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Unknown factors regulate mitochondrial U-insertion/deletion (U-indel) RNA editing in procyclic-form (PCF) and bloodstream-form (BSF) T. brucei. This editing, directed by anti-sense gRNAs, creates canonical protein-encoding mRNAs and may developmentally control respiration. Canonical editing by gRNAs that specify protein-encoding mRNA sequences occurs amid massive non-canonical editing of unclear sources and biological significance. We found PCF-specific repression at a major early checkpoint in mRNA ND7, involving helicase KREH2-dependent opposite modulation of canonical and non-canonical 'terminator' gRNA utilization. Terminator-programmed editing derails canonical editing and installs proposed repressive structure in 30% of the ND7 transcriptome. BSF-to-PCF differentiation in vitro recreated this negative control. Remarkably, KREH2-RNAi knockdown relieved repression and increased editing progression by reverting canonical/terminator gRNA utilization. ND7 transcripts lacking early terminator-directed editing in PCF exhibited similar negative editing control along the mRNA sequence, suggesting global modulation of gRNA utilization fidelity. The terminator is a 'moonlighting' gRNA also associated with mRNA COX3 canonical editing, so the gRNA transcriptome seems multifunctional. Thus, KREH2 is the first identified repressor in developmental editing control. This and our prior work support a model whereby KREH2 activates or represses editing in a stage and substrate-specific manner. KREH2's novel dual role tunes mitochondrial gene expression in either direction during development.
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The aim of the present study was to develop a novel formulation of berberine (BBR) and demonstrate its anti-seizure effect in pentylenetetrazole (PTZ) induced kindling model in rats. Nanoparticles of BBR were formulated using Poly Lactic-co-Glycolic Acid (PLGA) as a polymer. Emulsification and solvent evaporation technique was used. PTZ induced kindling model in male wistar rat was used to demonstrate the anti-seizure effect of nano-BBR. The particle size obtained for the final formulation was 242.8 ± 67.35â¯nm with a PDI of 0.140 ± 0.01. PLGA encapsulated BBR nanoparticles showed the % encapsulation efficiency of 87.33 ± 2.42â¯% and % drug loading of 48.47 ± 1.34â¯%. In-vitro drug release data showed sustained release of nano-BBR as compared to BBR. Kinetic study data showed increase in AUC of nano-BBR (35,429.46â¯h.ng/ml) as compared to BBR (28,211.07â¯h.ng/ml). Cmax for nano- BBR (2251.90â¯ng/ml) is approximately 1.6 times greater than BBR (1505.50â¯ng/ml). Nano- BBR has shown the significant effect on the seizure score. The PLGA encapsulated berberine nanoparticles were prepared by an innovative simple method and offers excellent potential as an antiepileptic agent.
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INTRODUCTION: Sleep Disordered Breathing (SDB) has been shown to increase the risk of stroke and despite recommendations, routine evaluation for SDB in acute stroke is not consistent across institutions. The necessary logistics and expertise required to conduct sleep studies in hospitalized patients remain a significant barrier. This study aims to evaluate the feasibility of high-resolution pulse-oximetry (HRPO) for the screening of SDB in acute stroke. Secondarily, considering impact of SDB on acute stroke, we investigated whether SDB at acute stroke predicts functional outcome at discharge and at 3 months post-stroke. METHODS: Patients with acute mild to moderate ischemic stroke underwent an overnight HRPO within 48 h of admission. Patients were divided into SDB and no-SDB groups based on oxygen desaturations index(ODI > 10/h). Stepwise multivariate logistic regression analysis was applied to identify the relevant predictors of functional outcome (favorable [mRS 1-2 points] versus unfavorable [mrS > = 3 points]). RESULTS: Of the 142 consecutively screened patients, 96 were included in the analysis. Of these, 33/96 (34%) were identified as having SDB and were more likely to have unfavorable mRS scores as compared to those without SDB (odds ratio = 2.70, p-value = 0.032). CONCLUSION: HRPO may be a low-cost and easily administered screening method to detect SDB among patients hospitalized for acute ischemic stroke. Patients with SDB (as defined by ODI) have a higher burden of neurological deficits as compared to those without SDB during hospitalization.
