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BACKGROUND: Adrenal hemorrhage (AH) can occur in patients with antiphospholipid Syndrome (APS). We aimed to characterize the clinical manifestations, treatments, and outcomes of patients presenting with APS-associated AH (APS-AH) through a retrospective cohort and a systematic literature review (SLR). METHODS: We performed a mixed-source approach combining a multicenter cohort with an SLR of patients with incident APS-AH. We included patients from Mayo Clinic and published cases with persistent positivity for antiphospholipid antibodies and presenting with AH, demonstrated by imaging or biopsy. We extracted demographics, clinical characteristics, laboratory findings, treatment strategies, and outcomes (primary adrenal insufficiency and mortality). We used Kaplan-Meier and Cox models for survival analysis. RESULTS: We included 256 patients in total, 61 (24%) from Mayo Clinic and 195 (76%) from the SLR. The mean age was 46.8 (SD 15.2) years, and 45% were female. 69% of patients had bilateral adrenal involvement and 64% presented adrenal insufficiency. The most common symptoms at presentation were abdominal pain in 79%, and nausea and vomiting 46%. Hyponatremia (77%) was the most common electrolyte abnormality. Factors associated with primary adrenal insufficiency were bilateral adrenal involvement at initial imaging (OR 3.73, CI; 95%, 1.47-9.46) and anticardiolipin IgG positivity (OR 3.80, CI; 95%, 1.30-11.09). The survival rate at five years was 82%. History of stroke was associated with 3.6-fold increase in mortality (HR 3.62, 95% CI; 1.33-9.85). CONCLUSION: AH is a severe manifestation of APS with increased mortality. Most patients developed permanent primary adrenal insufficiency, particularly those positive for anticardiolipin IgG and bilateral adrenal involvement.
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Doença de Addison , Síndrome Antifosfolipídica , Hemorragia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Addison/etiologia , Síndrome Antifosfolipídica/complicações , Hemorragia/etiologia , Imunoglobulina G , Estudos Multicêntricos como Assunto , Estudos Retrospectivos , AdultoRESUMO
Kidney stone diseases are increasing globally in prevalence and recurrence rates, indicating an urgent medical need for developing new therapies that can prevent stone formation. One approach we have been working on is to develop small molecule inhibitors that can interfere with the crystallization process of the chemical substances that form the stones. For these drug discovery efforts, it is critical to have available easily accessible assay methods to evaluate the potential inhibitors and rank them for structure-activity relationship studies. Herein, we report a convenient, medium-to-high throughput assay platform using, as an example, the screening and evaluation of inhibitors of L-cystine crystallization for the prevention of kidney stones in cystinuria. The assay involves preparing a supersaturated solution, followed by incubating small volumes (<1 mL) of the supersaturated solution with test inhibitors for 72 hours, and finally measuring L-cystine concentrations in the supernatants after centrifugation using either a colorimetric or fluorometric method. Compared to traditional techniques for studying crystallization inhibitors, this miniaturized multi-well assay format is simple to implement, cost-effective, and widely applicable in determining and distinguishing the activities of compounds that inhibit crystallization. This assay has been successfully employed to discover L-cystine diamides as highly potent inhibitors of L-cystine crystallization such as LH708 with an EC50 of 0.058 µM, 70-fold more potent than L-CDME (EC50 = 4.31 µM).
