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Background: Osteochondral autologous transplantation (OAT) has been widely used in the treatment of osteochondral lesion of the talus (OLT). Previous studies have reported successful outcomes following the use of osteochondral autogenous grafts from the intercondylar notch of the knee or a non-weight-bearing region of the femoral condyle. However, donor-site morbidity of the knee joint has been observed in several cases. This study aimed to investigate the outcomes and safety of OAT with autografts from the ipsilateral lateral talar articular facet as an alternative donor site for medial OLT. Methods: Among 40 patients who underwent OAT, 29 patients were excluded. Eleven patients who underwent OAT with an osteochondral graft harvested from the ipsilateral lateral talar articular facet from 2011 to 2022 were retrospectively analyzed. The size of OLT was measured on ankle magnetic resonance imaging, including coronal length, sagittal length, depth, and area. Clinical outcomes were evaluated using the American Orthopaedic Foot and Ankle Society (AOFAS) ankle-hindfoot scale and a visual analog scale (VAS). Weight-bearing ankle radiographs were obtained postoperatively and at 1 year after surgery. Results: The average follow-up time after surgery was 64.7 months (range, 14-137 months). The average diameter of lesions was 8.8 mm (range, 8-9.9 mm). The average size of lesions was 51.2 mm2 (range, 33.6-71.3 mm2) , and all lesions included subchondral cysts. The average depth of lesions was 7.3 mm (range, 6.2-9.1 mm). Graft sizes ranged from 8 to 10 mm in diameter (8 mm, n = 1; 10 mm, n = 10) All measured clinical outcomes improved postoperatively, including the AOFAS scores (preoperative, 55.4 ± 9.0; 1-year follow-up, 92.1 ± 7.6; p = 0.001) and VAS scores (preoperative, 5.5 ± 0.7; 1-year follow-up, 1.9 ± 0.8; p = 0.001). All weight-bearing ankle radiographs of the graft and donor sites did not reveal arthritic change in the ankle joint, lateral talar dome collapse, and graft-site delayed union or nonunion at 1 year after surgery. Conclusions: For a single medial OLT, harvesting autografts from the ipsilateral lateral talar articular facet without knee donor-site morbidities can be a good alternative in OAT for OLT.
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Transplante Ósseo , Tálus , Transplante Autólogo , Humanos , Tálus/cirurgia , Masculino , Feminino , Adulto , Estudos Retrospectivos , Transplante Ósseo/métodos , Pessoa de Meia-Idade , Cartilagem Articular/cirurgia , Adulto Jovem , Autoenxertos , Adolescente , Imageamento por Ressonância Magnética , Resultado do TratamentoRESUMO
Background: Benzophenone-3 is a type of ketone with 2 benzene rings attached to a carbonyl group (C=O) and one benzene ring attached to a hydroxyl group (-OH). As an endocrine-disrupting chemical, benzophenone-3 is known to be associated with reproductive, developmental, thyroid, and endocrine toxicities. Benzophenone-3 is commonly used in hair products, cosmetics, and ultraviolet (UV) filters because of its characteristic property to absorb UV light. This study aims to investigate the association between the use of hair products and urine benzophenone-3 using the data from the Korean National Environmental Health Survey (KoNEHS) cycle 4 (2018-2020), which represents the Korean population. Methods: Using the KoNEHS cycle 4 survey, the data of 3,796 adults aged ≥ 19 years were analyzed. Based on the 75th percentile concentration of urine benzophenone-3, the participants were divided into the low- and high-concentration groups. Chi-square test was conducted to analyze the association of urine benzophenone-3 with distribution of general characteristics, use of personal care products, consumption of marine foods, and use of plastic products as the variable. Logistic regression analysis was conducted to calculate odds ratios (ORs) for the high-concentration group of urine benzophenone-3 based on the use of hair products. Results: Women with < 6 times or ≥ 6 times of hair product usage had significantly higher adjusted ORs compared to those who did not use hair products. The calculated ORs were 1.24 (95% confidence interval [CI]: 1.12-1.38) for women with < 6 times of usage and 1.54 (95% CI: 1.33-1.79) for women with ≥ 6 times of usage. Conclusions: This study revealed the association between the use of hair products and the concentration of urine benzophenone-3 in the general Korean population.
