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This is a pragmatic, two-armed, parallel, single-center, randomized controlled clinical trial for comparative evaluation between the effectiveness of integrated Korean medicine (IKM) and herbal medicine treatment with that of IKM monotherapy (control) for post-accident syndrome persistent after the acute phase. Participants were randomized into Herbal Medicine (HM, n = 20) and Control groups (n = 20) to receive the allocated treatment of 1-3 sessions/week for 4 weeks. Intention-to-treat analysis was conducted. The Difference of Numeric Rating Scale (NRS) change of overall post-accident syndromes from baseline to week 5 for the two groups was 1.78 (95% CI: 1.08-2.48; p < 0.001). Regarding secondary outcomes, a significant decrease compared to the baseline values was confirmed for NRS of musculoskeletal, neurological, psychiatric complaints and general symptoms of post-accident syndromes. In a survival analysis based on the recovery criteria of "patients with a reduction in the NRS of overall post-accident syndromes of ≥50%," the HM group showed a shorter time to recovery than the control group during the 17-week study period (p < 0.001 by the log-rank test). IKM combined with herbal medicine treatment significantly improved the quality of life by relieving somatic pain and alleviating the overall post-accident syndrome persistent after the acute phase; this effect was maintained for at least 17 weeks.
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The deregulation of polypeptide N-acetyl-galactosaminyltransferases (GALNTs) contributes to several cancers, but their roles in lung cancer remain unclear. In this study, we have identified a tumor-suppressing role of GALNT3 in lung cancer. We found that GALNT3 suppressed lung cancer development and progression in both xenograft and syngeneic mouse models. Specifically, GALNT3 suppressed lung cancer initiation by inhibiting the self-renewal of lung cancer cells. More importantly, GALNT3 attenuated lung cancer growth by preventing the creation of a favorable tumor microenvironment (TME), which was attributed to GALNT3's ability to inhibit myeloid-derived suppressor cell (MDSC) infiltration into tumor sites and subsequent angiogenesis. We also identified a GALNT3-regulated gene (GRG) signature and found that lung cancer patients whose tumors exhibit the GRG signature showed more favorable prognoses. Further investigation revealed that GALNT3 suppressed lung cancer cell self-renewal by reducing ß-catenin levels, which led to reduced expression of the downstream targets of the WNT pathway. In addition, GALNT3 inhibited MDSC infiltration into tumor sites by suppressing both the TNFR1-NFκB and cMET-pAKT pathways. Specifically, GALNT3 inhibited the nuclear localization of NFκB and the c-MET-induced phosphorylation of AKT. This then led to reduced production of CXCL1, a chemokine required for MDSC recruitment. Finally, we confirmed that the GALNT3-induced inhibition of the TNFR1-NFκB and cMET-pAKT pathways involved the O-GalNAcylation of the TNFR1 and cMET receptors. In summary, we have identified GALNT3 as the first GALNT member capable of suppressing lung cancer and uncovered a novel mechanism by which GALNT3 regulates the TME.
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Malignant characteristics of cancers, represented by rapid cell proliferation and high metastatic potential, are a major cause of high cancer-related mortality. As a multifunctional RNA-binding protein, heterogeneous nuclear ribonucleoprotein K (hnRNPK) is closely associated with cancer progression in various types of cancers. In this study, we sought to identify hnRNPK-regulated long intergenic non-coding RNAs (lincRNAs) that play a critical role in the regulation of cancer malignancy. We found that hnRNPK controlled malignant phenotypes including invasiveness, proliferation, and clonogenicity. RNA sequencing and functional studies revealed that LINC00263, a novel target of hnRNPK, is involved in the oncogenic functions of hnRNPK. Knockdown of LINC00263 mitigated the malignant capabilities. Conversely, increased malignant phenotypes were observed in LINC00263-overexpressing cells. Since LINC00263 was mainly localized in the cytosol and highly enriched in Argonaute 2-immunoprecipitation (Ago2-IP), we hypothesized that LINC00263 acts as a competitive endogenous RNA (ceRNA), and thus sought to identify LINC00263-associated microRNAs. Using small RNA sequencing followed by antisense oligonucleotide pull-down, miR-147a was selected for further study. We found that miR-147a negatively regulates LINC00263 via direct interaction, thus suppressing malignant capabilities. Moreover, knockdown of hnRNPK and LINC00263 upregulated miR-147a, indicating that LINC00263 serves as a ceRNA for miR-147a. By analyzing RNA sequencing data and miRNA target prediction, calpain 2 (CAPN2) was identified as a putative target of miR-147a. Ago2-IP and luciferase reporter assay revealed that miR-147a suppressed CAPN2 expression by directly binding to the 3'UTR of CAPN2 mRNA. In addition, we found that the weakened malignant capabilities following knockdown of hnRNPK or LINC00263 were restored by miR-147a inhibition or CAPN2 overexpression. Furthermore, our findings were validated in various other types of cancer cells including lung cancer, colorectal cancer, neuroblastoma, and melanoma. Collectively, we demonstrate that hnRNPK-regulated LINC00263 plays an important role in cancer malignancy by acting as a miR-147a decoy and thus upregulating CAPN2.