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BACKGROUND: Transcatheter pulmonary valve replacement (TPVR) with the Harmony valve (Medtronic, Inc.) was recently approved to treat postoperative native outflow tract pulmonary regurgitation. While the 22 mm Harmony valve Early Feasibility Study demonstrated ventricular tachycardia (VT) in only 5% of patients, little is known about ventricular arrhythmias after TPVR with the larger 25 mm valve (TPV25). METHODS: A single center review was performed of patients with TPV25 implant from 2020 to 2021. Demographic, cardiac, procedural, and postimplant cardiac telemetry data were collected and compared between patients who did and did not have peri-implant ventricular arrhythmia. RESULTS: Thirty patients underwent TPV25 at a median age of 30 years. On postimplant telemetry, VT events were documented in 12 patients (40%); 11 nonsustained VT (NSVT) (median 3 episodes per patient and 6 beats per episode, maximum 157 episodes) and 1 sustained VT (3%), with Torsades de Pointes secondary to a short coupled premature ventricular contraction (PVC). VT events were associated with annular valve positioning (p < 0.001) and increased postimplant PVC burden (p < 0.0001), but there was no association between VT and other demongraphic, historical, or procedural factors. The frequency of NSVT events fell from 3/h from 0 to 12 h postimplant to 0.5/hr from 12 to 24 h (p < 0.001). CONCLUSION: VT occurred commonly (40%) in the first 24 h after TPV25 implant, with self-limited NSVT in 11 of 12 patients and 1 patient with cardiac arrest secondary to Torsades de Pointes. VT only occurred with annular valve positioning. Larger, longer-term studies are needed to determine risk factors for and natural history of post-TPVR VT.
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Implante de Prótese de Valva Cardíaca , Valva Pulmonar , Taquicardia Ventricular , Torsades de Pointes , Complexos Ventriculares Prematuros , Adulto , Humanos , Cateterismo Cardíaco/efeitos adversos , Implante de Prótese de Valva Cardíaca/efeitos adversos , Valva Pulmonar/diagnóstico por imagem , Valva Pulmonar/cirurgia , Taquicardia Ventricular/diagnóstico , Taquicardia Ventricular/etiologia , Torsades de Pointes/etiologia , Torsades de Pointes/cirurgia , Resultado do Tratamento , Complexos Ventriculares Prematuros/diagnóstico , Complexos Ventriculares Prematuros/etiologiaRESUMO
BACKGROUND: To evaluate the impact of a clinical pathway on the incidence and severity of acute kidney injury in patients undergoing heart transplant. METHODS: This was a 2.5-year retrospective evaluation using 3 years of historical controls within a cardiac intensive care unit in an academic children's hospital. Patients undergoing heart transplant between May 27, 2014, and April 5, 2017 (pre-pathway) and May 1, 2017, and November 30, 2019 (pathway) were included. The clinical pathway focused on supporting renal perfusion through hemodynamic management, avoiding or delaying nephrotoxic medications, and providing pharmacoprophylaxis against AKI. RESULTS: There were 57 consecutive patients included. There was an unadjusted 20% reduction in incidence of any acute kidney injury (p = .05) and a 17% reduction in Stage 2/3 acute kidney injury (p = .09). In multivariable adjusted analysis, avoidance of Stage 2/3 acute kidney injury was independently associated with the clinical pathway era (AOR -1.3 [95% CI -2.5 to -0.2]; p = .03), achieving a central venous pressure of or less than 12 mmHg (AOR -1.3 [95% CI -2.4 to -0.2]; p = .03) and mean arterial pressure above 60 mmHg (AOR -1.6 [95% CI -3.1 to -0.01]; p = .05) in the first 48 h post-transplant, and older age at transplant (AOR - 0.2 [95% CI -0.2 to -0.06]; p = .002). CONCLUSIONS: This report describes a renal protection clinical pathway associated with a reduction in perioperative acute kidney injury in patients undergoing heart transplant and highlights the importance of normalizing perioperative central venous pressure and mean arterial blood pressure to support optimal renal perfusion.
