RESUMEN
Gemcitabine is a nucleoside analog widely used as an anticancer agent against several types of cancer. Although gemcitabine sometimes shows excellent effectiveness, cancer cells are often poorly responsive to or resistant to the drug. Recently, specific strains or dysbiosis of the human microbiome were correlated with drug reactivity and resistance acquisition. Therefore, we aimed to identify antibiotic compounds that can modulate the microbiome to enhance the responsiveness to gemcitabine. To achieve this, we confirmed the gemcitabine responsiveness based on public data and conducted drug screening on a set of 250 antibiotics compounds. Subsequently, we performed experiments to investigate whether the selected compounds could enhance the responsiveness to gemcitabine. First, we grouped a total of seven tumor cell lines into resistant and sensitive group based on the IC50 value (1 µM) of gemcitabine obtained from the public data. Second, we performed high-throughput screening with compound treatments, identifying seven compounds from the resistant group and five from the sensitive group based on dose dependency. Finally, the combination of the selected compound, puromycin dihydrochloride, with gemcitabine in gemcitabine-resistant cell lines resulted in extensive cell death and a significant increase in cytotoxic efficacy. Additionally, mRNA levels associated with cell viability and stemness were reduced. Through this study, we screened antibiotics to further improve the efficacy of existing anticancer drugs and overcome resistance. By combining existing anticancer agents and antibiotic substances, we hope to establish various drug combination therapies and ultimately improve cancer treatment efficacy.
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Antibacterianos , Desoxicitidina , Resistencia a Antineoplásicos , Ensayos de Selección de Medicamentos Antitumorales , Gemcitabina , Ensayos Analíticos de Alto Rendimiento , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacología , Humanos , Ensayos Analíticos de Alto Rendimiento/métodos , Resistencia a Antineoplásicos/efectos de los fármacos , Línea Celular Tumoral , Antibacterianos/farmacología , Ensayos de Selección de Medicamentos Antitumorales/métodos , Puromicina/farmacología , Antimetabolitos Antineoplásicos/farmacología , Sinergismo Farmacológico , Antineoplásicos/farmacología , Bibliotecas de Moléculas Pequeñas/farmacologíaRESUMEN
The asymmetric division of stem cells permits the maintenance of the cell population and differentiation for harmonious progress. Developing mouse incisors allows inspection of the role of the stem cell niche to provide specific insights into essential developmental phases. Microtubule-associated serine/threonine kinase family member 4 (Mast4) knockout (KO) mice showed abnormal incisor development with low hardness, as the size of the apical bud was decreased and preameloblasts were shifted to the apical side, resulting in amelogenesis imperfecta. In addition, Mast4 KO incisors showed abnormal enamel maturation, and stem cell maintenance was inhibited as amelogenesis was accelerated with Wnt signal downregulation. Distal-Less Homeobox 3 (DLX3), a critical factor in tooth amelogenesis, is considered to be responsible for the development of amelogenesis imperfecta in humans. MAST4 directly binds to DLX3 and induces phosphorylation at three residues within the nuclear localization site (NLS) that promotes the nuclear translocation of DLX3. MAST4-mediated phosphorylation of DLX3 ultimately controls the transcription of DLX3 target genes, which are carbonic anhydrase and ion transporter genes involved in the pH regulation process during ameloblast maturation. Taken together, our data reveal a novel role for MAST4 as a critical regulator of the entire amelogenesis process through its control of Wnt signaling and DLX3 transcriptional activity.
