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BACKGROUND: Patients with end-stage renal disease (ESRD) who are on hemodialysis (HD) have reduced vascular compliance and are likely to develop heart failure (HF). In this study, we estimated the prevalence of HF pre- and post-HD in ESRD using the current guidelines. METHODS: We prospectively investigated HF in ESRD patients on HD using echocardiography pre- and post-HD. We used the structural and functional abnormality criteria of the 2021 European Society of Cardiology guidelines. RESULTS: A total of 54 patients were enrolled. The mean age was 62.6 years, and 40.1% were male. Forty-five patients (83.3%) had hypertension, 28 (51.9%) had diabetes, and 20 (37.0%) had ischemic heart disease. The mean N-terminal-pro brain natriuretic peptide BNP (NT-proBNP) level was 12,388.8 ± 2,592.2 pg/dL. The mean ideal body weight was 59.3 kg, mean hemodialysis time was 237.4 min, and mean real filtration was 2.8 kg. The mean left ventricular ejection fraction (LVEF) was 62.4%, and mean left ventricular end-diastolic diameter was 52.0 mm in pre-HD. Post-HD echocardiography showed significantly lower left atrial volume index (33.3 ± 15.9 vs. 40.6 ± 17.1, p = 0.030), tricuspid regurgitation jet V (2.5 ± 0.4 vs. 2.8 ± 0.4 m/s, p < 0.001), and right ventricular systolic pressure (32.1 ± 10.3 vs. 38.4 ± 11.6, p = 0.005) compared with pre-HD. There were no differences in LVEF, E/E' ratio, or left ventricular global longitudinal strain. A total of 88.9% of pre-HD patients and 66.7% of post-HD patients had either structural or functional abnormalities in echocardiographic parameters according to recent HF guidelines (p = 0.007). CONCLUSIONS: Our data showed that the majority of patients undergoing hemodialysis satisfy the diagnostic criteria for HF according to current HF guidelines. Pre-HD patients had a 22.2% higher incidence in the prevalence of functional or structural abnormalities as compared with post-HD patients.
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BACKGROUND: We aimed to analyze the effects of an antimicrobial stewardship program (ASP) on the proportion of antimicrobial-resistant pathogens in bacteremia, antimicrobial use, and mortality in pediatric patients. METHODS: A retrospective single-center study was performed on pediatric inpatients under 19 years old who received systemic antimicrobial treatment from 2001 to 2019. A pediatric infectious disease attending physician started ASP in January 2008. The study period was divided into the pre-intervention (2001-2008) and the post-intervention (2009-2019) periods. The amount of antimicrobial use was defined as days of therapy per 1,000 patient-days, and the differences were compared using delta slope (= changes in slopes) between the two study periods by an interrupted time-series analysis. The proportion of resistant pathogens and the 30-day overall mortality rate were analyzed by the χ². RESULTS: The proportion of extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli and Klebsiella pneumoniae bacteremia increased from 17% (39 of 235) in the pre-intervention period to 35% (189 of 533) in the post-intervention period (P < 0.001). The total amount of antimicrobial use significantly decreased after the introduction of ASP (delta slope value = -16.5; 95% confidence interval [CI], -30.6 to -2.3; P = 0.049). The 30-day overall mortality rate in patients with bacteremia did not increase, being 10% (55 of 564) in the pre-intervention and 10% (94 of 941) in the post-intervention period (P = 0.881). CONCLUSION: The introduction of ASP for pediatric patients reduced the delta slope of the total antimicrobial use without increasing the mortality rate despite an increased incidence of ESBL-producing gram-negative bacteremia.
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Antibacterianos , Gestão de Antimicrobianos , Bacteriemia , Análise de Séries Temporais Interrompida , Klebsiella pneumoniae , Humanos , Estudos Retrospectivos , Criança , Bacteriemia/tratamento farmacológico , Bacteriemia/mortalidade , Bacteriemia/microbiologia , Feminino , Masculino , Pré-Escolar , Antibacterianos/uso terapêutico , Lactente , Klebsiella pneumoniae/efeitos dos fármacos , Klebsiella pneumoniae/isolamento & purificação , Adolescente , Escherichia coli/efeitos dos fármacos , Escherichia coli/isolamento & purificação , Hospitais PediátricosRESUMO
Limited research has explored the relationship between falls, cognitive decline, and dementia onset in older adults with aging. Therefore, this study aimed to investigate the impact of cognitive function on the development of dementia and explore the association between falls and dementia among older adults. This study utilized data from the Korean Longitudinal Study of Aging, which tracked a sample group at 2-year intervals from the initial wave in 2006 to the eighth wave in 2020. Among the older adults (≥60 years) surveyed, 2829 were included in the analysis, and cognitive function and number of falls per year were recorded. We hypothesized that these variables were associated with dementia and tested the variables using dementia diagnosis data. The participants were assigned to either a dementia group (dementia diagnosis) or a control group (no dementia diagnosis). Analyses were performed to enhance generalizability of the hypothesis to all participants (≥45 years, n = 7130). Cognitive decline and dementia incidence increased with aging among older adults. The dementia group had a significantly higher rate of cognitive decline than the control group, as well as a higher number of falls and magnitude of annual changes in falls. The changes in falls were irregular regardless of cognitive function. Furthermore, falls were associated only with the development of dementia, not cognitive function. Similar trends were observed across the total participant group. Our findings highlight the importance of monitoring cognitive function and falls as potential markers for predicting dementia onset in older adults.