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Dupilumab is a biologic medication that is used for the treatment of moderate-to-severe atopic dermatitis (AD). Long-term data on dupilumab drug survival in Asia patients with AD are limited. A single-center, retrospective study was performed to assess drug survival between March 2019 and March 2023. Drug survival and associated characteristics were analyzed using Kaplan-Meier survival curves and multivariate Cox regression analysis, respectively. A total of 124 patients with AD (Mean age [standard deviation], 26.0 [8.6] years) with a 4 years-overall dupilumab drug survival rate of 87.9%, were included in this study. Characteristics associated with shorter drug survival were the low eczema area and severity index (EASI) scores at baseline (hazard ratio [HR] 0.84; 95% confidence interval [CI] 0.75-0.94, p-value = 0.003) and non-insurance coverage of dupilumab (HR 11.87; 95% CI 3.28-42.99, p-value = 0.001). This retrospective study demonstrated good overall 4-year dupilumab survival (87.6%) in South Korea. Patients with low baseline EASI scores and those who did not have insurance for dupilumab treatment discontinued the therapy frequently. To the best of our knowledge, this is the first long-term dupilumab drug survival study conducted in Asia with predictors.
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Anticorpos Monoclonais Humanizados , Dermatite Atópica , Humanos , Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/mortalidade , Anticorpos Monoclonais Humanizados/uso terapêutico , Feminino , Masculino , Estudos Retrospectivos , Adulto , República da Coreia , Adulto Jovem , Índice de Gravidade de Doença , Adolescente , Estimativa de Kaplan-Meier , Resultado do Tratamento , Pessoa de Meia-IdadeRESUMO
PURPOSE: To investigate the prognostic factors for recurrent rhegmatogenous retinal detachment following silicone oil removal. METHODS: This retrospective review included 147 consecutive patients with rhegmatogenous retinal detachment treated with silicone oil tamponade at a high-volume referral-based tertiary hospital between January 2012 and May 2022. All patients underwent follow-up for a minimum of 6 months after subsequent silicone oil removal. The primary outcome measure was the rate of recurrent retinal detachment following silicone oil removal, and the secondary outcome was best-corrected visual acuity after silicone oil removal. RESULTS: The mean silicone oil tamponade duration was 4.7 ± 5.01 months (range, 1-38 months; median, 3 months), and the recurrent retinal detachment rate after silicone oil removal was 15.6%. Logistic regression analysis revealed that argon endolaser photocoagulation during silicone oil removal (odds ratio [OR], 0.309; 95% confidence interval [CI], 0.106-0.898; p = 0.031) was associated with a lower rate of anatomical success after silicone oil removal. Demographics, preoperative ocular characteristics, proliferative vitreoretinopathy, previous scleral encircling or buckling, previous retinectomy, concomitant phacoemulsification, duration of silicone oil tamponade, and gas tamponade after silicone oil removal were not significantly associated with recurrent retinal redetachment after silicone oil removal. Duration of silicone oil tamponade (OR, 1.226; 95% CI, 1.073-1.402; p = 0.003) and recurrent retinal detachment after silicone oil removal (OR, 3.400; 95% CI, 1.311-8.817; p = 0.012) were associated with poor visual outcomes after silicone oil removal. CONCLUSIONS: Among all factors examined in this study, including the duration of silicone oil tamponade, laser retinopexy was the only significant prognostic factor for recurrent retinal detachment after silicone oil removal. A longer duration of silicone oil tamponade was associated with worse visual outcomes and a lower rate of visual improvement after silicone oil removal.