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Amelogénesis , Proteínas de Homeodominio , Ratones Noqueados , Células Madre , Factores de Transcripción , Animales , Humanos , Ratones , Amelogénesis/genética , Diferenciación Celular/genética , Epitelio/metabolismo , Proteínas de Homeodominio/metabolismo , Proteínas de Homeodominio/genética , Fosforilación , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Células Madre/metabolismo , Células Madre/citología , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Vía de Señalización WntRESUMEN
Advances in brain-machine interfaces and wearable biomedical sensors for healthcare and human-computer interactions call for precision electrophysiology to resolve a variety of biopotential signals across the body that cover a wide range of frequencies, from the mHz-range electrogastrogram (EGG) to the kHz-range electroneurogram (ENG). Existing integrated wearable solutions for minimally invasive biopotential recordings are limited in detection range and accuracy due to trade-offs in bandwidth, noise, input impedance, and power consumption. This article presents a 16-channel wide-band ultra-low-noise neural recording system-on-chip (SoC) fabricated in 65nm CMOS for chronic use in mobile healthcare settings that spans a bandwidth of 0.001 Hz to 1 kHz through a featured sample-level duty-cycling (SLDC) mode. Each recording channel is implemented by a delta-sigma analog-to-digital converter (ADC) achieving 1.0 µ V rms input-referred noise over 1Hz-1kHz bandwidth with a Noise Efficiency Factor (NEF) of 2.93 in continuous operation mode. In SLDC mode, the power supply is duty-cycled while maintaining consistently low input-referred noise levels at ultra-low frequencies (1.1 µV rms over 0.001Hz-1Hz) and 435 M Ω input impedance. The functionalities of the proposed SoC are validated with two human electrophysiology applications: recording low-amplitude electroencephalogram (EEG) through electrodes fixated on the forehead to monitor brain waves, and ultra-slow-wave electrogastrogram (EGG) through electrodes fixated on the abdomen to monitor digestion.
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Ondas Encefálicas , Electroencefalografía , Humanos , Diseño de Equipo , Electrodos , Impedancia Eléctrica , Amplificadores ElectrónicosRESUMEN
We here demonstrate that SERTAD1 is an adaptor protein responsible for the regulation of lysine 63 (K63)-linked NLRP3 polyubiquitination by the Cullin1 E3 ubiquitin ligase upon inflammasome activation. SERTAD1 specifically binds to NLRP3 but not to other inflammasome sensors. This endogenous interaction increases after inflammasome activation, interfering with the interaction between NLRP3 and Cullin1. Interleukin (IL)-1ß and IL-18 secretion, as well as the cleavage of gasdermin D, are decreased in SERTAD1 knockout bone-marrow-derived macrophages, together with reduced formation of the NLRP3 inflammasome complex. Additionally, SERTAD1-deficient mice show attenuated severity of monosodium-uric-acid-induced peritonitis and experimental autoimmune encephalomyelitis. Analysis of public datasets indicates that expression of SERTAD1 mRNA is significantly increased in the patients of autoimmune diseases. Thus, our findings uncover a function of SERTAD1 that specifically reduces Cullin1-mediated NLRP3 polyubiquitination via direct binding to NLRP3, eventually acting as a crucial factor to regulate the initiation of NLRP3-mediated inflammasome activation.
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Inflamasomas , Proteína con Dominio Pirina 3 de la Familia NLR , Animales , Humanos , Ratones , Inflamasomas/metabolismo , Macrófagos/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , UbiquitinaciónRESUMEN
BACKGROUND: Multinucleation is a hallmark of osteoclast formation and has a unique ability to resorb bone matrix. During osteoclast differentiation, the cytoskeleton reorganization results in the generation of actin belts and eventual bone resorption. Tetraspanins are involved in adhesion, migration and fusion in various cells. However, its function in osteoclast is still unclear. In this study, we identified Tm4sf19, a member of the tetraspanin family, as a regulator of osteoclast function. MATERIALS AND METHODS: We investigate the effect of Tm4sf19 deficiency on osteoclast differentiation using bone marrow-derived macrophages obtained from wild type (WT), Tm4sf19 knockout (KO) and Tm4sf19 LELΔ mice lacking the large extracellular loop (LEL). We analyzed bone mass of young and aged WT, KO and LELΔ mice by µCT analysis. The effects of Tm4sf19 LEL-Fc fusion protein were accessed in osteoclast differentiation and osteoporosis animal model. RESULTS: We found that deficiency of Tm4sf19 inhibited osteoclast function and LEL of Tm4sf19 was responsible for its function in osteoclasts in vitro. KO and LELΔ mice exhibited higher trabecular bone mass compared to WT mice. We found that Tm4sf19 interacts with integrin αvß3 through LEL, and that this binding is important for cytoskeletal rearrangements in osteoclast by regulating signaling downstream of integrin αvß3. Treatment with LEL-Fc fusion protein inhibited osteoclast function in vitro and administration of LEL-Fc prevented bone loss in an osteoporosis mouse model in vivo. CONCLUSION: We suggest that Tm4sf19 regulates osteoclast function and that LEL-Fc may be a promising drug to target bone destructive diseases caused by osteoclast hyper-differentiation.