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Injúria Renal Aguda/prevenção & controle , Procedimentos Clínicos , Transplante de Coração , Complicações Pós-Operatórias/prevenção & controle , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Unidades de Terapia Intensiva Pediátrica , Masculino , Estudos RetrospectivosRESUMO
OBJECTIVES: The objective of this study is to investigate the change in functional status in infants, children, and adolescents undergoing congenital heart surgery using the Functional Status Scale. DESIGN: A single-center retrospective study. SETTING: A 26-bed cardiac ICU in a free-standing university-affiliated tertiary children's hospital. PATIENTS: All patients 0-18 years who underwent congenital heart surgery from January 1, 2014, to December 31, 2017. INTERVENTIONS: None. MEASUREMENTS AND MIN RESULTS: The primary outcome variable was change in Functional Status Scale scores from admission to discharge. Additionally, two binary outcomes were derived from the primary outcome: new morbidity (change in Functional Status Scale ≥ 3) and unfavorable functional outcome (change in Functional Status Scale ≥ 5); their association with risk factors was assessed using modified Poisson regression. Out of 1,398 eligible surgical encounters, 65 (4.6%) and 15 (1.0%) had evidence of new morbidity and unfavorable functional outcomes, respectively. Higher Surgeons Society of Thoracic and the European Association for Cardio-Thoracic Surgery score, single-ventricle physiology, and longer cardiopulmonary bypass time were associated with new morbidity. Longer hospital length of stay was associated with both new morbidity and unfavorable outcome. CONCLUSIONS: This study demonstrates the novel application of the Functional Status Scale on patients undergoing congenital heart surgery. New morbidity was noted in 4.6%, whereas unfavorable outcome in 1%. There was a small change in the total Functional Status Scale score that was largely attributed to changes in the feeding domain. Higher Society of Thoracic and the European Association for Cardio-Thoracic Surgery score, single-ventricle physiology, and longer cardiopulmonary bypass times were associated with new morbidity, whereas longer hospital length of stay was associated with both new morbidity and unfavorable outcome. Further studies with larger sample size will need to be done to confirm our findings and to better ascertain the utility of Functional Status Scale on this patient population.
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Procedimentos Cirúrgicos Cardíacos , Cardiopatias Congênitas , Adolescente , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Criança , Estado Funcional , Cardiopatias Congênitas/cirurgia , Hospitais , Humanos , Lactente , Tempo de Internação , Estudos RetrospectivosRESUMO
Epidermal growth factor receptor (EGFR) is essential for normal cellular functions. Mutations of EGFR's kinase domain can cause dysregulation leading to non-small cell lung cancer (NSCLC). Exon 20 insertion (ex20ins) mutations in EGFR are one of the leading contributors to oncogenesis and confer insensitivity to most available therapeutics. Mobocertinib is a novel tyrosine kinase inhibitor (TKI) recently approved by the US FDA as a first-in-class small molecule therapeutic for EGFR ex20ins-positive NSCLC. When compared to osimertinib, a TKI indicated for the treatment of EGFR T790M-positive NSCLC, mobocertinib differs only by the presence of an additional C5-carboxylate isopropyl ester group on the middle pyrimidine core. Together with the acrylamide side chain that is responsible for irreversible inhibition, this additional C5-substituent affords mobocertinib high anticancer potency and specificity to EGFR ex20ins-positive lung cancer that is resistant to other EGFR TKIs. This review article provides an overview of the discovery of mobocertinib from osimertinib including their structure-activity relationships, mechanisms of action, preclinical pharmacology, pharmacokinetics, and clinical applications. The discovery and use of mobocertinib and other EGFR TKIs demonstrate the power of structure-based drug design and promising therapeutic outcomes of using precision medicine approaches in the management of molecularly defined tumors. Graphical abstract.
