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Formation of transport vesicles requires the coordinate activity of the coating machinery that selects cargo into the nascent vesicle and the membrane bending machinery that imparts curvature to the forming bud. Vesicle coating at the trans-Golgi Network (TGN) involves AP1, GGA2 and clathrin, which are recruited to membranes by activated ARF GTPases. The ARF activation at the TGN is mediated by the BIG1 and BIG2 guanine nucleotide exchange factors (GEFs). Membrane deformation at the TGN has been shown to be mediated by lipid flippases, including ATP8A1, that moves phospholipids from the inner to the outer leaflet of the TGN membrane. We probed a possible coupling between the coating and deformation machineries by testing for an interaction between BIG1, BIG2 and ATP8A1, and by assessing whether such an interaction may influence coating efficiency. Herein, we document that BIG1 and BIG2 co-localize with ATP8A1 in both, static and highly mobile TGN elements, and that BIG1 and BIG2 bind ATP8A1. We show that the interaction involves the catalytic Sec7 domain of the GEFs and the cytosolic C-terminal tail of ATP8A1. Moreover, we report that the expression of ATP8A1, but not ATP8A1 lacking the GEF-binding cytosolic tail, increases the generation of activated ARFs at the TGN and increases the selective recruitment of AP1, GGA2 and clathrin to TGN membranes. This occurs without increasing BIG1 or BIG2 levels at the TGN, suggesting that the binding of the ATP8A1 flippase tail to the Sec7 domain of BIG1/BIG2 increases their catalytic activity. Our results support a model in which a flippase component of the deformation machinery impacts the activity of the GEF component of the coating machinery.
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Fatores de Ribosilação do ADP , Fatores de Troca do Nucleotídeo Guanina , Rede trans-Golgi , Rede trans-Golgi/metabolismo , Humanos , Fatores de Ribosilação do ADP/metabolismo , Fatores de Ribosilação do ADP/genética , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Fatores de Troca do Nucleotídeo Guanina/genética , Adenosina Trifosfatases/metabolismo , Células HeLa , Ligação Proteica , Proteínas de Membrana , Proteínas de Transferência de FosfolipídeosRESUMO
This study investigated the acute effects of natural antioxidants, derived from yeast fermentation containing glutathione and dietary vitamin C supplementation, on metabolic function, skeletal muscle oxygenation, cardiac function, and antioxidant function during submaximal exercise in middle-aged triathlon athletes. Twelve participants (aged 49.42 ± 5.9 years) completed 90 min submaximal cycling trials corresponding to 70% maximal oxygen uptake with either vitamin C and glutathione (VitC+Glu), vitamin C (VitC), glutathione (Glu) supplementation, or placebo. Metabolic function (minute ventilation, oxygen uptake, carbon dioxide output [VCO2], respiratory exchange ratio [RER], oxygen pulse [O2pulse], carbohydrate oxidation, fat oxidation, and energy expenditure), skeletal muscle oxygenation (oxidized hemoglobin and myoglobin in skeletal muscle tissue, total hemoglobin and myoglobin in skeletal muscle tissue [tHb]), cardiac function (heart rate [HR], stroke volume [SV], cardiac output, end-diastolic volume, end-systolic volume, and ejection fraction), and antioxidant function parameters (blood lactate, superoxide dismutase, catalase, glutathione peroxidases, glutathione [GSH], diacron reactive oxygen metabolite [dROM], and biological antioxidant potential [BAP]) were measured during submaximal exercise and recovery. VCO2, RER, HR, blood lactate after exercise, and dROM were significantly lower, and O2pulse, tHb, and BAP were significantly higher for VitC+Glu than for the other trials (p < 0.05). In conclusion, combined vitamin C and glutathione supplementation was more effective in improving metabolic function, skeletal oxygenation, cardiac function, and antioxidant function during prolonged submaximal exercise in middle-aged triathletes.