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Acidentes por Quedas , Envelhecimento , Disfunção Cognitiva , Demência , Humanos , Idoso , Acidentes por Quedas/estatística & dados numéricos , Masculino , Estudos Longitudinais , Feminino , República da Coreia/epidemiologia , Demência/epidemiologia , Disfunção Cognitiva/epidemiologia , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais , Incidência , Cognição , Fatores de RiscoRESUMO
PURPOSE: To evaluate the outcomes of wavefront-optimized (WFO) and topography-guided (TG) transepithelial photorefractive keratectomy (transPRK) in the treatment of myopia and myopic astigmatism. METHODS: Patients who underwent transPRK using the WaveLight EX500 excimer laser for the correction of myopia and myopic astigmatism between January 2022 and March 2023 were divided into groups of WFO transPRK (77 eyes of 36 patients) or TG transPRK (63 eyes of 31 patients) in this retrospective, observational cohort study. The preoperative and postoperative 3-month refractive and visual outcomes of the two groups were analyzed. RESULTS: In both groups, the uncorrected distance visual acuity was 0.0 logarithm of the minimum angle of resolution or better in 95% of eyes 3 months postoperatively, and the mean manifest refraction spherical equivalent was within ±1.0 diopter in 90% of eyes. No significant differences were observed between the groups in terms of the uncorrected distance visual acuity or astigmatism. A significant induction of higher order aberrations (HOAs) was observed in both groups. However, the induction of total corneal HOAs (p = 0.014) and spherical aberrations (p < 0.001) was significantly lower in the TG group than that in the WFO group. CONCLUSIONS: WFO and TG transPRK effectively improved the visual and refractive outcomes; however, the induction of total corneal HOAs and spherical aberration was lesser following the TG ablation.
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Topografia da Córnea , Lasers de Excimer , Miopia , Ceratectomia Fotorrefrativa , Refração Ocular , Acuidade Visual , Humanos , Estudos Retrospectivos , Ceratectomia Fotorrefrativa/métodos , Feminino , Masculino , Acuidade Visual/fisiologia , Refração Ocular/fisiologia , Adulto , Lasers de Excimer/uso terapêutico , Miopia/cirurgia , Miopia/fisiopatologia , Resultado do Tratamento , Adulto Jovem , Astigmatismo/cirurgia , Astigmatismo/fisiopatologia , Seguimentos , Aberrações de Frente de Onda da Córnea/fisiopatologia , Aberrações de Frente de Onda da Córnea/diagnóstico , Cirurgia Assistida por Computador/métodosRESUMO
Introduction: The long-term effects of fenestration in patients with Fontan circulation remain unclear. We aim to evaluate the fenestration impact on early and late outcomes in patients with extracardiac Fontan (ECF) using a propensity score matching analysis. Methods: We performed an extensive retrospective multicenter clinical data review of the Korean Fontan registry and included 1,233 patients with surgical ECF (779 fenestrated, 454 non-fenestrated). Demographics, baseline, and follow-up data were collected and comprehensively analyzed. Patients were divided into two groups according to the baseline presence or absence of surgical fenestration. Subsequently, patients were sub-divided according to the fenestration status at the last follow-up. Propensity-score matching was performed to account for collected data between the 2 groups using a multistep approach. The primary outcomes were survival and freedom from Fontan failure (FFF). We also looked at postoperative hemodynamics, cardiopulmonary exercise test results, oxygen saturations, and functional status. Results: After propensity-score matching (454 matched pairs), there was no difference in survival or FFF between the 2 groups. However, ECF patients with baseline fenestration had significantly lower oxygen saturation (p = 0.001) and lower functional status (p < 0.001). Patients with fenestration had significantly longer bypass times, higher postoperative central venous pressure, higher postoperative left atrial pressure, and less prolonged pleural effusion in the early postoperative period. The propensity score matching according to the fenestration status at the last follow-up (148 matched pairs) showed that patients with a persistent fenestration had significantly lower oxygen saturation levels (p < 0.001). However there were no intergroup differences in the functional status, survival and FFF. Conclusions: Our results showed no long-term benefits of the Fenestration in terms of survival and FFF. Patients with persistent fenestration showed oxygen desaturation but no difference in exercise intolerance was shown between the 2 groups.