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BACKGROUND: Pembrolizumab, a monoclonal antibody against PD-1, has shown limited efficacy in patients with microsatellite stable or mismatch repair proficient (MSS/pMMR) metastatic colorectal cancer (CRC). We evaluated vicriviroc (small-molecule C-C motif chemokine ligand 5 antagonist) plus pembrolizumab in patients with advanced or metastatic MSS/pMMR CRC. PATIENTS AND METHODS: This open-label, phase 2 trial (NCT03631407) enrolled adults with histologically confirmed, locally advanced, unresectable or metastatic CRC that was MSS per local assessment. All patients had received previous treatment with standard therapies. Patients were randomized 1:1 to vicriviroc 150 mg orally once daily plus pembrolizumab 200 mg intravenously every 3 weeks or vicriviroc 250 mg orally once daily plus pembrolizumab 200 mg intravenously every 3 weeks for up to 35 cycles (2 years). Primary endpoints were the objective response rate (ORR) as assessed by the investigator per RECIST v1.1, dose-limiting toxicities (DLTs), adverse events (AEs), and discontinuations due to AEs. RESULTS: Forty patients were enrolled and treated. ORR was 5% (95% CI, 0.1%-24.9%) in both treatment groups. There were no complete responses; 1 patient in each treatment group experienced a partial response. No patient in the vicriviroc 150 mg plus pembrolizumab group experienced a DLT. Two patients in the vicriviroc 250 mg plus pembrolizumab group experienced DLTs (1 grade 4 encephalopathy and 1 grade 4 pneumonitis). CONCLUSION: The combination of vicriviroc at doses of 150 or 250 mg plus pembrolizumab 200 mg showed limited antitumor activity in patients with advanced or metastatic MSS/pMMR CRC. Toxicity with the combination was manageable.
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Anionic carboxylated cellulose nanofibers (CNF) are effective media to remove cationic contaminants from water. In this study, sustainable cationic CNF-based adsorbents capable of removing anionic contaminants were demonstrated using a simple approach. Specifically, the zero-waste nitro-oxidization process was used to produce carboxylated CNF (NOCNF), which was subsequently converted into a cationic scaffold by crosslinking with aluminum ions. The system, termed Al-CNF, is found to be effective for the removal of fluoride ions from water. Using the Langmuir isotherm model, the fluoride adsorption study indicates that Al-CNF has a maximum adsorption capacity of 43.3 mg/g, which is significantly higher than that of alumina-based adsorbents such as activated alumina (16.3 mg/g). The selectivity of fluoride adsorption in the presence of other anionic species (nitrate or sulfate) by Al-CNF at different pH values was also evaluated. The results indicate that Al-CNF can maintain a relatively high selectivity towards the adsorption of fluoride. Finally, the sequential applicability of using spent Al-CNF after the fluoride adsorption to further remove cationic contaminant such as Basic Red 2 dye was demonstrated. The low cost and relatively high adsorption capacity of Al-CNF make it suitable for practical applications in fluoride removal from water.
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Microsatellite stable metastatic colorectal cancer (MSS mCRC; mismatch repair proficient) has previously responded poorly to immune checkpoint blockade. Botensilimab (BOT) is an Fc-enhanced multifunctional anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody designed to expand therapy to cold/poorly immunogenic solid tumors, such as MSS mCRC. BOT with or without balstilimab (BAL; anti-PD-1 antibody) is being evaluated in an ongoing expanded phase 1 study. The primary endpoint is safety and tolerability, which was evaluated separately in the dose-escalation portion of the study and in patients with MSS mCRC (using combined dose-escalation/dose-expansion data). Secondary endpoints include investigator-assessed RECIST version 1.1-confirmed objective response rate (ORR), disease control rate (DCR), duration of response (DOR) and progression-free survival (PFS). Here we present outcomes in 148 heavily pre-treated patients with MSS mCRC (six from the dose-escalation cohort; 142 from the dose-expansion cohort) treated with BOT and BAL, 101 of whom were considered response evaluable with at least 6 months of follow-up. Treatment-related adverse events (TRAEs) occurred in 89% of patients with MSS mCRC (131/148), most commonly fatigue (35%, 52/148), diarrhea (32%, 47/148) and pyrexia (24%, 36/148), with no grade 5 TRAEs reported and a 12% discontinuation rate due to a TRAE (18/148; data fully mature). In the response-evaluable population (n = 101), ORR was 17% (17/101; 95% confidence interval (CI), 10-26%), and DCR was 61% (62/101; 95% CI, 51-71%). Median DOR was not reached (NR; 95% CI, 5.7 months-NR), and median PFS was 3.5 months (95% CI, 2.7-4.1 months), at a median follow-up of 10.3 months (range, 0.5-42.6 months; data continuing to mature). The combination of BOT plus BAL demonstrated a manageable safety profile with no new immune-mediated safety signals and encouraging clinical activity with durable responses. ClinicalTrials.gov identifier: NCT03860272 .