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Antioxidantes , Desempenho Atlético , Humanos , Pessoa de Meia-Idade , Antioxidantes/farmacologia , Ácido Ascórbico , Saccharomyces cerevisiae/metabolismo , Estudos Cross-Over , Fermentação , Mioglobina/metabolismo , Vitaminas/farmacologia , Glutationa/metabolismo , Músculo Esquelético/metabolismo , Atletas , Oxigênio/metabolismo , Lactatos/metabolismo , Suplementos NutricionaisRESUMO
INTRODUCTION: Uterine smooth muscle tumor of uncertain malignant potential (STUMP) is a rare tumor that arises in the myometrium of the uterus. It is regarded as an intermediate malignant tumor according to the recent World Health Organization classification. Few studies have reported the radiologic findings of STUMP, and the differentiation of STUMP from leiomyoma remains controversial. CASE DESCRIPTION: A 42-year-old nulliparous female presented at our institution with massive vaginal bleeding. Radiological studies, including ultrasonography, computed tomography (CT), and magnetic resonance imaging, revealed an oval-shaped mass with well-defined margins in the uterus protruding into the vagina. The patient underwent a total abdominal hysterectomy, and the final pathology was confirmed as STUMP. CONCLUSION: Distinguishing STUMP from leiomyomas based solely on radiological findings can be challenging. However, if the uterine mass appears as a single mass lacking acoustic shadowing on ultrasound and demonstrates diffusion restriction with high T2 signal intensity on magnetic resonance imaging, consideration of STUMP may be necessary for proper patient management, given the poor prognosis associated with this tumor.
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INTRODUCTION: Clear cell hepatocellular carcinoma (HCC) is a rare subtype of HCC. Histologically, clear cell HCC is characterized by the cytoplasmic accumulation of glycogen with a clear cell appearance, constituting > 80% of tumor cells. Radiologically, clear cell HCC demonstrates early enhancement and washout similar to conventional HCC. Occasionally, enhancing capsule and intratumoral fat are accompanied by clear cell HCC. CASE DESCRIPTION: A 57-year-old male presented to our hospital with right upper quadrant abdominal pain. Ultrasonography, computed tomography, and magnetic resonance imaging revealed a large mass with a well-defined margin in the right hemiliver. The patient underwent a right hemihepatectomy, and the final histopathology revealed clear cell-type HCC. CONCLUSION: Distinguishing clear cell types from other types of HCC solely based on radiological findings is challenging. If hepatic tumors exhibit encapsulated margins, enhancing rims, intratumoral fat, and arterial phase hyperenhancement/washout pattern despite their large size, consideration of clear cell subtypes in the differential diagnosis list will aid patient management, implying better prognosis than not-otherwise-specified HCC.
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In this study, we designed and synthesized novel 1,4-dialkoxynaphthalene-2-alkyl imidazolium salt (IMS) derivatives containing both 1,4-dialkoxynaphthalene and imidazole, which are well known as pharmacophores. The cytotoxicities of these newly synthesized IMS derivatives were investigated in order to explore the possibility of using them to develop anticancer drugs. It was found that some of the new IMS derivatives showed good cytotoxic activities. In addition, an initial, qualitative structure-activity relationship is presented on the basis of observations of activity changes corresponding to structural changes.
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Antineoplásicos , Neoplasias , Sais/farmacologia , Sais/química , Linhagem Celular , Antineoplásicos/química , Relação Estrutura-Atividade , Cloreto de Sódio , Estrutura Molecular , Ensaios de Seleção de Medicamentos Antitumorais , Linhagem Celular TumoralRESUMO
Myxoid pleomorphic liposarcoma is characterized by pathological features of both pleomorphic liposarcoma and myxoid liposarcoma, as the name suggests. In this case, a myxoid pleomorphic liposarcoma was observed in a 5-year-old male African pygmy hedgehog. It consisted of ~60% of the myxoid substance area with proliferating round cells and ~30% of pleomorphic neoplastic cells. The subject presented with extrapulmonary metastasis, but a good prognosis during 6 months of follow-up, which is similar to the characteristics of myxoid liposarcoma. The histopathological features of myxoid pleomorphic liposarcoma may reflect the features of either myxoid liposarcoma or pleomorphic liposarcoma depending on the proportion of each histopathological feature. The proportion of the pleomorphic area and the myxoid area may offer information on the prognosis and metastasis of myxoid pleomorphic liposarcoma, which will be helpful for setting up a treatment plan. Thus, analyzing the proportion of pleomorphic area and myxoid area could be suggested as one of the ways to predict clinical outcomes. In addition to the fact that this is the first case of a myxoid pleomorphic liposarcoma in hedgehogs, this case is meaningful, considering the unique histopathological characteristics and rare incidence of myxoid pleomorphic liposarcoma that could be important in humans as well.