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OBJECTIVES: Children raised by depressed mothers perform lower on measures of cognitive, emotional, and behavioral skills, compared to children of non-depressed mothers. It is unclear how maternal depressive symptoms (MDS), which persist and accrue over time, impact child development. The purpose of this study was to determine whether cumulative MDS from pre-pregnancy to postpartum influences child development in children by age 2.5. METHODS: Using a longitudinal population-based study design, 2679 racially and ethnically diverse mothers completed the 2014 Los Angeles Mommy and Baby (LAMB) and 2016 Follow-Up surveys. A total MDS score was created based on responses to standardized questions, including the Patient Health Questionnaire-2 (PHQ-2). Data was collected for before pregnancy, during pregnancy, and 4 months postpartum in the 2014 survey, and at 2.5 years postpartum in the 2016 survey. Child development was measured using the CDC's Learn the Signs. Act Early Milestones Checklist. Bivariate and multivariate logistic regressions were conducted. RESULTS: The prevalence of any cumulative MDS was 45.2%. Language, cognitive/adaptive, motor, and social-emotional delays for surveyed toddlers were 7.7%, 4.0%, 1.2%, and 14.2%. After adjusting for covariates, mothers reporting depressive symptoms at all four time points were significantly more likely to report a social-emotional delay in their child (aOR = 4.39, 95% CI - 1.72 to 11.18). CONCLUSIONS FOR PRACTICE: Mothers with cumulative depressive symptoms are at-risk of reporting social-emotional delays by age 2.5. Understanding these effects may help direct resources to target interventions that support mothers with depressive symptoms early-on and promote positive developmental outcomes among their children.
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Filho de Pais com Deficiência/psicologia , Depressão Pós-Parto/complicações , Depressão/diagnóstico , Depressão/psicologia , Deficiências do Desenvolvimento/etiologia , Mães/psicologia , Período Pós-Parto/psicologia , Complicações na Gravidez/psicologia , Adulto , Desenvolvimento Infantil/fisiologia , Pré-Escolar , Depressão/epidemiologia , Depressão Pós-Parto/psicologia , Emoções , Feminino , Humanos , Lactente , Estudos Longitudinais , Los Angeles , Masculino , Vigilância da População , Gravidez , Inquéritos e QuestionáriosRESUMO
Cancer immunotherapy has made great strides in the recent decade, especially in the area of immune checkpoint blockade. The outstanding efficacy, prolonged durability of effect, and rapid assimilation of anti-PD-1 and anti-PD-L1 monoclonal antibodies in clinical practice have been nothing short of a medical breakthrough in the treatment of numerous malignancies. The major advantages of these therapeutic antibodies over their small molecule counterparts have been their high binding affinity and target specificity. However, antibodies do have their flaws including immune-related toxicities, inadequate pharmacokinetics and tumor penetration, and high cost burden to manufacturers and consumers. These limitations hinder broader clinical applications of the antibodies and have heightened interests in developing the alternative small molecule platform that includes peptidomimetics and peptides to target the PD-1/PD-L1 immune checkpoint system. The progress on these small molecule alternatives has been relatively slow compared to that of the antibodies. Fortunately, recent structural studies of the interactions among PD-1, PD-L1, and their respective antibodies have revealed key hotspots on PD-1 and PD-L1 that may facilitate drug discovery efforts for small molecule immunotherapeutics. This review is intended to discuss key concepts in immuno-oncology, describe the successes and shortcomings of PD-1/PD-L1 antibody-based therapies, and to highlight the recent development of small molecule inhibitors of the PD-1/PD-L1 protein-protein interaction.
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Anticorpos Monoclonais/farmacologia , Antígeno B7-H1/metabolismo , Fatores Imunológicos/farmacologia , Receptor de Morte Celular Programada 1/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Humanos , Fatores Imunológicos/química , Neoplasias/imunologia , Neoplasias/patologia , Ligação Proteica/efeitos dos fármacosRESUMO
In this work, a new phosphonium-containing cationic polyelectrolyte (PE1) has been rationally designed and developed via a facile click-chemistry type postfunctionalization, which can form complexes with highly polarizable anionic cyanines to significantly reduce the strong and random cyanine-cyanine interactions (i.e., aggregation) in the solid-state. This material design strategy enables an efficient translation of the favorable molecular properties of cyanines into macroscopic material properties. One of such complexes exhibits a very large third-order susceptibility over 10-10 esu with low nonlinear optical loss suitable for all optical signal processing.