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Tamponamento Interno , Recidiva , Descolamento Retiniano , Óleos de Silicone , Acuidade Visual , Vitrectomia , Humanos , Descolamento Retiniano/cirurgia , Descolamento Retiniano/diagnóstico , Descolamento Retiniano/etiologia , Estudos Retrospectivos , Masculino , Feminino , Óleos de Silicone/administração & dosagem , Pessoa de Meia-Idade , Prognóstico , Vitrectomia/efeitos adversos , Seguimentos , Adulto , Idoso , Drenagem/métodos , Fotocoagulação a Laser/efeitos adversos , Fotocoagulação a Laser/métodosRESUMO
Background: Perfluoroalkyl substances (PFASs) are non-aromatic organic compounds, whose hydrogen atoms in the carbon chain substituted by fluorine atoms. PFASs exhibit developmental toxicity, carcinogenicity, hepatotoxicity, reproductive toxicity, immunotoxicity, and hormone toxicity. PFASs are used in the production of disposable food packages, aircraft and automobile devices, cooking utensils, outdoor gear, furniture and carpets, aqueous film forming foam (AFFF), cables and wires, electronics, and semiconductors. This study aimed to determine the association between crustacean consumption and serum PFASs. Methods: Adult participants (2,993) aged ≥ 19 years were extracted from the 4th cycle data of the Korean National Environmental Health Survey (KoNEHS). Based on the 50th percentile concentrations of serum PFASs, participants were divided into the low-concentration group (LC) and the high-concentration group (HC). General characteristics, dietary factors, coated product usage, and personal care product usage, an independent t-test and χ2 test were analyzed. The odds ratio (OR) of serum PFAS concentration against crustacean consumption was estimated via logistic regression analysis adjusting for general characteristics, dietary factors, coated product usage, and personal care product usage. Results: The OR for the HC of serum PFASs was higher in individuals with ≥once a week crustacean consumption than in those with < once a week crustacean consumption. Estimated ORs were perfluorohexanesulfonic acid 2.15 (95% confidence interval [CI]: 1.53-3.02), perfluorononanoic acid (PFNA) 1.23 (95% CI: 1.07-1.41), and perfluorodecanoic acid (PFDeA) 1.42 (95% CI: 1.17-1.74) in males, and perfluorooctanoic acid 1.48 (95% CI: 1.19-1.84), perfluorooctanesulfonic acid 1.39 (95% CI: 1.27-1.52), PFNA 1.70 (95% CI: 1.29-2.26) and PFDeA 1.43 (95% CI: 1.32-1.54) in females. Conclusions: This study revealed the association between the crustacean consumption and concentrations of serum PFASs in general Korean population.
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Obesity has emerged as a prominent risk factor for the development of malignant tumors. However, the existing literature on the role of adipocytes in the tumor microenvironment (TME) to elucidate the correlation between obesity and cancer remains insufficient. Here, we aim to investigate the formation of cancer-associated adipocytes (CAAs) and their contribution to tumor growth using mouse models harboring dysfunctional adipocytes. Specifically, we employ adipocyte-specific BECN1 KO (BaKO) mice, which exhibit lipodystrophy due to dysfunctional adipocytes. Our results reveal the activation of YAP/TAZ signaling in both CAAs and BECN1-deficient adipocytes, inducing adipocyte dedifferentiation and formation of a malignant TME. The additional deletion of YAP/TAZ from BaKO mice significantly restores the lipodystrophy and inflammatory phenotypes, leading to tumor regression. Furthermore, mice fed a high-fat diet (HFD) exhibit decreased BECN1 and increased YAP/TAZ expression in their adipose tissues. Treatment with the YAP/TAZ inhibitor, verteporfin, suppresses tumor progression in BaKO and HFD-fed mice, highlighting its efficacy against mice with metabolic dysregulation. Overall, our findings provide insights into the key mediators of CAA and their significance in developing a TME, thereby suggesting a viable approach targeting adipocyte homeostasis to suppress cancer growth.