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BACKGROUND: Although there are growing demands for stem cell-based therapy for companion animals in various diseases, a few clinical trials have been reported. Moreover, most of them are the results from only one or a few times of stem cell injection. OBJECTIVES: The aim of this study is to describe a long-term treatment with allogeneic adipose-derived stem cells (ASCs) in a dog with rheumatoid arthritis (RA), which is a rare canine disease. METHODS: The dog with RA received intravascular injection of allogeneic ASCs derived from two healthy donors once a month for 11 months. To assess therapeutic effects of ASCs, orthopedic examination and clinical evaluation was performed. Cytokines of tumor necrosis factor-α and interleukin-6 in the plasma were measured using ELISA analysis. RESULTS: Despite this repeated and long-term administration of allogeneic ASCs, there were no side effects such as immunorejection responses or cell toxicity. The orthopedic examination score for the dog decreased after ASCs treatment, and the clinical condition of the dog and owner's satisfaction were very good. CONCLUSIONS: Although ASCs has been suggested as one of the options for RA treatment because of its anti-inflammatory and immunosuppressive functions, it has never been used to treat RA in dogs. The present report describes a case of canine RA treated with allogeneic ASCs for long-term in which the dog showed clinical improvement without adverse effects.
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Artrite Reumatoide , Doenças do Cão , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Mesenquimais , Tecido Adiposo , Animais , Artrite Reumatoide/patologia , Artrite Reumatoide/terapia , Artrite Reumatoide/veterinária , Doenças do Cão/terapia , Cães , Transplante de Células-Tronco Hematopoéticas/veterináriaRESUMO
BACKGROUND: Cordyceps species have been used as tonics to enhance energy, stamina, and libido in traditional Asian medicine for more than 1600 years, indicating their potential for improving reproductive hormone disorders and energy metabolic diseases. Among Cordyceps, Cordyceps militaris has been reported to prevent metabolic syndromes including obesity and benefit the reproductive hormone system, suggesting that Cordyceps militaris can also regulate obesity induced by the menopause. We investigated the effectiveness of Cordyceps militaris extraction (CME) on menopausal obesity and its mechanisms. METHODS: We applied an approach combining in vivo, in vitro, and in silico methods. Ovariectomized rats were administrated CME, and their body weight, area of adipocytes, liver and uterus weight, and lipid levels were measured. Next, after the exposure of MCF-7 human breast cancer cells to CME, cell proliferation and the phosphorylation of estrogen receptor and mitogen-activated protein kinases (MAPK) were measured. Finally, network pharmacological methods were applied to predict the anti-obesity mechanisms of CME. RESULTS: CME prevented overweight, fat accumulation, liver hypertrophy, and lowered triglyceride levels, some of which were improved in a dose-dependent manner. In MCF-7 cell lines, CME showed not only estrogen receptor agonistic activity through an increase in cell proliferation and the phosphorylation of estrogen receptors, but also phosphorylation of extracellular-signal-regulated kinase and p38. In the network pharmacological analysis, bioactive compounds of CME such as cordycepin, adenine, and guanosine were predicted to interact with non-overlapping genes. The targeted genes were related to the insulin signaling pathway, insulin resistance, the MARK signaling pathway, the PI3K-Akt signaling pathway, and the estrogen signaling pathway. CONCLUSIONS: These results suggest that CME has anti-obesity effects in menopause and estrogenic agonistic activity. Compounds in CME have the potential to regulate obesity-related and menopause-related pathways. This study will contribute to developing the understanding of anti-obesity effects and mechanisms of Cordyceps militaris.