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Ribonucleoproteína Heterogénea-Nuclear Grupo K/metabolismo , MicroARNs/metabolismo , Oncogenes/genética , Células HeLa , Humanos , Fenotipo , TransfecciónRESUMEN
Three Apiaceae species Ledebouriella seseloides, Peucedanum japonicum, and Glehnia littoralis are used as Asian herbal medicines, with the confusingly similar common name "Bang-poong". We characterized the complete chloroplast (cp) genomes and 45S nuclear ribosomal DNA (45S nrDNA) sequences of two accessions for each species. The complete cp genomes of G. littoralis, L. seseloides, and P. japonicum were 147,467, 147,830, and 164,633 bp, respectively. Compared to the other species, the P. japonicum cp genome had a huge inverted repeat expansion and a segmental inversion. The 45S nrDNA cistron sequences of the three species were almost identical in size and structure. Despite the structural variation in the P. japonicum cp genome, phylogenetic analysis revealed that G. littoralis diverged 5-6 million years ago (Mya), while P. japonicum diverged from L. seseloides only 2-3 Mya. Abundant copy number variations including tandem repeats, insertion/deletions, and single nucleotide polymorphisms, were found at the interspecies level. Intraspecies-level polymorphism was also found for L. seseloides and G. littoralis. We developed nine PCR barcode markers to authenticate all three species. This study characterizes the genomic differences between L. seseloides, P. japonicum, and G. littoralis; provides a method of species identification; and sheds light on the evolutionary history of these three species.
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Apiaceae/clasificación , Apiaceae/genética , Código de Barras del ADN Taxonómico , Reordenamiento Génico , Genoma del Cloroplasto , Plantas Medicinales/clasificación , Plantas Medicinales/genética , Cloroplastos/genética , Variaciones en el Número de Copia de ADN , Genómica/métodos , Mutación , Sistemas de Lectura Abierta , Filogenia , ARN Ribosómico/genética , Análisis de Secuencia de ADN , Secuencias Repetidas en TándemRESUMEN
A missense mutation in C. elegans RAD-54, a homolog of RAD54 that operates in the homologous recombination (HR) pathway, was found to decrease ATPase activity in vitro. The hypomorphic mutation caused hypersensitivity of C. elegans germ cells to double-strand DNA breaks (DSBs). Although the formation of RAD-51 foci at DSBs was normal in both the mutant and knockdown worms, their subsequent dissipation was slow. The rad-54-deficient phenotypes were greatly aggravated when combined with an xpf-1 mutation, suggesting a conservative role of single-strand annealing (SSA) for DSB repair in HR-defective worms. The phenotypes of doubly-deficient rad-54;xpf-1 worms were partially suppressed by a mutation of lig-4, a nonhomologous end-joining (NHEJ) factor. In summary, RAD-54 is required for the dissociation of RAD-51 from DSB sites in C. elegans germ cells. Also, NHEJ and SSA exert negative and positive effects, respectively, on genome stability when HR is defective.