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Background: Dalbavancin's unique properties have led to an increase in its off-licence use in complex infection and in vulnerable populations including people who inject drugs (PWID), but data remain limited. In this retrospective cohort study, we describe the characteristics, treatment rationale and outcomes for all adult inpatients treated with dalbavancin at a UK tertiary hospital. Results: Fifty-eight inpatients were treated with dalbavancin between 1 January 2018 and 1 January 2021, 98.3% for off-licence diagnoses. Acute bacterial skin and skin structure infection, infective endocarditis and endovascular infections were each diagnosed in 22.4% of patients. Bone and joint infections were diagnosed in 18.9%, discitis in 12.1% and central line-associated bloodstream infections in 5.2%. Sixty-nine percent of patients were bacteraemic; 52.5% Staphylococcus aureus, 5.0% MRSA. Two mild adverse reactions were attributed to dalbavancin. Treatment was successful in 43 (75.4%) patients, and failed in seven (12.3%). Seven (12.3%) were lost to follow-up.Thirty-five patients (60.3%) were PWID, with low median age (41.0 years) and Charlson Comorbidity scores (0). Self-discharge was taken by 17.1% of PWID, and 20.6% were lost to follow-up. At 90â days, three (8.6%) PWID were deceased. Conclusions: In this first UK cohort, dalbavancin was used off licence and in persons facing barriers to conventional therapies. Where data is available, it was safe and effective. Dalbavancin appears a potentially valuable tool in improving outcomes for PWID.
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Contaminated fresh produce remains a prominent catalyst for food-borne illnesses, prompting the need for swift and precise pathogen detection to mitigate health risks. This paper introduces an innovative strategy for identifying food-borne pathogens in fresh produce samples from local markets and grocery stores, utilizing optical sensing and machine learning. The core of our approach is a photonics-based sensor system, which instantaneously generates optical signals to detect pathogen presence. Machine learning algorithms process the copious sensor data to predict contamination probabilities in real time. Our study reveals compelling results, affirming the efficacy of our method in identifying prevalent food-borne pathogens, including Escherichia coli (E. coli) and Salmonella enteric, across diverse fresh produce samples. The outcomes underline our approach's precision, achieving detection accuracies of up to 95%, surpassing traditional, time-consuming, and less accurate methods. Our method's key advantages encompass real-time capabilities, heightened accuracy, and cost-effectiveness, facilitating its adoption by both food industry stakeholders and regulatory bodies for quality assurance and safety oversight. Implementation holds the potential to elevate food safety and reduce wastage. Our research signifies a substantial stride toward the development of a dependable, real-time food safety monitoring system for fresh produce. Future research endeavors will be dedicated to optimizing system performance, crafting portable field sensors, and broadening pathogen detection capabilities. This novel approach promises substantial enhancements in food safety and public health.
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Escherichia coli , Microbiología de Alimentos , Aprendizaje Automático , Microbiología de Alimentos/métodos , Escherichia coli/aislamiento & purificación , Enfermedades Transmitidas por los Alimentos/microbiología , Enfermedades Transmitidas por los Alimentos/prevención & control , Inocuidad de los Alimentos/métodos , Humanos , Verduras/microbiología , Contaminación de Alimentos/análisis , Salmonella/aislamiento & purificaciónRESUMEN
A study to determine the impact of cyclosporine (Neoral), an inhibitor of P-gp, on the pharmacokinetics of pralsetinib (trade name GAVRETO®) was conducted in 15 healthy adult volunteers. A single 200 mg dose of pralsetinib was administered orally alone and in combination with cyclosporine with a 9-day washout between treatments. Co-administration with cyclosporine resulted in a clinically relevant increase in pralsetinib maximum plasma concentration (Cmax) and area under the plasma concentration-time curve extrapolated to infinity (AUC0-∞) with associated geometric mean ratios (GMRs) and 90% confidence intervals (CIs) of 148% (109, 201) and 181% (136, 241), respectively. These findings provide insight into concomitant dosing of pralsetinib with inhibitors of P-gp given the increases in pralsetinib exposure observed when administered with cyclosporine. Based on these results, co-administration of pralsetinib with P-gp inhibitors is not recommended. In the event that co-administration cannot be avoided, it is recommended that the dose of pralsetinib be reduced.