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Proteínas Adaptadoras de Transdução de Sinal , Adipócitos , Dieta Hiperlipídica , Camundongos Knockout , Proteínas com Motivo de Ligação a PDZ com Coativador Transcricional , Microambiente Tumoral , Proteínas de Sinalização YAP , Animais , Camundongos , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Adipócitos/metabolismo , Adipócitos/patologia , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genética , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Dieta Hiperlipídica/efeitos adversos , Progressão da Doença , Lipodistrofia/metabolismo , Lipodistrofia/patologia , Lipodistrofia/genética , Camundongos Endogâmicos C57BL , Neoplasias/metabolismo , Neoplasias/patologia , Neoplasias/genética , Obesidade/metabolismo , Obesidade/patologia , Transdução de Sinais , Transativadores/metabolismo , Transativadores/genética , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Verteporfina/farmacologia , Proteínas de Sinalização YAP/metabolismoRESUMO
As the biopharmaceutical industry continues to mature in its cost-effectiveness and productivity, many companies have begun employing larger-scale biomanufacturing and bioprocessing protocols. While many of these protocols require cells with anchorage-independent growth, it remains challenging to induce the necessary suspension adaptations in many different cell types. In addition, although transfection efficiency is an important consideration for all cells, especially for therapeutic protein production, cells in suspension are generally more difficult to transfect than adherent cells. Thus, much of the biomanufacturing industry is focused on the development of new human cell lines with properties that can support more efficient biopharmaceutical production. With this in mind, we identified a set of "Adherent-to-Suspension Transition" (AST) factors, IKZF1, BTG2 and KLF1, the expression of which induces adherent cells to acquire anchorage-independent growth. Working from the HEK293A cell line, we established 293-AST cells and 293-AST-TetR cells for inducible and reversible reprogramming of anchorage dependency. Surprisingly, we found that the AST-TetR system induces the necessary suspension adaptations with an accompanying increase in transfection efficiency and protein expression rate. Our AST-TetR system therefore represents a novel technological platform for the development of cell lines used for generating therapeutic proteins.
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Proteínas Recombinantes , Humanos , Células HEK293 , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Adesão Celular/genética , Transfecção/métodos , Técnicas de Cultura de Células/métodosRESUMO
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has chemotherapeutic potential as a regulator of an extrinsic apoptotic ligand, but its effect as a drug is limited by innate and acquired resistance. Recent findings suggest that an intermediate drug tolerance could mediate acquired resistance, which has made the main obstacle for limited utility of TRAIL as an anti-cancer therapeutics. We propose miRNA-dependent epigenetic modification drives the drug tolerant state in TRAIL-induced drug tolerant (TDT). Transcriptomic analysis revealed miR-29 target gene activation in TDT cells, showing oncogenic signature in lung cancer. Also, the restored TRAIL-sensitivity was associated with miR-29ac and 140-5p expressions, which is known as tumor suppressor by suppressing oncogenic protein RSK2 (p90 ribosomal S6 kinase), further confirmed in patient samples. Moreover, we extended this finding into 119 lung cancer cell lines from public data set, suggesting a significant correlation between TRAIL-sensitivity and RSK2 mRNA expression. Finally, we found that increased RSK2 mRNA is responsible for NF-κB activation, which we previously showed as a key determinant in both innate and acquired TRAIL-resistance. Our findings support further investigation of miR-29ac and -140-5p inhibition to maintain TRAIL-sensitivity and improve the durability of response to TRAIL in lung cancer.
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The process of cancer metastasis is dependent on the cancer cells' capacity to detach from the primary tumor, endure in a suspended state, and establish colonies in other locations. Anchorage dependence, which refers to the cells' reliance on attachment to the extracellular matrix (ECM), is a critical determinant of cellular shape, dynamics, behavior, and, ultimately, cell fate in nonmalignant and cancer cells. Anchorage-independent growth is a characteristic feature of cells resistant to anoikis, a programmed cell death process triggered by detachment from the ECM. This ability to grow and survive without attachment to a substrate is a crucial stage in the progression of metastasis. The recently discovered phenomenon named "adherent-to-suspension transition (AST)" alters the requirement for anchoring and enhances survival in a suspended state. AST is controlled by four transcription factors (IKAROS family zinc finger 1, nuclear factor erythroid 2, BTG anti-proliferation factor 2, and interferon regulatory factor 8) and can detach cells without undergoing the typical epithelial-mesenchymal transition. Notably, AST factors are highly expressed in circulating tumor cells compared to their attached counterparts, indicating their crucial role in the spread of cancer. Crucially, the suppression of AST substantially reduces metastasis while sparing primary tumors. These findings open up possibilities for developing targeted therapies that inhibit metastasis and emphasize the importance of AST, leading to a fundamental change in our comprehension of how cancer spreads.