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Enfermedades Óseas , Resorción Ósea , Osteoporosis , Tetraspaninas , Animales , Ratones , Resorción Ósea/genética , Resorción Ósea/metabolismo , Diferenciación Celular , Integrina alfaVbeta3/metabolismo , Osteoclastos , Osteoporosis/genética , Osteoporosis/metabolismo , Tetraspaninas/genética , Tetraspaninas/metabolismoRESUMEN
Atopic dermatitis (AD) treatment has largely relied on non-specific broad immunosuppressants despite their long-term toxicities until the approval of dupilumab, which blocks IL-4 signaling to target Th2 cell responses. Here, we report the discovery of compound 4aa, a novel compound derived from the structure of chlorophyll a, and the efficacy of chlorophyll a to alleviate AD symptoms by oral administration in human AD patients. 4aa downregulated GATA3 and IL-4 in differentiating Th2 cells by potently blocking IL-4 receptor dimerization. In the murine model, oral administration of 4aa reduced the clinical severity of symptoms and scratching behavior by 76% and 72%, respectively. Notably, the elevated serum levels of Th2 cytokines reduced to levels similar to those in the normal group after oral administration of 4aa. Additionally, the toxicological studies showed favorable safety profiles and good tolerance. In conclusion, 4aa may be applied for novel therapeutic developments for patients with AD.
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Dermatitis Atópica , Humanos , Ratones , Animales , Dermatitis Atópica/tratamiento farmacológico , Células Th2 , Clorofila A , Interleucina-4 , Citocinas , Diferenciación CelularRESUMEN
KIAA1324 is a transmembrane protein largely reported as a tumor suppressor and favorable prognosis marker in various cancers, including gastric cancer. In this study, we report the role of N-linked glycosylation in KIAA1324 as a functional post-translational modification (PTM). Loss of N-linked glycosylation eliminated the potential of KIAA1324 to suppress cancer cell proliferation and migration. Furthermore, we demonstrated that KIAA1324 undergoes fucosylation, a modification of the N-glycan mediated by fucosyltransferase, and inhibition of fucosylation also significantly suppressed KIAA1324-induced cell growth inhibition and apoptosis of gastric cancer cells. In addition, KIAA1324-mediated apoptosis and tumor regression were inhibited by the loss of N-linked glycosylation. RNA sequencing (RNAseq) analysis revealed that genes most relevant to the apoptosis and cell cycle arrest pathways were modulated by KIAA1324 with the N-linked glycosylation, and Gene Regulatory Network (GRN) analysis suggested novel targets of KIAA1324 for anti-tumor effects in the transcription level. The N-linked glycosylation blockade decreased protein stability through rapid proteasomal degradation. The non-glycosylated mutant also showed altered localization and lost apoptotic activity that inhibits the interaction between GRP78 and caspase 7. These data demonstrate that N-linked glycosylation of KIAA1324 is essential for the suppressive role of KIAA1324 protein in gastric cancer progression and indicates that KIAA1324 may have anti-tumor effects by targeting cancer-related genes with N-linked glycosylation. In conclusion, our study suggests the PTM of KIAA1324 including N-linked glycosylation and fucosylation is a necessary factor to consider for cancer prognosis and therapy improvement.