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Ciclosporina , Interacciones Farmacológicas , Voluntarios Sanos , Humanos , Masculino , Adulto , Ciclosporina/administración & dosificación , Ciclosporina/farmacocinética , Femenino , Adulto Joven , Área Bajo la Curva , Persona de Mediana Edad , Administración Oral , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/antagonistas & inhibidores , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Relación Dosis-Respuesta a Droga , Bencimidazoles/farmacocinética , Bencimidazoles/administración & dosificaciónRESUMEN
STUDY OBJECTIVE: This study aimed to prospectively validate the performance of an artificially augmented home sleep apnea testing device (WVU-device) and its patented technology. METHODOLOGY: The WVU-device, utilizing patent pending (US 20210001122A) technology and an algorithm derived from cardio-pulmonary physiological parameters, comorbidities, and anthropological information was prospectively compared with a commercially available and Center for Medicare and Medicaid Services (CMS) approved home sleep apnea testing (HSAT) device. The WVU-device and the HSAT device were applied on separate hands of the patient during a single night study. The oxygen desaturation index (ODI) obtained from the WVU-device was compared to the respiratory event index (REI) derived from the HSAT device. RESULTS: A total of 78 consecutive patients were included in the prospective study. Of the 78 patients, 38 (48%) were women and 9 (12%) had a Fitzpatrick score of 3 or higher. The ODI obtained from the WVU-device corelated well with the HSAT device, and no significant bias was observed in the Bland-Altman curve. The accuracy for ODI > = 5 and REI > = 5 was 87%, for ODI> = 15 and REI > = 15 was 89% and for ODI> = 30 and REI of > = 30 was 95%. The sensitivity and specificity for these ODI /REI cut-offs were 0.92 and 0.78, 0.91 and 0.86, and 0.94 and 0.95, respectively. CONCLUSION: The WVU-device demonstrated good accuracy in predicting REI when compared to an approved HSAT device, even in patients with darker skin tones.
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Inteligencia Artificial , Síndromes de la Apnea del Sueño , Humanos , Femenino , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Síndromes de la Apnea del Sueño/diagnóstico , Síndromes de la Apnea del Sueño/fisiopatología , Anciano , Polisomnografía/instrumentación , Polisomnografía/métodos , Algoritmos , AdultoRESUMEN
The Phase 2 portion of this study evaluated safety and efficacy of polatuzumab vedotin 1.8 mg/kg and venetoclax 800 mg, plus fixed-dose obinutuzumab 1000 mg or rituximab 375 mg/m2 in patients with relapsed/refractory (R/R) follicular lymphoma (FL) or diffuse large B-cell lymphoma (DLBCL), respectively. Patients with complete response (CR) or partial response (PR)/stable disease (FL) or CR/PR (DLBCL) at end of induction (EOI; six 21-day cycles) received post-induction therapy with venetoclax and obinutuzumab or rituximab, respectively. Primary endpoint was CR rate at EOI. Safety-evaluable populations included 74 patients (FL cohort; median age 64 years; progression of disease within 24 months on first-line treatment, 25.7%; FL International Prognostic Index 3-5, 54.1%; ≥2 previous therapies, 74.3%) and 57 patients (DLBCL cohort; median age 65 years; International Prognostic Index 3-5, 54.4%; ≥2 previous therapies, 77.2%). The most common non-hematologic adverse events (mostly Grades 1-2) in the FL and DLBCL cohorts were diarrhea (55.4% and 47.4%, respectively) and nausea (47.3% and 36.8%); neutropenia was the most common Grades 3-4 toxicity (39.2% and 52.6%). Efficacy-evaluable populations included patients treated at the recommended Phase 2 dose (FL, n = 49; DLBCL, n = 48). CR rates at EOI were 59.2% (FL) and 31.3% (DLBCL); median progression-free survival was 22.8 months (95% confidence interval [CI], 14.5-not evaluable) and 4.6 months (95% CI, 3.6-8.1), respectively. Polatuzumab vedotin plus venetoclax and obinutuzumab/rituximab had acceptable safety in patients with R/R FL or DLBCL, with promising response rates in R/R FL, including high-risk patients.