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Caenorhabditis elegans/citología , Caenorhabditis elegans/genética , Roturas del ADN de Doble Cadena , Reparación del ADN , ADN de Cadena Simple/metabolismo , Células Germinativas/metabolismo , Recombinación Homóloga , Animales , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , ADN de Cadena Simple/genética , MutaciónRESUMEN
Some polypeptide N-acetyl-galactosaminyltransferases (GALNTs) are associated with cancer, but their function in organ-specific metastasis remains unclear. Here, we report that GALNT14 promotes breast cancer metastasis to the lung by enhancing the initiation of metastatic colonies as well as their subsequent growth into overt metastases. Our results suggest that GALNT14 augments the self-renewal properties of breast cancer cells (BCCs). Furthermore, GALNT14 overcomes the inhibitory effect of lung-derived bone morphogenetic proteins (BMPs) on self-renewal and therefore facilitates metastasis initiation within the lung microenvironment. In addition, GALNT14 supports continuous growth of BCCs in the lung by not only inducing macrophage infiltration but also exploiting macrophage-derived fibroblast growth factors (FGFs). Finally, we identify KRAS-PI3K-c-JUN signalling as an upstream pathway that accounts for the elevated expression of GALNT14 in lung-metastatic BCCs. Collectively, our findings uncover an unprecedented role for GALNT14 in the pulmonary metastasis of breast cancer and elucidate the underlying molecular mechanisms.
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Neoplasias de la Mama/patología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Neoplasias Pulmonares/secundario , N-Acetilgalactosaminiltransferasas/metabolismo , Animales , Benzamidas/farmacología , Receptores de Proteínas Morfogenéticas Óseas/antagonistas & inhibidores , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Diaminas/farmacología , Dioxoles/farmacología , Femenino , Glicosilación , Factores de Intercambio de Guanina Nucleótido , Humanos , Pulmón/patología , Pulmón/fisiología , Ratones , Ratones Desnudos , Mutación , N-Acetilgalactosaminiltransferasas/genética , Neoplasias Experimentales/patología , Pirazoles/farmacología , Quinolinas/farmacología , Receptores Notch/antagonistas & inhibidores , Receptores de Factores de Crecimiento Transformadores beta/antagonistas & inhibidores , Tiazoles/farmacología , Polipéptido N-AcetilgalactosaminiltransferasaRESUMEN
Ceramics in the system (Bi0.5K0.5)TiO3-BiFeO3 have good electromechanical properties and temperature stability. However, the high conductivity inherent in BiFeO3-based ceramics complicates measurement of the ferroelectric properties. In the present work, doping with niobium (Nb) is carried out to reduce the conductivity of (Bi0.5K0.5)TiO3-BiFeO3. Powders of composition 0.4(K0.5Bi0.5)Ti1-xNbxO3-0.6BiFe1-xNbxO3 (x = 0, 0.01 and 0.03) are prepared by the mixed oxide method and sintered at 1050 °C for 1 h. The effect of Nb doping on the structure is examined by X-ray diffraction. The microstructure is examined by scanning electron microscopy. The variation in relative permittivity with temperature is measured using an impedance analyzer. Ferroelectric properties are measured at room temperature using a Sawyer Tower circuit. Piezoelectric properties are measured using a d33 meter and a contact type displacement sensor. All the samples have high density, a rhombohedral unit cell and equiaxed, micron-sized grains. All the samples show relaxor-like behavior. Nb doping causes a reduction in conductivity by one to two orders of magnitude at 200 °C. The samples have narrow P-E loops reminiscent of a linear dielectric. The samples all possess bipolar butterfly S-E loops characteristic of a classic ferroelectric material. Nb doping causes a decrease in d33 and Smax/Emax.
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The Fanconi anemia (FA) pathway recognizes interstrand DNA crosslinks (ICLs) and contributes to their conversion into double-strand DNA breaks, which can be repaired by homologous recombination. Seven orthologs of the 15 proteins associated with Fanconi anemia are functionally conserved in the model organism C. elegans. Here we report that RNF-113, a ubiquitin ligase, is required for RAD-51 focus formation after inducing ICLs in C. elegans. However, the formation of foci of RPA-1 or FCD-2/FANCD2 in the FA pathway was not affected by depletion of RNF-113. Nevertheless, the RPA-1 foci formed did not disappear with time in the depleted worms, implying serious defects in ICL repair. As a result, RNF-113 depletion increased embryonic lethality after ICL treatment in wild-type worms, but it did not increase the ICL-induced lethality of rfs-1/rad51C mutants. In addition, the persistence of RPA-1 foci was suppressed in doubly-deficient rnf-113;rfs-1 worms, suggesting that there is an epistatic interaction between the two genes. These results lead us to suggest that RNF-113 and RFS-1 interact to promote the displacement of RPA-1 by RAD-51 on single-stranded DNA derived from ICLs.