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Metástase Neoplásica , Neoplasias , Humanos , Neoplasias/patologia , Adesão Celular , Matriz Extracelular/metabolismo , Transição Epitelial-Mesenquimal , Anoikis , Fatores de Transcrição/metabolismoRESUMO
Cancer cells metastasize to distant organs by altering their characteristics within the tumor microenvironment (TME) to effectively overcome challenges during the multistep tumorigenesis. Plasticity endows cancer cell with the capacity to shift between different morphological states to invade, disseminate, and seed metastasis. The epithelial-to-mesenchymal transition (EMT) is a theory derived from tissue biopsy, which explains the acquisition of EMT transcription factors (TFs) that convey mesenchymal features during cancer migration and invasion. On the other hand, adherent-to-suspension transition (AST) is an emerging theory derived from liquid biopsy, which describes the acquisition of hematopoietic features by AST-TFs that reprograms anchorage dependency during the dissemination of circulating tumor cells (CTCs). The induction and plasticity of EMT and AST dynamically reprogram cell-cell interaction and cell-matrix interaction during cancer dissemination and colonization. Here, we review the mechanisms governing cellular plasticity of AST and EMT during the metastatic cascade and discuss therapeutic challenges posed by these two morphological adaptations to provide insights for establishing new therapeutic interventions. [BMB Reports 2024; 57(6): 273-280].
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Plasticidade Celular , Transição Epitelial-Mesenquimal , Neoplasias , Microambiente Tumoral , Humanos , Transição Epitelial-Mesenquimal/fisiologia , Plasticidade Celular/fisiologia , Neoplasias/patologia , Neoplasias/metabolismo , Microambiente Tumoral/fisiologia , Células Neoplásicas Circulantes/metabolismo , Células Neoplásicas Circulantes/patologia , Metástase Neoplásica , Fatores de Transcrição/metabolismo , Animais , Invasividade NeoplásicaRESUMO
BACKGROUND: Regarding the pathophysiology of renal infarction (RI), cardioembolic causes could have large proportion. However, there are notable variations in prevalence of atrial fibrillation (AF) among patients with RI across different studies, ranging from 17 to 65%. The primary objective of this study is to analyze the incidence of AF in patients with RI. METHODS: This nationwide retrospective cohort study enrolled 5200 patients with RI from the Korean National Institute of Health Services database spanning the years 2013 to 2019. The study accessed the AF incidence rate within 12 months in patients without a prior history of AF. Events occurring within 3 months of RI diagnosis were excluded to mitigate cases diagnosed during the initial screening or those with AF diagnoses that were potentially overlooked in the past. RESULTS: AF occurred in 19.1% of patients with RI over the entire period (median: 2.5 years, interquartile range 1.04-4.25 years). The majority of AF cases (16.1%) occured within the first year, resulting in an overall incidence rate of 7.0 per 100 person-years. Patients with newly developed AF were, on average, older than those who did not develop AF (64.1 vs. 57.3 years, P < 0.001). The independent predictors of AF were identified as age, male sex, higher body mass index, current smoking, ischemic heart disease, and heart failure. CONCLUSIONS: Physicians should consider the implementation of active rhythm monitoring for patients with RI to identify potential occurrence of subclinical AF, even if not initially diagnosed during the initial screening after RI diagnosis.