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Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Compuestos Bicíclicos Heterocíclicos con Puentes , Linfoma de Células B Grandes Difuso , Rituximab , Sulfonamidas , Humanos , Persona de Mediana Edad , Anciano , Masculino , Sulfonamidas/administración & dosificación , Sulfonamidas/uso terapéutico , Sulfonamidas/efectos adversos , Femenino , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes/administración & dosificación , Compuestos Bicíclicos Heterocíclicos con Puentes/efectos adversos , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Adulto , Anciano de 80 o más Años , Rituximab/administración & dosificación , Rituximab/uso terapéutico , Rituximab/efectos adversos , Linfoma Folicular/tratamiento farmacológico , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Recurrencia , InmunoconjugadosRESUMEN
STUDY OBJECTIVES: Obstructive sleep apnea (OSA) is a highly prevalent, yet underdiagnosed, condition. Due to its adverse impact on risk for cardiopulmonary disorders, there is interest in proactive screening of OSA in hospitalized patients. We studied the long-term outcome of such screened patients who were initiated on positive airway pressure therapy. METHODS: Hospitalized patients who screened positive for OSA and were confirmed with postdischarge polysomnography were dichotomized by positive airway pressure therapy adherence and followed for a period of 12 months to evaluate for the composite end point of hospital readmissions and emergency department visits for cardiopulmonary reasons. Cost analysis between the 2 groups was also conducted. RESULTS: A total of 2,042 hospitalized patients were assessed for OSA as part of a hospital sleep medicine program from August 2019-June 2023. Of these, 293 patients were diagnosed with OSA and prescribed positive airway pressure therapy. Of these 293 patients, 108 were adherent to therapy and 185 were nonadherent. The overall characteristics of the groups included a mean (standard deviation) age of 58 years (12.82), mean body mass index (kg/m2) of 39.72 (10.71), 57% male sex, and apnea-hypopnea index of 25.49 (26). Of the patients, 78%, 41%, and 43% had hypertension, congestive heart failure, and diabetes mellitus, respectively. The composite end point of hospital readmissions and emergency department visits for cardiovascular and pulmonary reasons was significantly higher in the nonadherent group than in the adherent group (hazard ratio, 1.24; 95% confidence interval, 1-1.54) (P = .03). The cost of care for both hospital billing as well as professional billing was higher for the nonadherent group ($1,455.60 vs $1,723.50, P = .004 in hospital billing cost and $130.90 vs $144.70, P < .001 in professional billing). Length of stay was higher for nonadherent patients (2.7 ± 5.1 days vs 2.3 ± 5.9 days). CONCLUSIONS: Hospitalized patients diagnosed with OSA and adherent to therapy have reduced readmissions and emergency department visits for cardiopulmonary reasons 12 months after discharge. Adherent patients have reduced cost of health care and length of stay during hospitalizations. CITATION: Sharma S, Stansbury R, Srinivasan P, et al. Early recognition and treatment of OSA in hospitalized patients and its impact on health care utilization in rural population: a real-world study. J Clin Sleep Med. 2024;20(8):1313-1319.
