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Advances in sequencing technologies have facilitated the discovery of previously unknown genetic variants in both inherited and acquired disorders, and tools to correct these pathogenic variants are rapidly evolving. Since the first introduction of CRISPR-Cas9 in 2012, the field of CRISPR-based genome editing has progressed immensely, giving hope to many patients suffering from genetic disorders that lack effective treatment. In this review, we will examine the basic principles of CRISPR-based genome editing, explain the mechanisms of new genome editors, including base editors and prime editors, and evaluate the therapeutic possibilities of CRISPR-based genome editing by focusing on recently published clinical trials and animal studies. Although efficacy and safety issues remain a large concern, we cannot deny that CRISPR-based genome editing will soon be prevalent in clinical practice.
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Hidradenitis suppurativa (HS) is a chronic recurrent inflammatory condition presenting with painful, deep-seated abscesses and sinus tracts in multifocal locations. Rarely, longstanding inflammation in HS may lead to serious complications, such as cutaneous squamous cell carcinoma (SCC) (also termed Marjolin ulcer). Herein, we report a case of invasive cutaneous SCC arising from chronic ulcers of a HS patient. A 40-year old Korean male, a current smoker with 20 pack-year history, presented with a history of painful, recurrent, deep-seated abscesses and ulcers on the buttocks since his late teens, thus classified as Hurley stage III. A large purulent ulcer developed on the right buttock several months ago. Initial treatment was focused on controlling infection and facilitating wound healing. The lesion showed 50% reduction of size in 6 weeks, but also developed foul odor and showed fungating margins. Multiple skin biopsies were consistent with invasive SCC. Magnetic resonance imaging revealed a few enlarged lymph nodes on the right inguinal area, which was confirmed as metastasis on frozen biopsy.Slow Mohs micrographic surgery and radical right inguinal lymph node dissection was done. Incidence rates of SCC aris-ing from HS have been reported up to 4.6%. To our knowledge, this is the first report of cutaneous SCC arising from HS in Korea. Our case emphasizes that the diagnosis of cutaneous SCC in HS should not be delayed, and early surgical intervention is crucial for better outcomes.
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Paraneoplastic pemphigus is a rare, life-threatening autoimmune mucocutaneous blistering disease associated with underlying neoplasia, commonly lymphoproliferative tumors. Herein we report a case of paraneoplastic pemphigus with a unique autoantibody profile associated with a malignant thymoma. A 56-year-old female patient presented with relapsing oral ulcerations accompanied by erythematous papules and patches on her extremities for 2 months. Skin and mucosal biopsies identified interface dermatitis with lichenoid lymphocytic infiltration in the upper dermis. Immunoblotting and enzyme-linked immunosorbent assays revealed that the patient had multiple autoantibodies against desmoglein 1, desmocollin 1, 2, 3, laminin gamma-1, envoplakin, and periplakin. The skin lesions completely healed following thymectomy and systemic corticosteroid therapy, but the oral ulcerations persisted through a follow-up period of over 2 years.
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Femenino , Humanos , Persona de Mediana Edad , Autoanticuerpos , Biopsia , Vesícula , Dermatitis , Dermis , Desmogleína 1 , Ensayo de Inmunoadsorción Enzimática , Extremidades , Estudios de Seguimiento , Immunoblotting , Laminina , Úlceras Bucales , Síndromes Paraneoplásicos , Pénfigo , Piel , Timectomía , TimomaRESUMEN
The axis of nuclear factor kappaB (NF-kappaB)-inducible NO synthase (iNOS)-nitric oxide plays a key role in cytokine- and streptozotocin-mediated pancreatic beta-cell damage. In this study, we investigated the effects of kazinol C and isokazinol D isolated from Broussonetia kazinoki on the beta-cell viability and function. RINm5F cells and primary islets were used for in vitro and ex vivo cytokine toxicity experiments, respectively. For type 1 diabetes induction, mice were injected with multiple low-dose streptozotocin (MLDS). Cytokine-induced toxicity was completely abolished in both RINm5F cells and islets that were pretreated with either kazinol C or isokazinol D. Both kazinols inhibited the NF-kappaB signaling pathway, thereby inhibiting cytokine-mediated iNOS induction, nitric oxide production, apoptotic cell death and defects in insulin secretion. Moreover, the occurrence of diabetes in MLDS-treated mice was efficiently attenuated in kazinol-pretreated mice. Immunohistochemical analysis revealed that the numbers of terminal deoxynucleotidyl transferase dUTP nick end labeling-positive apoptotic cells and nuclear p65-positive cells were significantly decreased in kazinol-pretreated mice. Our results suggest that kazinol C and isokazinol D block the NF-kappaB pathway, thus reducing the extent of beta-cell damage. Therefore, kazinol C and isokazinol D may have therapeutic value in delaying pancreatic beta-cell damage in type 1 diabetes.