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Fibrilação Atrial , Sistema de Registros , Humanos , Fibrilação Atrial/epidemiologia , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/complicações , Masculino , Feminino , Incidência , Estudos Retrospectivos , Pessoa de Meia-Idade , República da Coreia/epidemiologia , Idoso , Infarto/epidemiologia , Infarto/diagnóstico , Programas Nacionais de Saúde/estatística & dados numéricos , Estudos de Coortes , Nefropatias/epidemiologia , Nefropatias/diagnóstico , AdultoRESUMO
Proprotein convertase subtilisin/kexin type-9 (PCSK9) binds to and degrades low-density lipoprotein (LDL) receptor, leading to increase of LDL cholesterol in blood. Its blockers have emerged as promising therapeutics for cardiovascular diseases. Here we show that PCSK9 itself directly induces inflammation and aggravates atherosclerosis independently of the LDL receptor. PCSK9 exacerbates atherosclerosis in LDL receptor knockout mice. Adenylyl cyclase-associated protein 1 (CAP1) is the main binding partner of PCSK9 and indispensable for the inflammatory action of PCSK9, including induction of cytokines, Toll like receptor 4, and scavenger receptors, enhancing the uptake of oxidized LDL. We find spleen tyrosine kinase (Syk) and protein kinase C delta (PKCδ) to be the key mediators of inflammation after PCSK9-CAP1 binding. In human peripheral blood mononuclear cells, serum PCSK9 levels are positively correlated with Syk, PKCδ, and p65 phosphorylation. The CAP1-fragment crystallizable region (CAP1-Fc) mitigates PCSK9-mediated inflammatory signal transduction more than the PCSK9 blocking antibody evolocumab does.
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Aterosclerose , Pró-Proteína Convertase 9 , Animais , Camundongos , Humanos , Pró-Proteína Convertase 9/genética , Pró-Proteína Convertase 9/metabolismo , NF-kappa B/metabolismo , Leucócitos Mononucleares/metabolismo , Aterosclerose/metabolismo , Receptores de LDL/metabolismo , Inflamação , LDL-Colesterol , Camundongos KnockoutRESUMO
Introduction: A fracture of the ceramic head in bipolar hemiarthroplasty using an inner polyliner has not been reported yet, and there seems to be no report of simultaneous breakage of the fourth-generation BIOLOX Delta ceramic head and liner in total hip arthroplasty. Method: A 44-year-old male patient underwent bipolar hemiarthroplasty using a third-generation BIOLOX Forte ceramic head 3 years and 9 months earlier for osteonecrosis of femoral head (ONFH) and visited our hospital due to a ceramic head fracture. Conversion total hip arthroplasty was performed. A 64-year-old female patient underwent total hip arthroplasty using a fourth-generation BIOLOX Delta ceramic head and liner articulation for osteoarthritis of the hip. The ceramic head and liner were fractured during the third dislocation. Ceramic head and liner exchange revision surgery was performed. Conclusion: When using ceramic bearings, fractures or delamination following trauma can occur, confirming the need to carefully evaluate the condition of the ceramic components in symptomatic patients.
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RNA nanotechnology, including rolling circle transcription (RCT), has gained increasing interest as a fascinating siRNA delivery nanoplatform for biostable and tumor-targetable RNA-based therapies. However, due to the lack of fine-tuning technologies for RNA nanostructures, the relationship between physicochemical properties and siRNA efficacy of polymeric siRNA nanoparticles (PRNs) with different sizes has not yet been fully elucidated. Herein, we scrutinized the effects of size/surface chemistry-tuned PRNs on the biological and physiological interactions with tumors. PRNs with adjusted size and surface properties were prepared using sequential engineering processes: RCT, condensation, and nanolayer deposition of functional biopolymers. Through the RCT process, nanoparticles of three sizes with a diameter of 50-200 nm were fabricated and terminated with three types of biopolymers: poly-l-lysine (PLL), poly-l-glutamate (PLG), and hyaluronic acid (HA) for different surface properties. Among the PRNs, HA-layered nanoparticles with a diameter of â¼200 nm exhibited the most effective systemic delivery, resulting in superior anticancer effects in an orthotopic breast tumor model due to the CD44 receptor targeting and optimized nanosized structure. Depending on the type of PRNs, the in vivo siRNA delivery with protein expression inhibition differed by up to approximately 20-fold. These findings indicate that the types of layered biopolymers and the PRNs size mediate efficient polymeric siRNA delivery to the targeted tumors, resulting in high RNAi-induced therapeutic efficacy. This RNA-nanotechnology-based size/surface editing can overcome the limitations of siRNA therapeutics and represents a potent built-in module method to design RNA therapeutics tailored for targeted cancer therapy.