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Neoplasias Gástricas , Humanos , Neoplasias Gástricas/genética , Glicosilación , Procesamiento Proteico-Postraduccional , FucosiltransferasasRESUMEN
The incidence of colitis-associated colorectal cancer (CAC) has increased due to a high-nutrient diet, increased environmental stimuli and inherited gene mutations. To adequately treat CAC, drugs should be developed by identifying novel therapeutic targets. E3 ubiquitin-protein ligase pellino homolog 3 (pellino 3; Peli3) is a RING-type E3 ubiquitin ligase involved in inflammatory signalling; however, its role in the development and progression of CAC has not been elucidated. In this study, we studied Peli3-deficient mice in an azoxymethane/dextran sulphate sodium-induced CAC model. We observed that Peli3 promotes colorectal carcinogenesis with increased tumour burden and oncogenic signalling pathways. Ablation of Peli3 reduced inflammatory signalling activation at the early stage of carcinogenesis. Mechanistic studies indicate that Peli3 enhances toll-like receptor 4 (TLR4)-mediated inflammation through ubiquitination-dependent degradation of interferon regulatory factor 4, a negative regulator of TLR4 in macrophages. Our study suggests an important molecular link between Peli3 and colonic inflammation-mediated carcinogenesis. Furthermore, Peli3 can be a therapeutic target in the prevention and treatment of CAC.
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Neoplasias Asociadas a Colitis , Receptor Toll-Like 4 , Animales , Ratones , Carcinogénesis/genética , Neoplasias Asociadas a Colitis/genética , Inflamación/complicaciones , Factores Reguladores del Interferón/metabolismo , Ratones Endogámicos C57BL , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/metabolismo , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
BACKGROUND: Silent information regulator 1 (SIRT1), a type III histone deacetylase, is involved in various cutaneous and systemic autoimmune diseases including systemic lupus erythematosus, rheumatoid arthritis, and psoriasis. However, little is known about the role of SIRT1 in the development of alopecia areata (AA). OBJECTIVES: This study investigated whether SIRT1 regulates the hair follicle immune system and is involved in AA pathogenesis. METHODS: SIRT1 expression in human scalp tissue was analyzed using immunohistochemical staining, qPCR, and western blotting. The regulatory effect of SIRT1 was evaluated after stimulation with the double-stranded RNA mimic polyinosinic:polycytidylic acid (poly I:C) in hair follicle outer root sheath (ORS) cells and C3H/HeJ mice. RESULTS: SIRT1 expression was significantly reduced in the AA scalp compared to the normal scalp. SIRT1 inhibition upregulated MHC class I polypeptide-related sequence A and UL16 binding protein 3 in hair follicle ORS cells. SIRT1 inhibition also promoted the production of Th1 cytokines (IFN-γ and TNF-α), IFN-inducible chemokines (CXCL9 and CXCL10), and T cell migration in ORS cells. Conversely, SIRT1 activation suppressed the autoreactive inflammatory responses. The counteractive effect of the immune response by SIRT1 was mediated through the deacetylation of NF-κB and phosphorylation of STAT3. CONCLUSION: SIRT1 downregulation induces immune-inflammatory responses in hair follicle ORS cells and may contribute to AA development.