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Hospitalización , Aceptación de la Atención de Salud , Población Rural , Apnea Obstructiva del Sueño , Humanos , Apnea Obstructiva del Sueño/terapia , Apnea Obstructiva del Sueño/economía , Apnea Obstructiva del Sueño/epidemiología , Masculino , Femenino , Persona de Mediana Edad , Aceptación de la Atención de Salud/estadística & datos numéricos , Población Rural/estadística & datos numéricos , Hospitalización/estadística & datos numéricos , Hospitalización/economía , Polisomnografía/estadística & datos numéricos , Polisomnografía/economía , Presión de las Vías Aéreas Positiva Contínua/estadística & datos numéricos , Presión de las Vías Aéreas Positiva Contínua/economía , Presión de las Vías Aéreas Positiva Contínua/métodos , Diagnóstico Precoz , Anciano , Readmisión del Paciente/estadística & datos numéricos , Readmisión del Paciente/economíaRESUMEN
3,3',5.5'-Tetrabromobisphenol A (TBBPA) is a widely used brominated flame-retardant utilized in the production of electronic devices and plastic paints. The objective of this study is to use zebrafish as a model and determine the effects of TBBPA exposure on early embryogenesis. We initiated TBBPA exposures (0, 10, 20 and 40µM) at 0.75 h post fertilization (hpf) and monitored early developmental events such as cleavage, blastula and epiboly that encompass maternal-to-zygotic transition (MZT) and zygotic genome activation (ZGA). Our data revealed that TBBPA exposures induced onset of developmental delays by 3 hpf (blastula). By 5.5 hpf (epiboly), TBBPA-exposed (10-20 µM) embryos showed concentration-dependent developmental lag by up to 3 stages or 100% mortality at 40 µM. Embryos exposed to sublethal TBBPA concentrations from 0.75-6 hpf and raised in clean water to 120 hpf showed altered larval photomotor response (LPR), suggesting a compromised developmental health. To examine the genetic basis of TBBPA-induced delays, we conducted mRNA-sequencing on embryos exposed to 0 or 40 µM TBBPA from 0.75 hpf to 2, 3.5 or 4.5 hpf. Read count data showed that while TBBPA exposures had no overall impacts on maternal or maternal-zygotic genes, collective read counts for zygotically activated genes were lower in TBBPA treatment at 4.5 hpf compared to time-matched controls, suggesting that TBBPA delays ZGA. Gene ontology assessments for both time- and stage-matched differentially expressed genes revealed TBBPA-induced inhibition of chromatin assembly- a process regulated by histone modifications. Since acetylation is the primary histone modification system operant during early ZGA, we immunostained embryos with an H3K27Ac antibody and demonstrated reduced acetylation in TBBPA-exposed embryos. Leveraging in silico molecular docking studies and in vitro assays, we also showed that TBBPA potentially binds to P300- a protein that catalyzes acetylation- and inhibits P300 activity. Finally, we co-exposed embryos to 20 µM TBBPA and 50 µM n-(4-chloro-3-trifluoromethyl-phenyl)-2-ethoxy-6-pentadecyl-benzamide (CTPB) -a histone acetyltransferase activator that promotes histone acetylation- and showed that TBBPA-CTPB co or pre-exposures significantly reversed TBBPA-only developmental delays, suggesting that TBBPA-induced phenotypes are indeed driven by repression of histone acetylation. Collectively, our work demonstrates that TBBPA disrupts ZGA and early developmental morphology, potentially by inhibiting histone acetylation. Future studies will focus on mechanisms of TBBPA-induced chromatin modifications.
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In this study, a sulfonation approach using chlorosulfonic acid (CSA) to prepare cellulose sulfate nanofibers (CSNFs) from raw jute fibers is demonstrated. Both elemental sulfur content and zeta potential in the CSNFs are found to increase with increasing CSA content used. However, the corresponding crystallinity in the CSNFs decreases with the increasing amount of CSA used due to degradation of cellulose chains under harsh acidic conditions. The ammonium adsorption results from the CSNFs with varying degrees of sulfonation were analyzed using the Langmuir isotherm model, and the analysis showed a very high maximum ammonium adsorption capacity (41.1 mg/g) under neutral pH, comparable to the best value from a synthetic hydrogel in the literature. The high ammonium adsorption capacity of the CSNFs was found to be maintained in a broad acidic range (pH = 2.5 to 6.5).