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Cordyceps , Animais , Feminino , Hormônios , Humanos , Obesidade/tratamento farmacológico , Fosfatidilinositol 3-Quinases , Ratos , Receptores de EstrogênioRESUMO
INTRODUCTION: Angiolipoleiomyoma (ALLM) is a rare hamartomatous tumor of mesenchymal origin composed of smooth muscle, mature adipose tissue, and blood vessels in various proportions. Because of its histologic similarity to renal Angiomyolipoma (AML), it is also called uterine angiomyolipoma. Preoperative diagnosis of uterine ALLM is very challenging due to its uncommon incidence and absence of established characteristic imaging findings. CASE PRESENTATION: A 50-year-old multiparous female patient visited our institution for gynecologic screening. Transvaginal Sonography (TVS), Abdominopelvic Computed Tomography (CT), and pelvic Magnetic Resonance Imaging (MRI) revealed large well-defined masses involving the posterior uterine wall with rectal indentation. The patient underwent a total abdominal hysterectomy for this tumor and the histopathological diagnosis was uterine ALLM. CONCLUSION: This report would contribute to understanding and establishing the radiologic findings of the uterine ALLM. Considering the benign characteristics and favorable prognosis of this rare tumor, familiarity with its imaging findings by radiologists will guide clinicians in better patient management and prevention of unnecessary radical surgery.
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Angiomiolipoma , Neoplasias Renais , Angiomiolipoma/diagnóstico por imagem , Angiomiolipoma/patologia , Feminino , Humanos , Neoplasias Renais/diagnóstico , Neoplasias Renais/patologia , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Tomografia Computadorizada por Raios X , ÚteroRESUMO
Background and Objectives: Human mesenchymal stem cells (MSCs) are emerging as a treatment for atopic dermatitis (AD), a chronic inflammatory skin disorder that affects a large number of people across the world. Treatment of AD using human umbilical cord blood-derived MSCs (hUCB-MSCs) has recently been studied. However, the mechanism underlying their effect needs to be studied continuously. Thus, the objective of this study was to investigate the immunomodulatory effect of epidermal growth factor (EGF) secreted by hUCB-MSCs on AD. Methods and Results: To explore the mechanism involved in the therapeutic effect of MSCs for AD, a secretome array was performed using culture medium of hUCB-MSCs. Among the list of genes common for epithelium development and skin diseases, we focused on the function of EGF. To elucidate the effect of EGF secreted by hUCB-MSCs, EGF was downregulated in hUCB-MSCs using EGF-targeting small interfering RNA. These cells were then co-cultured with keratinocytes, Th2 cells, and mast cells. Depletion of EGF disrupted immunomodulatory effects of hUCB-MSCs on these AD-related inflammatory cells. In a Dermatophagoides farinae-induced AD mouse model, subcutaneous injection of hUCB-MSCs ameliorated gross scoring, histopathologic damage, and mast cell infiltration. It also significantly reduced levels of inflammatory cytokines including interleukin (IL)-4, tumor necrosis factor (TNF)-α, thymus and activation-regulated chemokine (TARC), and IL-22, as well as IgE levels. These therapeutic effects were significantly attenuated at all evaluation points in mice injected with EGF-depleted hUCB-MSCs. Conclusions: EGF secreted by hUCB-MSCs can improve AD by regulating inflammatory responses of keratinocytes, Th2 cells, and mast cells.
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INTRODUCTION: Gangliocytic paraganglioma is an extremely rare tumor that is composed of epithelioid, ganglion, and spindle cells. It has a predilection site in the duodenum, especially the periampullary region. The clinical course is usually benign, but a few cases of metastasis to lymph nodes or distant sites have been noted. Several case reports or small series reviews of gangliocytic paraganglioma have been published, but so far, cecal gangliocytic paraganglioma has not been described. CASE DESCRIPTION: A 61-year-old man underwent an abdominal Computed Tomography (CT) scan for known GB stones, which revealed an incidental cecal mass. The patient underwent wedge resection of the cecum for diagnostic and therapeutic purposes. Histopathological examination of the cecal mass identified a gangliocytic paraganglioma. There was no evidence of metastasis in the dissected regional lymph nodes. No additional treatment, such as adjuvant chemotherapy or radiotherapy, was administered, and the patient underwent regular follow-up without any complications. CONCLUSION: The most common radiologic finding in gangliocytic paraganglioma is a circumscribed, enhancing subepithelial mass. Herein, we report an uncommon case of cecal-origin gangliocytic paraganglioma. With knowledge of the radiologic and histologic characteristics of gangliocytic paraganglioma, appropriate management can be provided without unnecessary radical resection.