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A mild and practical method for the catalytic installation of the amino group across alkenes and alkynes has long been recognized as a significant challenge in synthetic chemistry. As the direct hydroamination of olefins using ammonia requires harsh conditions, the development of suitable electrophilic aminating reagents for formal hydroamination methods is of importance. Herein, we describe the use of 1,2-benzisoxazole as a practical electrophilic primary amine source. Using this heterocycle as a new amino group delivery agent, a mild and general protocol for the copper-hydride-catalyzed hydroamination of alkenes and alkynes to form primary amines was developed. This method provides access to a broad range of chiral α-branched primary amines and linear primary amines, as demonstrated by the efficient synthesis of the antiretroviral drug maraviroc and the formal synthesis of several other pharmaceutical agents.
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Aminas/síntese química , Cobre/química , Nitrogênio/química , Aminação , Aminas/química , Catálise , Estrutura Molecular , EstereoisomerismoRESUMO
This report details a general and enantioselective means for the synthesis of alkyl-substituted aziridines. This protocol offers a direct route for the synthesis of alkyl-substituted chiral aziridines from achiral starting materials. Readily accessed allylic hydroxylamine esters undergo copper hydride-catalyzed intramolecular hydroamination with a high degree of regio- and enantiocontrol to afford the aziridine products in good to excellent yields in highly enantioenriched form. The utility of the products derived from this method is further demonstrated through derivatization of the chiral aziridine products to obtain a diverse array of functionalized enantioenriched amines.
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Aziridinas/química , Cobre/química , Aminação , Catálise , Ciclização , Estrutura Molecular , EstereoisomerismoRESUMO
To assess the visualization and efficacy of a wireless resonant circuit (wRC) catheter system for carotid artery occlusion and embolectomy under real-time MRI guidance in vivo, and to compare MR imaging modality with x-ray for analysis of qualitative physiological measures of blood flow at baseline and after embolectomy. The wRC catheter system was constructed using a MR compatible PEEK fiber braided catheter (Penumbra, Inc, Alameda, CA) with a single insulated longitudinal copper loop soldered to a printed circuit board embedded within the catheter wall. In concordance with IACUC protocol (AN103047), in vivo carotid artery navigation and embolectomy were performed in four farm pigs (40-45 kg) under real-time MRI at 1.5T. Industry standard clots were introduced in incremental amounts until adequate arterial occlusion was noted in a total of n=13 arteries. Baseline vasculature and restoration of blood flow were confirmed via MR and x-ray imaging, and graded by the Thrombolysis in Cerebral Infarction (TICI) scale. Wilcoxon signed-rank tests were used to analyze differences in recanalization status between DSA and MRA imaging. Successful recanalizations (TICI 2b/3) were compared to clinical rates reported in literature via binomial tests. The wRC catheter system was visible both on 5° sagittal bSSFP and coronal GRE sequence. Successful recanalization was demonstrated in 11 of 13 occluded arteries by DSA analysis and 8 of 13 by MRA. Recanalization rates based on DSA (0.85) and MRA (0.62) were not significantly different from the clinical rate of mechanical aspiration thrombectomy reported in literature. Lastly, a Wilcoxon signed rank test indicated no significant difference between TICI scores analyzed by DSA and MRA. With demonstrated compatibility and visualization under MRI, the wRC catheter system is effective for in vivo endovascular embolectomy, suggesting progress towards clinical endovascular interventional MRI.