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Nanopartículas , Neoplasias , Distribuição Tecidual , Linhagem Celular Tumoral , RNA Interferente Pequeno/genética , Nanopartículas/química , Polímeros/metabolismo , Biopolímeros/metabolismo , Neoplasias/tratamento farmacológicoRESUMO
Mosquitoes are the most notorious arthropod vectors of viral and parasitic diseases for which approximately half the world's population, ~4,000,000,000, is at risk. Integrated pest management programs (IPMPs) have achieved some success in mitigating the regional transmission and persistence of these diseases. However, as many vector-borne diseases remain pervasive, it is obvious that IPMP successes have not been absolute in eradicating the threat imposed by mosquitoes. Moreover, the expanding mosquito geographic ranges caused by factors related to climate change and globalization (travel, trade, and migration), and the evolution of resistance to synthetic pesticides, present ongoing challenges to reducing or eliminating the local and global burden of these diseases, especially in economically and medically disadvantaged societies. Abatement strategies include the control of vector populations with synthetic pesticides and eco-friendly technologies. These "green" technologies include SIT, IIT, RIDL, CRISPR/Cas9 gene drive, and biological control that specifically targets the aquatic larval stages of mosquitoes. Regarding the latter, the most effective continues to be the widespread use of Lysinibacillus sphaericus (Ls) and Bacillus thuringiensis subsp. israelensis (Bti). Here, we present a review of the health issues elicited by vector mosquitoes, control strategies, and lastly, focus on the biology of Ls and Bti, with an emphasis on the latter, to which no resistance has been observed in the field.
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Rationale: The surge of severe liver damage underscores the necessity for identifying new targets and therapeutic agents. Endoplasmic reticulum (ER) stress induces ferroptosis with Gα12 overexpression. NF-κB essential modulator (NEMO) is a regulator of inflammation and necroptosis. Nonetheless, the regulatory basis of NEMO de novo synthesis and its impact on hepatocyte ferroptosis need to be established. This study investigated whether Nrf2 transcriptionally induces IKBKG (the NEMO gene) for ferroptosis inhibition and, if so, how NEMO induction protects hepatocytes against ER stress-induced ferroptosis. Methods: Experiments were conducted using human liver tissues, hepatocytes, and injury models, incorporating NEMO overexpression and Gα12 gene modulations. RNA sequencing, immunoblotting, immunohistochemistry, reporter assays, and mutation analyses were done. Results: NEMO downregulation connects closely to ER and oxidative stress, worsening liver damage via hepatocyte ferroptosis. NEMO overexpression protects hepatocytes from ferroptosis by promoting glutathione peroxidase 4 (GPX4) expression. This protective role extends to oxidative and ER stress. Similar shifts occur in nuclear factor erythroid-2-related factor-2 (Nrf2) expression alongside NEMO changes. Nrf2 is newly identified as an IKBKG (NEMO gene) transactivator. Gα12 changes, apart from Nrf2, impact NEMO expression, pointing to post-transcriptional control. Gα12 reduction lowers miR-125a, an inhibitor of NEMO, while overexpression has the opposite effect. NEMO also counters ER stress, which triggers Gα12 overexpression. Gα12's significance in NEMO-dependent hepatocyte survival is confirmed via ROCK1 inhibition, a Gα12 downstream kinase, and miR-125a. The verified alterations or associations within the targeted entities are validated in human liver specimens and datasets originating from livers subjected to exposure to other injurious agents. Conclusions: Hepatic injury prompted by ER stress leads to the suppression of NEMO, thereby facilitating ferroptosis through the inhibition of GPX4. IKBKG is transactivated by Nrf2 against Gα12 overexpression responsible for the increase of miR-125a, an unprecedented NEMO inhibitor, resulting in GPX4 induction. Accordingly, the induction of NEMO mitigates ferroptotic liver injury.