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Neoplasias Duodenais , Paraganglioma , Ceco/diagnóstico por imagem , Ceco/patologia , Ceco/cirurgia , Neoplasias Duodenais/complicações , Neoplasias Duodenais/diagnóstico por imagem , Neoplasias Duodenais/cirurgia , Humanos , Linfonodos/patologia , Masculino , Pessoa de Meia-Idade , Paraganglioma/diagnóstico por imagem , Paraganglioma/cirurgiaRESUMO
Catatonia is a psychomotor syndrome which may occur in a wide variety of medical, neurological, and psychiatric conditions. In pediatrics, this condition is rare and is associated with high morbidity and mortality if not correctly diagnosed and treated. Catatonia in obsessive-compulsive disorder is an infrequent association that has been understudied and underdiagnosed. To add to the knowledge on this unusual clinical presentation, two pediatric patients are reported and discussed together with the other two cases described in the literature. These four cases in total of catatonia associated with OCD confirm that it is a relationship that is infrequently reported, possibly because of lack of awareness in clinicians that catatonia can also be caused by OCD, and because the similarity between some catatonic signs and some compulsive phenomena may compound the identification of the former. Most cases of catatonia in this small series seemed to have responded to the optimization of the treatment for OCD. This highlights the clinical importance of an accurate diagnosis of catatonia when associated with OCD.
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Catatonia , Transtorno Obsessivo-Compulsivo , Catatonia/complicações , Catatonia/diagnóstico , Criança , Humanos , Transtorno Obsessivo-Compulsivo/complicações , Transtorno Obsessivo-Compulsivo/diagnósticoRESUMO
Skeletal muscle atrophy in an inevitable occurrence with advancing age, and a consequence of disease including cancer. Muscle atrophy in the elderly is managed by a regimen of resistance exercise and increased protein intake. Understanding the signaling that regulates muscle mass may identify potential therapeutic targets for the prevention and reversal of muscle atrophy in metabolic and neuromuscular diseases. This review covers the major anabolic and catabolic pathways that regulate skeletal muscle mass, with a focus on recent progress and potential new players.
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Envelhecimento/metabolismo , Músculo Esquelético/metabolismo , Atrofia Muscular/metabolismo , Transdução de Sinais , Envelhecimento/patologia , Animais , Humanos , Hipertrofia , Músculo Esquelético/crescimento & desenvolvimento , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismoRESUMO
OBJECTIVES: This study aimed to determine whether self-educational intervention on patient safety via a smartphone application could improve the level of self-efficacy and safety behaviors of patients. In addition the effect of change in self-efficacy on the improvement of safety behaviors after self-educational intervention was investigated. METHODS: A one-group pre- and post-test design and convenience sampling were implemented. Self-educational intervention via smartphone application was provided to 94 participants in a tertiary university hospital in South Korea. The smartphone application included learning contents on why the participation of patients is critical in preventing hospital-acquired infections and surgery-related adverse events during hospitalization. Paired t-tests and hierarchical regression analysis were conducted to assess the effect of selfeducational intervention and self-efficacy on the improvement of safety behaviors of patients. RESULTS: After the intervention, the level of self-efficacy and safety behaviors significantly increased from 2.53 to 2.95 and from 2.00 to 2.62, respectively. In the hierarchical regression analysis, the change in self-efficacy accounted for 35.4% of the variance in the improvement of safety behaviors. CONCLUSIONS: The results of this study demonstrated that self-education on patient safety via a smartphone application was an effective strategy to enhance patients' self-efficacy and safety behaviors. This process could ultimately enhance patient safety by promoting patient involvement during hospitalization and preventing the occurrence of medical errors.