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Artérias Carótidas/diagnóstico por imagem , Cateterismo , Catéteres , Embolectomia , Imageamento por Ressonância Magnética , Animais , Cateterismo/instrumentação , Cateterismo/métodos , Embolectomia/instrumentação , Embolectomia/métodos , Imageamento por Ressonância Magnética/instrumentação , Imageamento por Ressonância Magnética/métodos , SuínosRESUMO
Purpose To assess the feasibility of a magnetically assisted remote-controlled (MARC) catheter system under magnetic resonance (MR) imaging guidance for performing a simple endovascular procedure (ie, renal artery embolization) in vivo and to compare with x-ray guidance to determine the value of MR imaging guidance and the specific areas where the MARC system can be improved. Materials and Methods In concordance with the Institutional Animal Care and Use Committee protocol, in vivo renal artery navigation and embolization were tested in three farm pigs (mean weight 43 kg ± 2 [standard deviation]) under real-time MR imaging at 1.5 T. The MARC catheter device was constructed by using an intramural copper-braided catheter connected to a laser-lithographed saddle coil at the distal tip. Interventionalists controlled an in-room cart that delivered electrical current to deflect the catheter in the MR imager. Contralateral kidneys were similarly embolized under x-ray guidance by using standard clinical catheters and guidewires. Changes in renal artery flow and perfusion were measured before and after embolization by using velocity-encoded and perfusion MR imaging. Catheter navigation times, renal parenchymal perfusion, and renal artery flow rates were measured for MR-guided and x-ray-guided embolization procedures and are presented as means ± standard deviation in this pilot study. Results Embolization was successful in all six kidneys under both x-ray and MR imaging guidance. Mean catheterization time with MR guidance was 93 seconds ± 56, compared with 60 seconds ± 22 for x-ray guidance. Mean changes in perfusion rates were 4.9 au/sec ± 0.8 versus 4.6 au/sec ± 0.6, and mean changes in renal flow rate were 2.1 mL/min/g ± 0.2 versus 1.9 mL/min/g ± 0.2 with MR imaging and x-ray guidance, respectively. Conclusion The MARC catheter system is feasible for renal artery catheterization and embolization under real-time MR imaging in vivo, and quantitative physiologic measures under MR imaging guidance were similar to those measured under x-ray guidance, suggesting that the MARC catheter system could be used for endovascular procedures with interventional MR imaging. (©) RSNA, 2016.
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Cateterismo Periférico/instrumentação , Embolização Terapêutica/instrumentação , Procedimentos Endovasculares/instrumentação , Imagem por Ressonância Magnética Intervencionista , Magnetismo , Artéria Renal , Animais , Modelos Animais , Projetos Piloto , Radiografia Intervencionista , SuínosRESUMO
To report a novel method using immobilized DNA within mesh to sequester drugs that have intrinsic DNA binding characteristics directly from flowing blood. DNA binding experiments were carried out in vitro with doxorubicin in saline (PBS solution), porcine serum, and porcine blood. Genomic DNA was used to identify the concentration of DNA that shows optimum binding clearance of doxorubicin from solution. Doxorubicin binding kinetics by DNA enclosed within porous mesh bags was evaluated. Flow model simulating blood flow in the inferior vena cava was used to determine in vitro binding kinetics between doxorubicin and DNA. The kinetics of doxorubicin binding to free DNA is dose-dependent and rapid, with 82-96 % decrease in drug concentration from physiologic solutions within 1 min of reaction time. DNA demonstrates faster binding kinetics by doxorubicin as compared to polystyrene resins that use an ion exchange mechanism. DNA contained within mesh yields an approximately 70 % decrease in doxorubicin concentration from solution within 5 min. In the IVC flow model, there is a 70 % drop in doxorubicin concentration at 60 min. A DNA-containing ChemoFilter device can rapidly clear clinical doses of doxorubicin from a flow model in simple and complex physiological solutions, thereby suggesting a novel approach to reduce the toxicity of DNA-binding drugs.