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The assessment of neurotoxicity for environmental chemicals is of utmost importance in ensuring public health and environmental safety. Multielectrode array (MEA) technology has emerged as a powerful tool for assessing disturbances in the electrophysiological activity. Although human embryonic stem cell (hESC)-derived neurons have been used in MEA for neurotoxicity screening, obtaining a substantial and sufficiently active population of neurons from hESCs remains challenging. In this study, we successfully differentiated neurons from a large population of human neuronal precursor cells (hNPC) purified using a polysialylated neural cell adhesion molecule (PSA-NCAM), referred to as hNPCPSA-NCAM+. The functional characterization demonstrated that hNPCPSA-NCAM+-derived neurons improve functionality by enhancing electrophysiological activity compared to total hNPC-derived neurons. Furthermore, three-dimensional (3D) neurons derived from hNPCPSA-NCAM+ exhibited reduced maturation time and enhanced electrophysiological activity on MEA. We employed subdivided population analysis of active mean firing rate (MFR) based on electrophysiological intensity to characterize the electrophysiological properties of hNPCPSA-NCAM+-3D neurons. Based on electrophysiological activity including MFR and burst parameters, we evaluated the sensitivity of hNPCPSA-NCAM+-3D neurons on MEA to screen both inhibitory and excitatory neuroactive environmental chemicals. Intriguingly, electrophysiologically active hNPCPSA-NCAM+-3D neurons demonstrated good sensitivity to evaluate neuroactive chemicals, particularly in discriminating excitatory chemicals. Our findings highlight the effectiveness of MEA approaches using hNPCPSA-NCAM+-3D neurons in the assessment of neurotoxicity associated with environmental chemicals. Furthermore, we emphasize the importance of selecting appropriate signal intensity thresholds to enhance neurotoxicity prediction and screening of environmental chemicals.
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Fenômenos Eletrofisiológicos , Poluentes Ambientais , Células-Tronco Neurais , Humanos , Células-Tronco Neurais/efeitos dos fármacos , Poluentes Ambientais/toxicidade , Fenômenos Eletrofisiológicos/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Ácidos Siálicos , Diferenciação Celular/efeitos dos fármacos , Molécula L1 de Adesão de Célula Nervosa , Testes de Toxicidade/métodosRESUMO
PURPOSE: We sought to assess associations between health-related quality of life (QOL), bladder-related QOL, bladder symptoms, and bladder catheterization route among adolescents and young adults with spina bifida. MATERIALS AND METHODS: Clinical questionnaires administered to individuals ≥ 12 years old requiring catheterization between June 2019 to March 2020 in a spina bifida center were retrospectively analyzed. Questionnaires were completed in English or Spanish independently or with caregiver assistance. Medical records were reviewed for demographic and clinical characteristics. Primary exposure was catheterization route (urethra or channel). Primary outcome was health-related QOL, measured by Patient-Reported Outcomes Measurement Information System Pediatric Global Health 7 (PGH-7). Secondary outcomes were bladder-related QOL and bladder symptoms, measured by Neurogenic Bladder Symptom Score (NBSS). Nested, multivariable linear regression models assessed associations between catheterization route and questionnaire scores. RESULTS: Of 162 patients requiring catheterization, 146 completed both the PGH-7 and NBSS and were included. Seventy-three percent were catheterized via urethra and 27% via channel. Median age was 17.5 years (range 12-31), 58% of patients were female, and 80% had myelomeningocele. Urinary incontinence was more common among those who catheterized via urethra (60%) compared to channel (33%). On adjusted analyses, catheterization route was not significantly associated with PGH-7 or NBSS bladder-related QOL scores. More bladder symptoms were associated with worse bladder-related QOL. Patients who catheterized via channel had fewer bladder symptoms than those who catheterized via urethra. CONCLUSIONS: Catheterization route was not significantly associated with QOL. Though catheterization via channel was associated with fewer bladder symptoms, only degree of current bladder symptoms was significantly associated with bladder-related QOL.