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Researchers have been interested in probing how the environmental factors associated with allergic diseases affect the use of medical services. Considering this demand, we have constructed a database, named the Allergic Disease Database, based on the National Health Insurance Database (NHID). The NHID contains information on demographic and medical service utilization for approximately 99% of the Korean population. This study targeted 3 major allergic diseases, including allergic rhinitis, atopic dermatitis, and asthma. For the target diseases, our database provides daily medical service information, including the number of daily visits from 2013 and 2017, categorized by patients' characteristics such as address, sex, age, and duration of residence. We provide additional information, including yearly population, a number of patients, and averaged geocoding coordinates by eup, myeon, and dong district code (the smallest-scale administrative units in Korea). This information enables researchers to analyze how daily changes in the environmental factors of allergic diseases (e.g., particulate matter, sulfur dioxide, and ozone) in certain regions would influence patients' behavioral patterns of medical service utilization. Moreover, researchers can analyze long-term trends in allergic diseases and the health effects caused by environmental factors such as daily climate and pollution data. The advantages of this database are easy access to data, additional levels of geographic detail, time-efficient data-refining and processing, and a de-identification process that minimizes the exposure of identifiable personal information. All datasets included in the Allergic Disease Database can be downloaded by accessing the National Health Insurance Service data sharing webpage (https://nhiss.nhis.or.kr).
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Asma/epidemiologia , Bases de Dados Factuais , Dermatite Atópica/epidemiologia , Programas Nacionais de Saúde , Rinite Alérgica/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , República da Coreia/epidemiologia , Adulto JovemRESUMO
The therapeutic effects of mesenchymal stem cells (MSCs) in musculoskeletal diseases (MSDs) have been verified in many human and animal studies. Although some tissues contain MSCs, the number of cells harvested from those tissues and rate of proliferation in vitro are not enough for continuous transplantation. In order to produce and maintain stable MSCs, many attempts are made to induce differentiation from pluripotent stem cells (iPSCs) into MSCs. In particular, it is also known that the paracrine action of stem cell-secreted factors could promote the regeneration and differentiation of target cells in damaged tissue. MicroRNAs (miRNAs), one of the secreted factors, are small non-coding RNAs that regulate the translation of a gene. It is known that miRNAs help communication between stem cells and their surrounding niches through exosomes to regulate the proliferation and differentiation of stem cells. While studies have so far been underway targeting therapeutic miRNAs of MSDs, studies on specific miRNAs secreted from MSCs are still minimal. Hence, our ultimate goal is to obtain sufficient amounts of exosomes from iPSC-MSCs and develop them into therapeutic agents, furthermore to select specific miRNAs and provide safe cell-free clinical setting as a cell-free status with purpose of delivering them to target cells. This review article focuses on stem cell therapy on MSDs, specific microRNAs regulating MSDs and updates on novel approaches.
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Rationale: In recent decades, diagnosis and treatment recommendations for idiopathic pulmonary fibrosis (IPF) have changed. In Korea, the average life expectancy has increased, unmet healthcare needs have been reduced, and the number of computed tomographic examinations performed has nearly doubled. The Korean Interstitial Lung Disease Study Group conducted a nationwide cohort study for idiopathic interstitial pneumonia, including IPF, and established a registry for IPF.Objectives: Using study data collected by the study group, this study aimed to evaluate longitudinal changes in clinical features, diagnosis, treatment, and mortality and analyze the extent to which changes in medication usage affected IPF-associated mortality.Methods: The study population included newly diagnosed patients with IPF from a cohort study (January 2002 to September 2008, n = 1,839, 2008 group) and prospective registry (January 2012 to August 2018, n = 1,345, 2018 group). Survival curves were estimated using the Kaplan-Meier method, and Cox regression models were used to identify mortality-associated risk factors in each group.Results: The 2018 group was younger, had fewer symptoms, had less honeycombing, underwent more serologic autoimmune marker and pulmonary function tests, had higher oxygen partial pressure and lower carbon dioxide partial pressure values, was less frequently diagnosed by surgical biopsy, and had better survival than the 2008 group. Steroid use and conservative care declined, whereas N-acetylcysteine use increased in this group. Antifibrotic agents were used in only the 2018 group. In the 2008 group, N-acetylcysteine was associated with lower mortality, whereas conservative care was associated with higher mortality. In the 2018 group, the use of antifibrotic agents was associated with lower mortality, and steroid use was associated with higher mortality. The survival rates in the 2008 and 2018 non-antifibrotic agent subgroups were similar.Conclusions: This study analyzed national IPF cohort data spanning 17 years. In clinical practice, the IPF diagnosis was made earlier, steroid and immunosuppressive agent use was reduced, and antifibrotic agents were administered. The survival of patients with IPF has improved over the decades, and antifibrotic use was consistently associated with improved survival.Clinical trial registered with clinicaltrials.gov (NCT04160715).
