination of fenofibrate and anti-Mir20b exhibited the synergic effect on improvement of NAFLD in MCD-fed mice. Conclusions: Taken together, our results demonstrate that the novel MIR20B targets PPARA, plays a significant role in hepatic lipid metabolism, and present an opportunity for the development of novel therapeutics for NAFLD. Funding: This research was funded by Korea Mouse Phenotyping Project (2016M3A9D5A01952411), the National Research Foundation of Korea (NRF) grant funded by the Korea government (2020R1F1A1061267, 2018R1A5A1024340, NRF-2021R1I1A2041463, 2020R1I1A1A01074940, 2016M3C9A394589324), and the Future-leading Project Research Fund (1.210034.01) of UNIST.


Subject(s)
Fenofibrate/pharmacology , Hypolipidemic Agents/pharmacology , Lipid Metabolism , MicroRNAs/genetics , Non-alcoholic Fatty Liver Disease/genetics , PPAR alpha/genetics , Animals , Female , Humans , Male , Mice , MicroRNAs/metabolism , Non-alcoholic Fatty Liver Disease/physiopathology , PPAR alpha/metabolism
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