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Alopecia Areata , Ratones , Animales , Humanos , Folículo Piloso/metabolismo , Sirtuina 1/metabolismo , Regulación hacia Abajo , Ratones Endogámicos C3H , InmunidadRESUMEN
The signaling pathways governing acetaminophen (APAP)-induced liver injury have been extensively studied. However, little is known about the ubiquitin-modifying enzymes needed for the regulation of APAP-induced liver injury. Here, we examined whether the Pellino3 protein, which has E3 ligase activity, is needed for APAP-induced liver injury and subsequently explored its molecular mechanism. Whole-body Peli3-/- knockout (KO) and adenovirus-mediated Peli3 knockdown (KD) mice showed reduced levels of centrilobular cell death, infiltration of immune cells, and biomarkers of liver injury, such as alanine aminotransferase (ALT) and aspartate aminotransferase (AST), upon APAP treatment compared to wild-type (WT) mice. Peli3 deficiency in primary hepatocytes decreased mitochondrial and lysosomal damage and reduced the mitochondrial reactive oxygen species (ROS) levels. In addition, the levels of phosphorylation at serine 9 in the cytoplasm and mitochondrial translocation of GSK3ß were decreased in primary hepatocytes obtained from Peli3-/- KO mice, and these reductions were accompanied by decreases in JNK phosphorylation and mitochondrial translocation. Pellino3 bound more strongly to GSK3ß compared with JNK1 and JNK2 and induced the lysine 63 (K63)-mediated polyubiquitination of GSK3ß. In rescue experiments, the ectopic expression of wild-type Pellino3 in Peli3-/- KO hepatocytes restored the mitochondrial translocation of GSK3ß, but this restoration was not obtained with expression of a catalytically inactive mutant of Pellino3. These findings are the first to suggest a mechanistic link between Pellino3 and APAP-induced liver injury through the modulation of GSK3ß polyubiquitination.
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Acetaminofén , Enfermedad Hepática Crónica Inducida por Sustancias y Drogas , Animales , Ratones , Acetaminofén/efectos adversos , Fosforilación , Glucógeno Sintasa Quinasa 3 beta/genética , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Enfermedad Hepática Crónica Inducida por Sustancias y Drogas/metabolismo , Hígado/metabolismo , Hepatocitos/metabolismo , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo , Ratones Endogámicos C57BLRESUMEN
Osteosarcoma (OS) is an aggressive malignant bone cancer, with refractory and metastatic disease remaining a significant challenge. Transforming growth factor-ß1 (TGF-ß) is a potent immune suppressive cytokine in OS and the TGF-ß is increased in the sera of OS patients and this increase is associated with high-grade OS and lung metastases. Therefore, blocking TGF-ß1 signaling may be a novel therapy for OS treatment. Here we show that blocking TGF-ß1 signaling using TGF-ßR1 inhibitor, Vactosertib, significantly inhibited OS proliferation in vitro and in vivo. Notably, Vactosertib inhibits c-Myc expression in the OS cells. Vactosertib increased immune effectors (IFNγ+CD8+ cells and NK cells) and inhibited immune suppressors (M2-like TAM, MDSC) in the OS tumor microenvironment. Our results suggest that inhibition of TGF-ß1 signaling is an effective therapeutic strategy against OS through a multi-pronged approach that targets tumor intrinsic and extrinsic factors to achieve optimal immune-effector functions and maximal clinical response.
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Animal models have been utilized to understand the pathogenesis of Zellweger spectrum disorders (ZSDs); however, the link between clinical manifestations and molecular pathways has not yet been clearly established. We generated peroxin 5 homozygous mutant zebrafish (pex5-/-) to gain insight into the molecular pathogenesis of peroxisome dysfunction. pex5-/- display hallmarks of ZSD in humans and die within one month after birth. Fasting rapidly depletes lipids and glycogen in pex5-/- livers and expedites their mortality. Mechanistically, deregulated mitochondria and mechanistic target of rapamycin (mTOR) signaling act together to induce metabolic alterations that deplete hepatic nutrients and accumulate damaged mitochondria. Accordingly, chemical interventions blocking either the mitochondrial function or mTOR complex 1 (mTORC1) or a combination of both improve the metabolic imbalance shown in the fasted pex5-/- livers and extend the survival of animals. In addition, the suppression of oxidative stress by N-acetyl L-cysteine (NAC) treatment rescued the apoptotic cell death and early mortality observed in pex5-/-. Furthermore, an autophagy activator effectively ameliorated the early mortality of fasted pex5-/-. These results suggest that fasting may be detrimental to patients with peroxisome dysfunction, and that modulating the mitochondria, mTORC1, autophagy activities, or oxidative stress may provide a therapeutic option to alleviate the symptoms of peroxisomal diseases associated with metabolic dysfunction.