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Fibrose Pulmonar Idiopática , Doenças Pulmonares Intersticiais , Biópsia , Estudos de Coortes , Humanos , Fibrose Pulmonar Idiopática/diagnóstico , Fibrose Pulmonar Idiopática/tratamento farmacológico , Testes de Função RespiratóriaRESUMO
Gene therapy is emerging as an effective treatment option for various inherited genetic diseases. Gutless adenovirus (GLAd), also known as helper-dependent adenovirus (HDAd), has many notable characteristics as a gene delivery vector for this particular type of gene therapy, including broad tropism, high infectivity, a large transgene cargo capacity, and an absence of integration into the host genome. Additionally, GLAd ensures long-term transgene expression in host organisms owing to its minimal immunogenicity, since it was constructed following the deletion of all the genes from an adenovirus. However, the clinical use of GLAd for the treatment of inherited genetic diseases has been hampered by unavoidable contamination of the highly immunogenic adenovirus used as a helper for GLAd production. Here, we report the production of GLAd in the absence of a helper adenovirus, which was achieved with a helper plasmid instead. Utilizing this helper plasmid, we successfully produced large quantities of recombinant GLAd. Importantly, our helper plasmid-based system exclusively produced recombinant GLAd with no generation of helper plasmid-originating adenovirus and replication-competent adenovirus (RCA). The recombinant GLAd that was produced efficiently delivered transgenes regardless of their size and exhibited therapeutic potential for Huntington's disease (HD) and Duchenne muscular dystrophy (DMD). Our data indicate that our helper plasmid-based GLAd production system could become a new platform for GLAd-based gene therapy.
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Adenoviridae/genética , Terapia Genética , Vetores Genéticos/genética , Transgenes/genética , Linhagem Celular , Vetores Genéticos/uso terapêutico , Genoma Humano/genética , Humanos , Doença de Huntington/genética , Doença de Huntington/terapia , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/terapia , Plasmídeos/genéticaRESUMO
In previous work, we established an equine induced pluripotent stem cell line (E-iPSCs) from equine adipose-derived stem cells (ASCs) using a lentiviral vector encoding four transcription factors: Oct4, Sox2, Klf4, and c-Myc. In the current study, we attempted to differentiate these established E-iPSCs into mesenchymal stem cells (MSCs) by serial passaging using MSC-defined media for stem cell expansion. Differentiation of the MSCs was confirmed by analyzing expression levels of the MSC surface markers CD44 and CD29, and the pluripotency markers Nanog and Oct4. Results indicated that the E-iPSC-derived MSCs (E-iPSC-MSCs) retained the characteristics of MSCs, including the ability to differentiate into chondrogenic, osteogenic, or myogenic lineages. E-iPSC-MSCs were rendered suitable for therapeutic use by inhibiting immune rejection through exposure to transforming growth factor beta 2 (TGF-ß2) in culture, which down-regulated the expression of major histocompatibility complex class I (MHC class I) proteins that cause immune rejection if they are incompatible with the MHC antigen of the recipient. We reported 16 cases of E-iPSC-MSC transplantations into injured horses with generally positive effects, such as reduced lameness and fraction lines. Our findings indicate that E-iPSC-MSCs can demonstrate MSC characteristics and be safely and practically used in the treatment of musculoskeletal injuries in horses.