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Qualidade de Vida , Disrafismo Espinal , Bexiga Urinaria Neurogênica , Cateterismo Urinário , Humanos , Adolescente , Feminino , Masculino , Disrafismo Espinal/complicações , Estudos Retrospectivos , Adulto Jovem , Adulto , Criança , Bexiga Urinaria Neurogênica/etiologia , Bexiga Urinaria Neurogênica/terapia , Uretra , Inquéritos e Questionários , Medidas de Resultados Relatados pelo PacienteRESUMO
BACKGROUND: We investigated the tumor suppression effect of an ultrasound-sensitive doxorubicin-loaded liposome-based nanoparticle, IMP301, to enhance the synergistic effect with focused ultrasound (FUS) in an animal model of pancreatic cancer. METHODS: Thirty nude mice with xenografts of PANC-1 human pancreatic cancer cells were randomly and prospectively allocated to 6 different groups (5 per group) each for Study-1 (dose-response test) and Study-2 (synergistic effect test). Study-1 consisted of control, gemcitabine, Doxil with FUS, and three different doses of IMP301 (2, 4, 6 mg/kg) with FUS groups. Study-2 consisted of control, FUS only, gemcitabine, Doxil with FUS, and IMP301 (4 mg/kg) with or without FUS groups. Differences in tumor volume and growth rate were evaluated by one-way ANOVA and Student-Newman-Keuls test. RESULTS: In Study-1, 4 mg/kg or greater IMP301 with FUS groups showed lower tumor growth rates of 14 ± 4 mm3/day (mean ± standard deviation) or less, compared to the control, gemcitabine, and Doxil with FUS groups with rates exceeding 28 ± 5 (p < 0.050). The addition of FUS in Study-2 decreased the tumor growth rate in the IMP301-treated groups from 36 ± 17 to 9 ± 6, which was lower than the control, FUS only, gemcitabine, and Doxil with FUS groups (p < 0.050). CONCLUSIONS: IMP301 combined with FUS exhibited higher tumor growth suppression compared to the use of a conventional drug alone or the combination with FUS. The present study showed the potential of IMP301 to enhance the synergistic effect with FUS for the treatment of pancreatic cancer. RELEVANCE STATEMENT: This article aims to evaluate the synergistic effect of FUS and ultrasound-responsive liposomal drug in tumor growth suppression by using xenograft mouse model of pancreatic ductal adenocarcinoma. FUS-induced ultrasound-sensitive drug release may be a potential noninvasive repeatable treatment option for patients with locally advanced or unresectable pancreatic cancer. KEY POINTS: ⢠Modification of conventional drugs combined with FUS would maximize tumor suppression. ⢠IMP301 with FUS had higher tumor suppression effect compared to conventional chemotherapy. ⢠This image-guided drug delivery would enhance therapeutic effects of systemic chemotherapy.
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Doxorrubicina/análogos & derivados , Nanopartículas , Neoplasias Pancreáticas , Humanos , Camundongos , Animais , Gencitabina , Xenoenxertos , Camundongos Nus , Linhagem Celular Tumoral , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , PolietilenoglicóisRESUMO
Cerium oxide nanoparticles (CeO2 NPs, NM-212) are well-known for their catalytic properties and antioxidant potential, and have many applications in various industries, drug delivery, and cosmetic formulations. CeO2 NPs exhibit strong antimicrobial activity and can be used to efficiently remove pathogens from different environments. However, knowledge of the toxicological evaluation of CeO2 NPs is too limited to support their safe use. In this study, CeO2 NPs were orally administered to Sprague Dawley rats for 13 weeks at the doses of 0, 10, 100, and 1000 mg/kg bw/day, followed by a four week recovery period. The hematology values for the absolute and relative reticulocyte counts in male rats treated with 1000 mg/kg bw/day CeO2 NPs were lower than those in control rats. The clinical chemistry values for sodium and chloride in the treated male rat groups (100 and 1000 mg/kg/day) and total protein and calcium in the treated female rat groups (100 mg/kg/day) were higher than those in the control groups. However, these changes were not consistent in both sexes, and no abnormalities were found in the corresponding pathological findings. The results showed no adverse effects on any of the parameters assessed. CeO2 NPs accumulated in the jejunum, colon, and stomach wall of rats administered 1000 mg/kg CeO2 NPs for 90 days. However, these changes were not abnormal in the corresponding histopathological and immunohistochemical examinations. Therefore, 1000 mg/kg bw/day may be considered the "no observed adverse effect level" of CeO2 NPs (NM-212) in male and female SD rats under the present experimental conditions.