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Ayuno , Mitocondrias , Receptor de la Señal 1 de Direccionamiento al Peroxisoma , Pez Cebra , Animales , Humanos , Autofagia/fisiología , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Mitocondrias/metabolismo , Peroxisomas/metabolismo , Serina-Treonina Quinasas TOR/genética , Serina-Treonina Quinasas TOR/metabolismo , Pez Cebra/genética , Pez Cebra/metabolismo , Receptor de la Señal 1 de Direccionamiento al Peroxisoma/genética , Receptor de la Señal 1 de Direccionamiento al Peroxisoma/metabolismoRESUMEN
Pancreatic ductal adenocarcinoma (PDAC) is the most lethal type of cancer and the third leading cause of cancer death with the lowest 5-year survival rate. Heterogeneity, difficulty in diagnosis, and rapid metastatic progression are the causes of high mortality in pancreatic cancer. Recent studies have shown that Protein arginine methyltransferase 5 (PRMT5) is overexpressed in pancreatic cancers, and these patients have a worse prognosis. Recently, PRMT5 as an anti-cancer target has gained considerable interest. In this study, we investigated whether inhibition of PRMT5 activity was synergistic with blockade of TGF-ß1 signaling, which plays an important role in the construction of the desmoplastic matrix in pancreatic cancer and induces therapeutic vulnerability. Compared with T1-44, a selective inhibitor of PRMT5 activity, the combination of T1-44 with the TGF-ß1 signaling inhibitor Vactosertib significantly reduced tumor size and surrounding tissue invasion and significantly improved long-term survival. RNA sequencing analysis of mouse tumors revealed that the combination of T1-44 and Vactosertib significantly altered the expression of genes involved in cancer progression, such as cell migration, extracellular matrix, and apoptotic processes. In particular, the expression of Btg2, known as a tumor suppressor factor in various cancers, was markedly induced by combination treatment. Ectopic overexpression of Btg2 inhibited the EMT response, blocking cell migration, and promoted cancer cell death. These data demonstrate that the combination therapy of T1-44 with Vactosertib is synergistic for pancreatic cancer, suggesting that this novel combination therapy has value in the treatment strategy of patients with pancreatic cancer.
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Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Animales , Ratones , Factor de Crecimiento Transformador beta1/metabolismo , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Inhibidores Enzimáticos/uso terapéutico , Línea Celular Tumoral , Neoplasias PancreáticasRESUMEN
Spermatogonial stem cell (SSC) self-renewal is regulated by reciprocal interactions between Sertoli cells and SSCs in the testis. In a previous study, microtubule-associated serine/threonine kinase 4 (MAST4) has been studied in Sertoli cells as a regulator of SSC self-renewal. The present study focused on the mechanism by which MAST4 in Sertoli cells transmits the signal and regulates SSCs, especially cell cycle regulation. The expression of PLZF, CDK2 and PLZF target genes was examined in WT and Mast4 KO testes by Immunohistochemistry, RT-qPCR and western blot. In addition, IdU and BrdU were injected into WT and Mast4 KO mice and cell cycle of SSCs was analysed. Finally, the testis tissues were cultured in vitro to examine the regulation of cell cycle by MAST4 pathway. Mast4 KO mice showed infertility with Sertoli cell-only syndrome and reduced sperm count. Furthermore, Mast4 deletion led to decreased PLZF expression and cell cycle progression in the testes. MAST4 also induced cyclin-dependent kinase 2 (CDK2) to phosphorylate PLZF and activated PLZF suppressed the transcriptional levels of genes related to cell cycle arrest, leading SSCs to remain stem cell state. MAST4 is essential for maintaining cell cycle in SSCs via the CDK2-PLZF interaction. These results demonstrate the pivotal role of MAST4 regulating cell cycle of SSCs and the significance of spermatogenesis.