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Artérias , DNA/química , Doxorrubicina/química , Doxorrubicina/isolamento & purificação , Filtração/instrumentação , Animais , Doxorrubicina/sangue , Doxorrubicina/uso terapêutico , Desenho de Equipamento , Estudos de Viabilidade , Cinética , SuínosRESUMO
PURPOSE: To establish that a magnetic device designed for intravascular use can bind small iron particles in physiologic flow models. MATERIALS AND METHODS: Uncoated iron oxide particles 50-100 nm and 1-5 µm in size were tested in a water flow chamber over a period of 10 minutes without a magnet (ie, control) and with large and small prototype magnets. These same particles and 1-µm carboxylic acid-coated iron oxide beads were likewise tested in a serum flow chamber model without a magnet (ie, control) and with the small prototype magnet. RESULTS: Particles were successfully captured from solution. Particle concentrations in solution decreased in all experiments (P < .05 vs matched control runs). At 10 minutes, concentrations were 98% (50-100-nm particles in water with a large magnet), 97% (50-100-nm particles in water with a small magnet), 99% (1-5-µm particles in water with a large magnet), 99% (1-5-µm particles in water with a small magnet), 95% (50-100-nm particles in serum with a small magnet), 92% (1-5-µm particles in serum with a small magnet), and 75% (1-µm coated beads in serum with a small magnet) lower compared with matched control runs. CONCLUSIONS: This study demonstrates the concept of magnetic capture of small iron oxide particles in physiologic flow models by using a small wire-mounted magnetic filter designed for intravascular use.
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Antineoplásicos/administração & dosagem , Portadores de Fármacos , Compostos Férricos/química , Compostos Ferrosos/química , Filtração/instrumentação , Imãs , Antineoplásicos/química , Composição de Medicamentos , Desenho de Equipamento , Injeções Intra-Arteriais , Teste de Materiais , Modelos Cardiovasculares , Tamanho da Partícula , Fluxo Sanguíneo Regional , Fatores de TempoRESUMO
A general, efficient method for C-N cross-coupling has been developed using N,N-dimethyloctanamide as a catalytic cosolvent for biphasic continuous-flow applications. The described method was used to generate a variety of biarylamines and was integrated into a two-step sequence which converted phenols into biarylamines via either triflates or tosylates. Additionally, the method was applied to a three-step synthesis of imatinib, the API of Gleevec, in good yield without the need of solvent switches.
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Amidas/química , Mesilato de Imatinib/síntese química , Solventes/química , CatáliseRESUMO
Acute kidney injury (AKI) is common after pediatric heart transplantation (HT) and is associated with inferior patient outcomes. Hemodynamic risk factors for pediatric heart transplant recipients who experience AKI are not well described. We performed a retrospective review of 99 pediatric heart transplant patients at Lucile Packard Children's Hospital Stanford from January 1, 2015, to December 31, 2019, in which clinical and demographic characteristics, intraoperative perfusion data, and hemodynamic measurements in the first 48 postoperative hours were analyzed as risk factors for severe AKI (Kidney Disease: Improving Global Outcomes [KDIGO] stage ≥ 2). Univariate analysis was conducted using Fisher's exact test, Chi-square test, and the Wilcoxon rank-sum test, as appropriate. Multivariable analysis was conducted using logistic regression. Thirty-five patients (35%) experienced severe AKI which was associated with lower intraoperative cardiac index ( p = 0.001), higher hematocrit ( p < 0.001), lower body temperature ( p < 0.001), lower renal near-infrared spectroscopy ( p = 0.001), lower postoperative mean arterial blood pressure (MAP: p = 0.001), and higher central venous pressure (CVP; p < 0.001). In multivariable analysis, postoperative CVP >12 mm Hg (odds ratio [OR] = 4.27; 95% confidence interval [CI]: 1.48-12.3, p = 0.007) and MAP <65 mm Hg (OR = 4.9; 95% CI: 1.07-22.5, p = 0.04) were associated with early severe AKI. Children with severe AKI experienced longer ventilator, intensive care, and posttransplant hospital days and inferior survival ( p = 0.01). Lower MAP and higher CVP are associated with severe AKI in pediatric HT recipients. Patients, who experienced AKI, experienced increased intensive care unit (ICU) morbidity and inferior survival. These data may guide the development of perioperative renal protective management strategies to reduce AKI incidence and improve patient outcomes.