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Cério , Nanopartículas Metálicas , Nanopartículas , Ratos , Masculino , Feminino , Animais , Ratos Sprague-Dawley , Nanopartículas/química , Cério/toxicidade , Cério/química , Sistemas de Liberação de Medicamentos , Nanopartículas Metálicas/toxicidade , Nanopartículas Metálicas/químicaRESUMO
Metastatic castration-resistant prostate cancer remains incurable regardless of recent therapeutic advances. Prostate cancer tumors display highly glycolytic phenotypes as the cancer progresses. Nonspecific inhibitors of glycolysis have not been utilized successfully for chemotherapy, because of their penchant to cause systemic toxicity. This study reports the preclinical activity, safety, and pharmacokinetics of a novel small-molecule preclinical candidate, BKIDC-1553, with antiglycolytic activity. We tested a large battery of prostate cancer cell lines for inhibition of cell proliferation, in vitro. Cell-cycle, metabolic, and enzymatic assays were used to demonstrate their mechanism of action. A human patient-derived xenograft model implanted in mice and a human organoid were studied for sensitivity to our BKIDC preclinical candidate. A battery of pharmacokinetic experiments, absorption, distribution, metabolism, and excretion experiments, and in vitro and in vivo toxicology experiments were carried out to assess readiness for clinical trials. We demonstrate a new class of small-molecule inhibitors where antiglycolytic activity in prostate cancer cell lines is mediated through inhibition of hexokinase 2. These compounds display selective growth inhibition across multiple prostate cancer models. We describe a lead BKIDC-1553 that demonstrates promising activity in a preclinical xenograft model of advanced prostate cancer, equivalent to that of enzalutamide. BKIDC-1553 demonstrates safety and pharmacologic properties consistent with a compound that can be taken into human studies with expectations of a good safety margin and predicted dosing for efficacy. This work supports testing BKIDC-1553 and its derivatives in clinical trials for patients with advanced prostate cancer.
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Proliferação de Células , Glicólise , Ensaios Antitumorais Modelo de Xenoenxerto , Masculino , Humanos , Animais , Camundongos , Glicólise/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Linhagem Celular Tumoral , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Neoplasias da Próstata/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêuticoRESUMO
The glucocerebrosidase (GCase) encoded by the GBA1 gene hydrolyzes glucosylceramide (GluCer) to ceramide and glucose in lysosomes. Homozygous or compound heterozygous GBA1 mutations cause the lysosomal storage disease Gaucher disease (GD) due to severe loss of GCase activity. Loss-of-function variants in the GBA1 gene are also the most common genetic risk factor for Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Restoring lysosomal GCase activity represents an important therapeutic approach for GBA1-associated diseases. We hypothesized that increasing the stability of lysosomal GCase protein could correct deficient GCase activity in these conditions. However, it remains unknown how GCase stability is regulated in the lysosome. We found that cathepsin L, a lysosomal cysteine protease, cleaves GCase and regulates its stability. In support of these data, GCase protein was elevated in the brain of cathepsin L-KO mice. Chemical inhibition of cathepsin L increased both GCase levels and activity in fibroblasts from patients with GD. Importantly, inhibition of cathepsin L in dopaminergic neurons from a patient GBA1-PD led to increased GCase levels and activity as well as reduced phosphorylated α-synuclein. These results suggest that targeting cathepsin L-mediated GCase degradation represents a potential therapeutic strategy for GCase deficiency in PD and related disorders that exhibit decreased GCase activity.
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Cisteína Proteases , Doença de Parkinson , Humanos , Animais , Camundongos , Glucosilceramidase/genética , Catepsina L/genética , Catepsina L/metabolismo , Catepsinas/metabolismo , Catepsinas/uso terapêutico , Cisteína Proteases/metabolismo , Cisteína Proteases/uso terapêutico , Doença de Parkinson/metabolismo , Lisossomos/metabolismoRESUMO
In the field of drug discovery, natural products have emerged as therapeutic agents for diseases such as cancer. However, their potential toxicity poses significant obstacles in the developing effective drug candidates. To overcome this limitation, we propose a pathway-screening method based on imaging analysis to evaluate cellular stress caused by natural products. We have established a cellular stress sensing system, named Hepa-ToxMOA, which utilizes HepG2 cells expressing green fluorescent protein (GFP) fluorescence under the control of transcription factor response elements (TREs) for transcription factors (AP1, P53, Nrf2, and NF-κB). Additionally, to augment the drug metabolic activity of the HepG2 cell line, we evaluated the cytotoxicity of 40 natural products with and without S9 fraction-based metabolic activity. Our finding revealed different activities of Hepa-ToxMOA depending on metabolic or non-metabolic activity, highlighting the involvement of specific cellular stress pathways. Our results suggest that developing a Hepa-ToxMOA system based on activity of drug metabolizing enzyme provides crucial insights into the molecular mechanisms initiating cellular stress during liver toxicity screening for natural products. The pathway-screening method addresses challenges related to the potential toxicity of natural products, advancing their translation into viable therapeutic agents.