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Células Madre Germinales Adultas , Proteínas Asociadas a Microtúbulos , Animales , Ratones , Células Madre Germinales Adultas/citología , Células Madre Germinales Adultas/fisiología , Ciclo Celular/fisiología , Proteínas Asociadas a Microtúbulos/fisiología , MasculinoRESUMEN
Liquid mobility is ubiquitous in nature, with droplets emerging at all size scales, and artificial surfaces have been designed to mimic such mobility over the past few decades. Meanwhile, millimeter-sized droplets are frequently used for wettability characterization, even with facial mask applications, although these applications have a droplet-size target range that spans from millimeters to aerosols measuring less than a few micrometers. Unlike large droplets, microdroplets can interact sensitively with the fibers they contact with and are prone to evaporation. However, wetting behaviors at the single-microfiber level remain poorly understood. Herein, we characterized the wettability of fibrous layers, which revealed that a multiscale landscape of droplets ranged from the millimeter to the micrometer scale. The contact angle (CA) values of small droplets on pristine fibrous media showed sudden decrements, especially on a single microfiber, owing to the lack of air cushions for the tiny droplets. Moreover, droplets easily adhered to the pristine layer during droplet impact tests and then yielding widespread areas of contamination on the microfibers. To resolve this, we carved nanowalls on the pristine fibers by plasma etching, which effectively suppressed such wetting phenomena. Significantly, the resulting topographies of the microfibers managed the dynamic wettability of droplets at the multiscale, which reduced the probability of contamination with impact droplets and suppressed the wetting transition upon evaporation. These findings for the dynamic wettability of fibrous media will be useful in the fight against infectious droplets.
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Máscaras , Humectabilidad , Fenómenos FísicosRESUMEN
(1) Background: Desmoid tumors have a relatively high local failure rate after primary treatment using surgery and/or radiotherapy. Moreover, desmoid tumors recur at the primary site for many patients. An effective therapeutic strategy for the desmoid tumor is needed to maintain quality of life and prolong survival. (2) Method: First of all, we collected desmoid tumor tissues and investigated the status of protein expression for beta-catenin and alpha-SMA through immunohistochemistry. Then, we performed targeted sequencing and whole RNA sequencing. To compare the data with other cancer types, we used NGS data from sarcoma patients at Yonsei Cancer Center (YCC-sarcoma cohort, n = 48) and The Cancer Genome Atlas (TCGA, n = 9235). Secondly, we established the novel patient-derived preclinical models (n = 2) for the validation of treatment strategy. The same gene alteration of primary tissue was demonstrated. (3) Results: We discovered specific gene sets related to the TGF-ß signaling pathway. Moreover, we selected the combination treatment comprising TGF-ß inhibitor, vactosertib, and imatinib. In screening for the anti-proliferation effect, the combination treatment of TGF-ß inhibitor was more effective for tumor suppression than monotherapy. (4) Conclusion: We found preclinical indications that TGF-ß inhibitors could prove useful as a potential treatment for patients with desmoid tumors. Moreover, we could find some examples in clinical trials.
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Patients with chronic itch describe their pruritus in a wide variety of ways. However, these subjective descriptions are often not taken into consideration by physicians. This study aimed to validate patients' descriptions of pruritus, and to investigate the relationship between various descriptions of pruritus and the patient burden of chronic pruritus by examining the mediating effects of sleep disturbance and sexual dysfunction on patient's quality of life, as predicted by various descriptions of pruritus. Exploratory and confirmatory factor analyses were performed to identify the factor structure measured by 11 descriptions of pruritus. The study then analysed differences in the degree of sleep disturbance, sexual dysfunction, and quality of life deterioration factors using a structural equation modelling method. Using data from 419 patients with chronic pruritus, 11 descriptions of pruritus were classified into 2 groups: (i) sensory pruritus (i.e. stinging, stabbing, burning, painful, formication, throbbing, and cold) that are linked with descriptions of pruritus patterns; and (ii) affective pruritus (i.e. annoying, unbearable, worrisome, and warm) from patient reports of psychological or emotional distress. The study found that affective pruritus decreases patient's quality of life either directly or indirectly through sleep disturbance. In conclusion, clues about a patients' sleep disturbance or poor quality of life can be obtained through their descriptions of pruritus.