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The effects of unilateral sciatic neurectomy on gastrocnemius muscle were studied in adult male rats. The morphological changes of both gastrocnemius muscles were observed by light and electron microscopy. Western blot analysis was performed to study the protein expression. Following the denervation, the affected muscle weights decreased significantly than normal. And the denervation led to a significant reduction in the area and diameter of muscle fibers on light microscopy. The affected muscle fibers showed the decreasing in size and the irregularity of myofibrilar arrangement on electron microscopy. On transverse view, the area of affected muscle fibers were smaller than normal. Their myofibrils were smaller and very irregular in size. The thin and thick myofilaments were not regular and partially lost. Mitochondria between myofibrils and subsarcolemmal area in affected muscle fibers were damaged and partially lost. The sacoplasmic reticulum and T-tubules were mostly lost and irregular. Some satellite cells were observed adjacent the muscle fiber, but they were inactive morphologically. On longitudinal view, most of myofibrils in affected muscle fibers were lost generally or partially although the their most sarcomeres were regularly arranged. Z line and myofilaments were lost partially and were partially irregularly arranged. The loss of thin myofilaments was more than that of thick myofilaments. Much debris of cell organelles were scattered among myofibrils. The expression of MyoD and myogenin were decrease significantly and the expression of p-mTOR and p-FOXO1 were decreased, too. On the other hand, MuRF1 was increased significantly. Taken together, the main effect of gastrocnemius muscle by sciatic neurectomy is the atrophy as a result of the loss of myofilaments and cell organelles through the decrease of protein synthesis and the increase of protein degradation.
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Adulto , Animales , Humanos , Masculino , Ratas , Atrofia , Western Blotting , Desnervación , Mano , Luz , Microscopía , Microscopía Electrónica , Mitocondrias , Músculo Esquelético , Músculos , Miofibrillas , Miogenina , Orgánulos , Proteolisis , Reticulum , Sarcómeros , Nervio Ciático , Pesos y MedidasRESUMEN
Radiotherapy would be the choice of treatment for human cancers, because of high cost-effectiveness. However, a certain population of patients shows a resistance to radiotherapy and recurrence. In an effort to increase the efficacy of radiotherapy, many efforts were driven to find the genes causing the unresponsiveness to ionizing radiation. In this paper, we compared the gene expression profiles of two lung cancer cell lines, H460 and H1299, which showed differential responses to ionizing radiations. Each cell were irradiated at 2 Gy, and harvested after 0, 2, 4, 8, 12 and 24 hours to examine the expressions. Two-way ANOVA analysis on time-series experiments of two cells could select 2863 genes differentially expressed upon ionizing radiation among 32,321 genes in microarray (p<0.05). We classified these genes into 21 clusters by SOM clustering according to the interaction between cell types and time. Two SOM clusters were enriched with apoptosis-related genes in pathway analysis. One cluster contained higher levels of phosphatidyl inositol 3-phosphate kinase (PI3K) subunits in H1299, radio resistant cells than H460, radiosensitive cells. TRAIL receptors were expressed in H460 cells while the decoy receptor for TRAIL was expressed in H1299 cells. From these results, we could characterize the differential responsiveness to ionizing radiation according to their differential expressions of apoptosis-related genes, which might be the candidates to increase the power of radiotherapy.
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Humanos , Apoptosis , Línea Celular , Fosfatos de Inositol , Pulmón , Neoplasias Pulmonares , Fosfatidilinositoles , Fosfotransferasas , Radiación Ionizante , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF , Recurrencia , TranscriptomaRESUMEN
Radiotherapy would be the choice of treatment for human cancers, because of high cost-effectiveness. However, a certain population of patients shows a resistance to radiotherapy and recurrence. In an effort to increase the efficacy of radiotherapy, many efforts were driven to find the genes causing the unresponsiveness to ionizing radiation. In this paper, we compared the gene expression profiles of two lung cancer cell lines, H460 and H1299, which showed differential responses to ionizing radiations. Each cell were irradiated at 2 Gy, and harvested after 0, 2, 4, 8, 12 and 24 hours to examine the expressions. Two-way ANOVA analysis on time-series experiments of two cells could select 2863 genes differentially expressed upon ionizing radiation among 32,321 genes in microarray (p<0.05). We classified these genes into 21 clusters by SOM clustering according to the interaction between cell types and time. Two SOM clusters were enriched with apoptosis-related genes in pathway analysis. One cluster contained higher levels of phosphatidyl inositol 3-phosphate kinase (PI3K) subunits in H1299, radio resistant cells than H460, radiosensitive cells. TRAIL receptors were expressed in H460 cells while the decoy receptor for TRAIL was expressed in H1299 cells. From these results, we could characterize the differential responsiveness to ionizing radiation according to their differential expressions of apoptosis-related genes, which might be the candidates to increase the power of radiotherapy.