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Regulação da Expressão Gênica , NF-kappa B , Humanos , NF-kappa B/metabolismo , Células Hep G2 , Proteínas de Fluorescência Verde/metabolismo , Fator 2 Relacionado a NF-E2/metabolismoRESUMO
Advancements in regenerative medicine have highlighted the potential of decellularized extracellular matrix (ECM) as a scaffold for organ bioengineering. Although the potential of ECM in major organ systems is well-recognized, studies focusing on the angiogenic effects of pancreatic ECM are limited. This study investigates the capabilities of pancreatic ECM, particularly its role in promoting angiogenesis. Using a Triton-X-100 solution, porcine pancreas was successfully decellularized, resulting in a significant reduction in DNA content (97.1% removal) while preserving key pancreatic ECM components. A three-dimensional ECM hydrogel was then created from this decellularized tissue and used for cell culture. Biocompatibility tests demonstrated enhanced adhesion and proliferation of mouse embryonic stem cell-derived endothelial cells (mES-ECs) and human umbilical vein endothelial cells (HUVECs) in this hydrogel compared to conventional scaffolds. The angiogenic potential was evaluated through tube formation assays, wherein the cells showed superior tube formation capabilities in ECM hydrogel compared to rat tail collagen. The RT-PCR analysis further confirmed the upregulation of pro-angiogenic genes in HUVECs cultured within the ECM hydrogel. Specifically, HUVECs cultured in the ECM hydrogel exhibited a significant upregulation in the expression of MMP2, VEGF and PAR-1, compared to those cultured in collagen hydrogel or in a monolayer condition. The identification of ECM proteins, specifically PRSS2 and Decorin, further supports the efficacy of pancreatic ECM hydrogel as an angiogenic scaffold. These findings highlight the therapeutic promise of pancreatic ECM hydrogel as a candidate for vascularized tissue engineering application.
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OBJECTIVE: To identify urinary biomarkers that can distinguish active renal involvement in Lupus Nephritis (LN), a severe manifestation of systemic lupus erythematosus (SLE). METHODS: Urine from 117 subjects, comprised of inactive SLE, active non-renal lupus, active LN, and healthy controls, were subjected to Proximity Extension Assay (PEA) based comprehensive proteomics followed by ELISA validation in an independent, ethnically diverse cohort. Proteomic data is also cross-referenced to renal transcriptomic data to elucidate cellular origins of biomarkers. RESULTS: Systems biology analyses revealed progressive activation of cytokine signaling, chemokine activity and coagulation pathways, with worsening renal disease. In addition to validating 30 previously reported biomarkers, this study uncovers several novel candidates. Following ELISA validation in an independent cohort of different ethnicity, the six most discriminatory biomarkers for active LN were urinary ICAM-2, FABP4, FASLG, IGFBP-2, SELE and TNFSF13B/BAFF, with ROC AUC ≥80%, with most correlating strongly with clinical disease activity. Transcriptomic analyses of LN kidneys mapped the likely origin of these proteins to intra-renal myeloid cells (CXCL16, IL-1RT2, TNFSF13B/BAFF), T/NK cells (FASLG), leukocytes (ICAM2) and endothelial cells (SELE). CONCLUSION: In addition to confirming the diagnostic potential of urine ALCAM, CD163, MCP1, SELL, ICAM1, VCAM1, NGAL and TWEAK for active LN, this study adds urine ICAM-2, FABP4, FASLG, IGFBP-2, SELE, and TNFSF13B/BAFF as additional markers that warrant systematic validation in larger cross-sectional and longitudinal cohorts.
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Lúpus Eritematoso Sistêmico , Nefrite Lúpica , Humanos , Nefrite Lúpica/diagnóstico , Nefrite Lúpica/genética , Proteína 2 de Ligação a Fator de Crescimento Semelhante à Insulina , Proteômica , Estudos Transversais , Células Endoteliais , Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/genética , Biomarcadores , Rim , Perfilação da Expressão GênicaRESUMO
Vibrio harveyi strain 22FBVib0145 was isolated from a diseased olive flounder farmed in Jeju, Korea. Here, we report the draft genome sequence of this strain. It is 6,238,277 bp in length with a G + C content of 44.8%.