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Cystinuria, a rare genetic disorder, is characterized by defective l-cystine reabsorption from the renal proximal tubule, resulting in abnormally high concentrations of l-cystine and subsequent l-cystine crystallization in urine and stone formation in the urinary tract. Inhibition of l-cystine crystallization by l-cystine diamides such as LH708 (2) represents a promising new approach to prevent stone formation in patients with cystinuria. While 2 shows promising in vivo efficacy and a good safety profile in a Slc3a1-knockout mouse model of cystinuria, further structural modification of 2 led to the discovery of 8-l-cystinyl bis(1,8-diazaspiro[4.5]decane) (LH1753, 3) incorporating a bioisosteric spiro bicyclic diamine 1,8-diazaspiro[4.5]decane for the N-methylpiperazine terminal groups in 2 as a promising candidate with 3 being about 120× more potent than l-cystine dimethyl ester (CDME, 1) and about 2× more potent than 2 in inhibiting l-cystine crystallization. Furthermore, 3 demonstrated good oral bioavailability and in vivo efficacy in preventing l-cystine stone formation in the Slc3a1-knockout mouse model of cystinuria.
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CDK2 is a critical regulator of the cell cycle. For a variety of human cancers, the dysregulation of CDK2/cyclin E1 can lead to tumor growth and proliferation. Historically, early efforts to develop CDK2 inhibitors with clinical applications proved unsuccessful due to challenges in achieving selectivity over off-target CDK isoforms with associated toxicity. In this report, we describe the discovery of (4-pyrazolyl)-2-aminopyrimidines as a potent class of CDK2 inhibitors that display selectivity over CDKs 1, 4, 6, 7, and 9. SAR studies led to the identification of compound 17, a kinase selective and highly potent CDK2 inhibitor (IC50 = 0.29 nM). The evaluation of 17 in CCNE1-amplified mouse models shows the pharmacodynamic inhibition of CDK2, measured by reduced Rb phosphorylation, and antitumor activity.
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Quinases Ciclina-Dependentes , Neoplasias , Animais , Humanos , Camundongos , Quinase 2 Dependente de Ciclina , Quinase 4 Dependente de Ciclina/metabolismo , Fosforilação , Pirimidinas/farmacologia , Pirazóis/química , Pirazóis/metabolismo , Pirazóis/farmacologiaRESUMO
Current therapies for treating cervical dysplasia are often inaccessible in low and middle-income countries (LMICs), highlighting the need for novel low-cost therapies that can be delivered at the point of care. Ethanol ablation is a low-cost therapy designed to treat locoregional cancers, which we augmented into an ethyl cellulose (EC)-ethanol gel formulation to enhance its efficacy. Here, we evaluated whether EC-ethanol ablation is able to safely achieve an ablation zone comparable to thermocoagulation, a commonly used therapy for cervical dysplasia. The study was performed in 20 female Yorkshire pigs treated with either a single 500 µL injection of EC-ethanol into the 12 o'clock position of the cervix or a single application of thermocoagulation at 100 °C for 20 s. The average temperature, heart rate, respiratory rate, and blood oxygen remained within normal ranges throughout the EC-ethanol procedure and were similar to the thermocoagulation group. No major side effects were observed. The reproductive tracts were excised after 24 h to examine ablation zones. Comparable depths of necrosis were seen for EC-ethanol (18.6 ± 1.6 mm) and thermocoagulation (19.7 ± 4.1 mm). The volumes of necrosis induced by a single injection of EC-ethanol (626.2 ± 122.8 µL) were comparable to the necrotic volumes induced by thermocoagulation in the top half of the cervices (664.6 ± 168.5 µL). This suggests that two EC-ethanol injections could be performed (e.g., at the 12 and 6 o'clock positions) to achieve comparable total necrotic volumes to thermocoagulation and safely and effectively treat women with cervical dysplasia in LMICs. This is the first study to systematically evaluate EC-ethanol ablation in a large animal model and compare its safety and efficacy to thermocoagulation, a commonly used ablative therapy for cervical dysplasia.