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Calidad de Vida , Trastornos del Sueño-Vigilia , Humanos , Análisis de Clases Latentes , Prurito/diagnóstico , Prurito/psicología , Trastornos del Sueño-Vigilia/diagnóstico , Parestesia , DolorRESUMEN
Although accumulating evidence indicates that alternative splicing is aberrantly altered in many cancers, the functional mechanism remains to be elucidated. Here, we show that epithelial and mesenchymal isoform switches of leucine-rich repeat Fli-I-interacting protein 2 (LRRFIP2) regulated by epithelial splicing regulatory protein 1 (ESRP1) correlate with metastatic potential of gastric cancer cells. We found that expression of the splicing variants of LRRFIP2 was closely correlated with that of ESRP1. Surprisingly, ectopic expression of the mesenchymal isoform of LRRFIP2 (variant 3) dramatically increased liver metastasis of gastric cancer cells, whereas deletion of exon 7 of LRRFIP2 by the CRISPR/Cas9 system caused an isoform switch, leading to marked suppression of liver metastasis. Mechanistically, the epithelial LRRFIP2 isoform (variant 2) inhibited the oncogenic function of coactivator-associated arginine methyltransferase 1 (CARM1) through interaction. Taken together, our data reveals a mechanism of LRRFIP2 isoform switches in gastric cancer with important implication for cancer metastasis.
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Neoplasias Hepáticas , Neoplasias Gástricas , Humanos , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Empalme Alternativo , Línea Celular Tumoral , Transición Epitelial-Mesenquimal , Neoplasias Hepáticas/genética , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Neoplasias Gástricas/genética , Factores de Transcripción/metabolismo , Metástasis de la NeoplasiaRESUMEN
A novel bacterium designated RR4-40T was isolated from a biofilter of seawater recirculating aquaculture system in Busan, South Korea. Cells are strictly aerobic, Gram-negative, irregular short rod, non-motile, and oxidase- and catalase-negative. Growth was observed at 15-30°C, 0.5-6% NaCl (w/v), and pH 5.0-9.5. The strain grew optimally at 28°C, 3% salinity (w/v), and pH 8.5. The phylogenetic analysis based on 16S rRNA gene sequences showed that strain RR4-40T was most closely related to Marinirhabdus gelatinilytica NH83T (94.16% of 16S rRNA gene similarity) and formed a cluster with genera within the family Flavobacteriaceae. The values of the average nucleotide identity (ANI), digital DNA-DNA hybridization (dDDH), and average amino acid identity (AAI) between genomes of strain RR4-40T and M. gelatinilytica NH83T were 72.91, 18.2, and 76.84%, respectively, and the values against the strains in the other genera were lower than those. The major fatty acids were iso-C15:0 (31.34%), iso-C17:0 3-OH (13.65%), iso-C16:0 3-OH (10.61%), and iso-C15:1 G (10.38%). The polar lipids comprised phosphatidylglycerol, diphosphatidylglycerol, aminophospholipid, aminolipid, glycolipid, and sphingolipid. The major respiratory quinone was menaquinone-6 (MK-6) and the DNA G + C content of strain RR4-40T was 37.4 mol%. According to the polyphasic analysis, strain RR4-40T is considered to represent a novel genus within the family Flavobacteriaceae, for which the name Rasiella rasia gen. nov, sp. nov. is proposed. The type strain is RR4-40T (= KCTC 52650T = MCCC 1K04210T).