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Triclosan (TCS), a biocide used in various day-to-day products, has been associated with several toxic effects in aquatic organisms. In the present study, biochemical and hematological alterations were evaluated after 14 d (sublethal) exposure of tap water (control), acetone (solvent control), 5, 10, 20, and 50 µg/L (environmentally relevant concentrations) TCS to the embryos/hatchlings of Cirrhinus mrigala, a major freshwater carp distributed in tropic and sub-tropical areas of Asia. A concentration-dependent increase in the content of urea and protein carbonyl, while a decrease in the total protein, glucose, cholesterol, triglycerides, uric acid, and bilirubin was observed after the exposure. Hematological analysis revealed a decrease in the total erythrocyte count, hemoglobin, and partial pressure of oxygen, while there was an increase in the total leucocyte count, carbon dioxide, and partial pressure of carbon dioxide and serum electrolytes. Comet assay demonstrates a concentration-dependent increase in tail length, tail moment, olive tail moment, and percent tail DNA. An amino acid analyzer showed a TCS-dose-dependent increase in various amino acids. Sodium dodecyl sulphate polyacrylamide gel electrophoresis analysis revealed different proteins ranging from 6.5 to 200 kDa, demonstrating TCS-induced upregulation. Fourier transform infrared spectra analysis exhibited a decline in peak area percents with an increase in the concentration of TCS in water. Curve fitting of amide I (1,700-1600 cm-1) showed a decline in α-helix and turns and an increase in ß-sheets. Nuclear magnetic resonance study also revealed concentration-dependent alterations in the metabolites after 14 d exposure. TCS caused alterations in the biomolecules and heamatological parameters of fish, raising the possibility that small amounts of TCS may change the species richness in natural aquatic habitats. In addition, consuming TCS-contaminated fish may have detrimental effects on human health. Consequently, there is a need for the proper utilisation and disposal of this hazardous compound in legitimate quantities.
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Carpas , Cyprinidae , Triclosán , Contaminantes Químicos del Agua , Animales , Humanos , Triclosán/toxicidad , Triclosán/metabolismo , Dióxido de Carbono/metabolismo , Cyprinidae/metabolismo , Agua/metabolismo , Contaminantes Químicos del Agua/toxicidad , Contaminantes Químicos del Agua/metabolismoRESUMEN
The lack of toxicity data for DHA-rich oil from Schizochytrium sp. (Strain ATCC-20889) leads to its exclusion from the Qualified Presumption of Safety list. Therefore, present study addresses toxicity evaluation of DHA-rich microalgae oil using ex-vivo (cytotoxicity assay) and in-vivo methods (acute (OECD 423 guidelines), sub-chronic (OECD 452 guidelines), and genotoxicity assay). The ex-vivo results showed >90% cell viability of Caco-2 cells after 48 h of treatment (200 µg/mL of DHA). Additionally, the in-vivo acute toxicity study found that microalgae oil was nontoxic and classified under category 5 molecule according to OECD 423 guidelines with a highest degree of safety at 2000 mg/kg b.w. The in-vivo sub-chronic study revealed no significant mortality and changes in feed intake, body weight, haematological, biochemical, neurological, and urine parameters after repeated 180-days administration of DHA-rich microalgae oil at 250 mg/kg, 500 mg/kg, and 1000 mg/kg. Moreover, histopathology evaluation, comet assay, chromosomal aberration, and micronuclei assay also confirmed the nontoxic behavior of DHA-rich oil. Thus, the results from the ex-vivo and in-vivo studies indicate that DHA-rich oil from Schizochytrium sp. (Strain ATCC-20889) is safe for use as a novel food, and can be included in infants, adults, pregnant women, and children formula.
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PURPOSE: This study aimed to report the results from an early-phase study of rivoceranib, an oral tyrosine kinase inhibitor highly selective for vascular endothelial growth factor receptor 2, in patients with advanced solid tumors. MATERIALS AND METHODS: In this open-label, single-arm, dose-escalating, multicenter three-part phase 1/2a trial, patients had advanced solid tumors refractory to conventional therapy. Part 1 evaluated the safety and pharmacokinetics of five ascending once-daily doses of rivoceranib from 81 mg to 685 mg. Part 2 evaluated the safety and antitumor activity of once-daily rivoceranib 685 mg. Part 3 was conducted later, due to lack of maximum tolerated dose determination in part 1, to evaluate the safety and preliminary efficacy of once-daily rivoceranib 805 mg in patients with unresectable or advanced gastric cancer. RESULTS: A total of 61 patients were enrolled in parts 1 (n=25), 2 (n=30), and 3 (n=6). In parts 1 and 2, patients were white (45.5%) or Asian (54.5%), and 65.6% were male. The most common grade ≥ 3 adverse events were hypertension (32.7%), hyponatremia (10.9%), and hypophosphatemia (10.9%). The objective response rate (ORR) was 15.2%. In part 3, dose-limiting toxicities occurred in two out of six patients: grade 3 febrile neutropenia decreased appetite, and fatigue. The ORR was 33%. CONCLUSION: The recommended phase 2 dose of rivoceranib was determined to be 685 mg once daily, which showed adequate efficacy with a manageable safety profile (NCT01497704 and NCT02711969).