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Ferroptose , Hepatopatias , MicroRNAs , Humanos , Estresse do Retículo Endoplasmático/genética , Ferroptose/genética , Quinase I-kappa B/genética , Quinase I-kappa B/metabolismo , MicroRNAs/genética , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Quinases Associadas a rhoRESUMO
The Lysinibacillus sphaericus proteins Tpp49Aa1 and Cry48Aa1 can together act as a toxin toward the mosquito Culex quinquefasciatus and have potential use in biocontrol. Given that proteins with sequence homology to the individual proteins can have activity alone against other insect species, the structure of Tpp49Aa1 was solved in order to understand this protein more fully and inform the design of improved biopesticides. Tpp49Aa1 is naturally expressed as a crystalline inclusion within the host bacterium, and MHz serial femtosecond crystallography using the novel nanofocus option at an X-ray free electron laser allowed rapid and high-quality data collection to determine the structure of Tpp49Aa1 at 1.62 Å resolution. This revealed the packing of Tpp49Aa1 within these natural nanocrystals as a homodimer with a large intermolecular interface. Complementary experiments conducted at varied pH also enabled investigation of the early structural events leading up to the dissolution of natural Tpp49Aa1 crystals-a crucial step in its mechanism of action. To better understand the cooperation between the two proteins, assays were performed on a range of different mosquito cell lines using both individual proteins and mixtures of the two. Finally, bioassays demonstrated Tpp49Aa1/Cry48Aa1 susceptibility of Anopheles stephensi, Aedes albopictus, and Culex tarsalis larvae-substantially increasing the potential use of this binary toxin in mosquito control.
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Bacillaceae , Bacillus , Culex , Praguicidas , Animais , Bacillaceae/química , Bacillaceae/metabolismo , Controle de Mosquitos , Larva/metabolismoRESUMO
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.
Assuntos
Crise Blástica , Leucemia Mielogênica Crônica BCR-ABL Positiva , Animais , Camundongos , Humanos , Crise Blástica/tratamento farmacológico , Crise Blástica/genética , Crise Blástica/patologia , Proteínas de Fusão bcr-abl/genética , Resistencia a Medicamentos Antineoplásicos/genética , Transdução de Sinais , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Inibidores de Proteínas Quinases/farmacologia , Tirosina Quinase 3 Semelhante a fms/metabolismoRESUMO
BACKGROUND: Not only hemo-dynamic (HD) factors but also hemo-metabolic (HM) risk factors reflecting multi-organ injuries are considered as important prognostic factors in ST-segment elevation myocardial infarction (STEMI). However, studies regarding HM risk factors in STEMI patients are currently limited. METHOD: Under analysis were 1,524 patients with STEMI who underwent primary percutaneous coronary intervention in the INTERSTELLAR registry. Patients were divided into HM (≥ 2 risk factors) and non-HM impairment groups. The primary outcome was in-hospital all-cause mortality, and the secondary outcome was 1-year all-cause mortality. RESULTS: Of 1,524 patients, 214 (14.0%) and 1,310 (86.0%) patients were in the HM and non-HM impairment groups, respectively. Patients with HM impairment had a higher incidence of in-hospital mortality than those without (24.3% vs. 2.7%, p < 0.001). After adjusting for confounders, HM impairment was independently associated with in-hospital mortality (inverse probability of treatment weighting [IPTW]-adjusted odds ratio: 1.81, 95% confidence interval: 1.08-3.14). In the third door-to-balloon (DTB) time tertile (≥ 82 min), HM impairment was strongly associated with in-hospital mortality. In the first DTB time tertile ( < 62 min), indicating relatively rapid revascularization, HM impairment was consistently associated with increased in-hospital mortality. CONCLUSIONS: Hemo-metabolic impairment is significantly associated with increased risk of in-hospital and 1-year mortality in patients with STEMI. It remains a significant prognostic factor, regardless of DTB time.