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Purpose: Metastatic castration-resistant prostate cancer remains incurable regardless of recent therapeutic advances. Prostate cancer tumors display highly glycolytic phenotypes as the cancer progresses. Non-specific inhibitors of glycolysis have not been utilized successfully for chemotherapy, because of their penchant to cause systemic toxicity. This study reports the preclinical activity, safety, and pharmacokinetics of a novel small molecule preclinical candidate, BKIDC-1553, with antiglycolytic activity. Experimental design: We tested a large battery of prostate cancer cell lines for inhibition of cell proliferation, in vitro. Cell cycle, metabolic and enzymatic assays were used to demonstrate their mechanism of action. A human PDX model implanted in mice and a human organoid were studied for sensitivity to our BKIDC preclinical candidate. A battery of pharmacokinetic experiments, absorption, distribution, metabolism, and excretion experiments, and in vitro and in vivo toxicology experiments were carried out to assess readiness for clinical trials. Results: We demonstrate a new class of small molecule inhibitors where antiglycolytic activity in prostate cancer cell lines is mediated through inhibition of hexokinase 2. These compounds display selective growth inhibition across multiple prostate cancer models. We describe a lead BKIDC-1553 that demonstrates promising activity in a preclinical xenograft model of advanced prostate cancer, equivalent to that of enzalutamide. BKIDC-1553 demonstrates safety and pharmacologic properties consistent with a compound that can be taken into human studies with expectations of a good safety margin and predicted dosing for efficacy. Conclusion: This work supports testing BKIDC-1553 and its derivatives in clinical trials for patients with advanced prostate cancer.
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INTRODUCTION AND OBJECTIVE: The incidence of concomitant psychiatric disorders in conjunction with bladder and bowel dysfunction (BBD) is thought to be higher than the general population. The identification of these disorders with validated tools followed by management may improve urological outcomes. The objective of this study was to determine the prevalence of undiagnosed psychiatric symptom groupings in children presenting with BBD. METHODS: Consecutive patients 6-18 yrs with a clinical diagnosis of BBD, a score ≥11 on the Vancouver Symptom Score (VSS) and no prior psychiatric diagnoses were recruited. Two validated questionnaires (Child Behavior Checklist for Ages 6-18 (CBCL) and Autism Spectrum Quotient 10 (AQ-10)) were used to screen for psychiatric comorbidities. Descriptive statistics for demographic variables were presented. Distribution of VSS for normal & abnormal categories (borderline/clinical) of CBCL scores were compared by Mann-Whitney U test. Spearman correlation coefficient was used to examine the relationship between VSS domain scores and CBCL. RESULTS: From Sept 2017-May 2022, 50 (17 male) of 110 eligible patients completed the study. Median VSS was 18 (11-33), indicating significant BBD. In 36 patients (72 %), at least one of the CBCL subscales scored as borderline/clinical. Thirty-two patients (64 %) scored in the abnormal range for Internalizing symptoms, 21 (42 %) for Externalizing symptoms, and 31 (62 %) for Total problem scores. Four patients of 48(8 %) scored ≥6 on the AQ-10. The only significant correlation found between CBCL and VSS sub scores was with the Bowel Habit Domain of VSS and Internalizing CBCL T-scores (P = 0.02). CONCLUSION: This study identified a high prevalence of previously undiagnosed psychiatric symptom groupings in patients presenting with BBD, with a higher prevalence of internalizing and externalizing symptoms and autism traits than reported in the general population. These findings should encourage urologists to use validated tools to screen for psychiatric comorbidities with referral for further assessment as appropriate. This may prevent unnecessary urological testing, save valuable health resources and potentially improve treatment outcomes of BBD in this population.
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Gastroenteropatias , Enteropatias , Transtornos Mentais , Humanos , Criança , Masculino , Bexiga Urinária , Prevalência , Transtornos Mentais/diagnóstico , Transtornos Mentais/epidemiologiaRESUMO
Flavobacterium can synthesize xanthophyll, particularly the pigment zeaxanthin, which has significant economic value in nutrition and pharmaceuticals. Recently, the use of carotenoid biosynthesis by bacteria and yeast fermentation technology has shown to be very efficient and offers significant advantages in large-scale production, cost-effectiveness, and safety. In the present study, JSWR-1 strain capable of producing xanthophyll pigment was isolated from a freshwater reservoir in Wanju-gun, Republic of Korea. Based on the morphological, physiological, and molecular characteristics, JSWR-1 classified as belonging to the Flavobacterium species. The bacterium is strictly aerobic, Gram-negative, rod-shaped, and psychrophilic. The completed genome sequence of the strain Flavobacterium sp. JSWR-1 is predicted to be a single circular 3,425,829-bp chromosome with a G+C content of 35.2% and 2,941 protein-coding genes. The optimization of carotenoid production was achieved by small-scale cultivation, resulting in zeaxanthin being identified as the predominant carotenoid pigment. The enhancement of zeaxanthin biosynthesis by applying different light-irradiation, variations in pH and temperature, and adding carbon and nitrogen supplies to the growth medium. A significant increase in intracellular zeaxanthin concentrations was also recorded during fed-batch fermentation achieving a maximum of 16.69 ± 0.71 mg/l, corresponding to a product yield of 4.05 ± 0.15 mg zeaxanthin per gram cell dry weight. Batch and fed-batch culture extracts exhibit significant antioxidant activity. The results demonstrated that the JSWR-1 strain can potentially serve as a source for zeaxanthin biosynthesis.
Assuntos
Flavobacterium , Xantofilas , Zeaxantinas , Flavobacterium/genética , Carotenoides , Luteína , Ácidos Graxos/análise , Filogenia , RNA Ribossômico 16S/genética , DNA Bacteriano/genética , Análise de Sequência de DNA , Técnicas de Tipagem BacterianaRESUMO
Cinnamaldehyde is a natural compound extracted from cinnamon bark essential oil, acclaimed for its versatile properties in both pharmaceutical and agricultural fields, including antimicrobial, antioxidant, and anticancer activities. Although potential of cinnamaldehyde against plant pathogenic bacteria like Agrobacterium tumefaciens and Pseudomonas syringae pv. actinidiae causative agents of crown gall and bacterial canker diseases, respectively has been documented, indepth studies into cinnamaldehyde's broader influence on plant pathogenic bacteria are relatively unexplored. Particularly, Pectobacterium spp., gram-negative soil-borne pathogens, notoriously cause soft rot damage across a spectrum of plant families, emphasizing the urgency for effective treatments. Our investigation established that the Minimum Inhibitory Concentrations (MICs) of cinnamaldehyde against strains P. odoriferum JK2, P. carotovorum BP201601, and P. versatile MYP201603 were 250 µg/ml, 125 µg/ml, and 125 µg/ml, respectively. Concurrently, their Minimum Bactericidal Concentrations (MBCs) were found to be 500 µg/ml, 250 µg/ml, and 500 µg/ml, respectively. Using RNA-sequencing analysis, we identified 1,907 differentially expressed genes in P. carotovorum BP201601 treated with 500 µg/ml cinnamaldehyde. Notably, our results indicate that cinnamaldehyde upregulated nitrate reductase pathways while downregulating the citrate cycle, suggesting a potential disruption in the aerobic respiration system of P. carotovorum during cinnamaldehyde exposure. This study serves as a pioneering exploration of the transcriptional response of P. carotovorum to cinnamaldehyde, providing insights into the bactericidal mechanisms employed by cinnamaldehyde against this bacterium.
Assuntos
Acroleína/análogos & derivados , Anti-Infecciosos , Pectobacterium , Pectobacterium carotovorum , Pectobacterium/metabolismo , Antibacterianos/farmacologia , Antibacterianos/metabolismo , Anti-Infecciosos/farmacologia , Bactérias/metabolismo , Plantas/metabolismo , Doenças das Plantas/microbiologiaRESUMO
OBJECTIVE: To compare differences in bowel-specific quality of life (QOL), overall qQOL, and neurogenic bowel dysfunction (NBD) severity by bowel management program in patients with spina bifida (SB). METHODS: We performed a retrospective cross-sectional study of patients ≥12 years old at our multidisciplinary SB center who completed both a modified Peristeen NBD questionnaire (assessing bowel symptom severity and bowel-specific QOL) and the Patient-Reported Outcomes Measurement Information System Pediatric Global Health questionnaire (assessing overall QOL). Nested, multivariable models were fit for associations between outcomes and bowel management program (enemas, conservative management, and none). RESULTS: A total of 173 patients, 56.1% female and 64.6% with myelomeningocele, were included in our analysis. Median age was 18.2 years old. Patients reported using enemas (n = 42), conservative management (n = 63), and no bowel program (n = 68). When adjusting for covariates, there was no significant association between bowel-specific QOL nor overall QOL across bowel management programs. However, the use of conservative management compared to enemas was associated with worse bowel symptoms severity (adjusted beta=2.58, 95%CI=[0.09,5.06]). Additionally, greater bowel symptom severity was significantly associated with lower overall QOL (adjusted beta=-0.33, 95%CI=[-0.57,-0.10]). CONCLUSION: NBD symptom severity in SB is more strongly associated with QOL than the individual bowel program being utilized. Our findings suggest that different degrees of NBD require different invasiveness of bowel programs, but it is the outcome of the bowel management program and not the specific program itself that is most associated with QOL.