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Wee1 is a tyrosine kinase that is highly expressed in several cancer types. Wee1 inhibition can lead to suppression of tumor cell proliferation and sensitization of cells to the effects of DNA-damaging agents. AZD1775 is a nonselective Wee1 inhibitor for which myelosuppression has been observed as a dose-limiting toxicity. We have applied structure-based drug design (SBDD) to rapidly generate highly selective Wee1 inhibitors that demonstrate better selectivity than AZD1775 against PLK1, which is known to cause myelosuppression (including thrombocytopenia) when inhibited. While selective Wee1 inhibitors described herein still achieved in vitro antitumor efficacy, thrombocytopenia was still observed in vitro.
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Introducción: En las personas que viven con el virus de la inmunodeficiencia humana (PVVIH) se han descripto desregulaciones metabólicas que podrían vincularse a un mayor riesgo cardiovascular.Objetivo: Evaluar el espesor del tejido adiposo epicárdico (ETAE) y la relación del mismo con parámetros clínicos y bioquímicos de riesgo cardiovascular en adultos que viven con VIH, comparados con controles seronegativos.Materiales y métodos: Observacional, inclusión prospectiva. Se incluyeron PVVIH >18 años y controles seronegativos para VIH, a los cuales se les midió el espesor de TAE en dos ejes por ecocardiograma transtorácico, así como el espesor de íntima media carotídea por ecografía doppler color.Resultados: 75 pacientes, 58,7% del sexo masculino, edad de 36 años (RIQ 22). 50,7% con VIH (CD4+: 512 cél/mm3 RIQ 382; 80% indetectables). IMC de 25,2 kg/m2 (RIQ 5,3) y circunferencia de cintura de 88,5 cm (DS 12,4), sin diferencias. Las PVVIH tuvieron menor HDL, mayor proteína C reactiva, mayor dímero D y mayor glucemia en ayunas. El ETAE fue mayor en las PVVIH (4,05 vs. 3,49 mm p=0,021), y se correlacionó con la edad, glucemia en ayunas y dímero D. En las PVVIH, se correlacionó con insulinemia, índice HOMA2-IR, HDL-c y dímero D. El tratamiento con Efavirenz se asoció a un mayor ETAE.Conclusión: Las PVVIH presentaron mayor inflamación sistémica de bajo grado y un mayor espesor de TAE que los controles sanos, el cual se asoció en este grupo a insulinorresistencia
Introduction: For people living with Human Immunodeficiency Virus (PLHIV), metabolic deregulations have been described, which could be related to a higher cardiovascular risk.Objective: To assess the epicardial adipose tissue thickness (EATT), and the relationship between this value and clinical and biochemical parameters of cardiovascular risk in adults living with HIV, if compared to a healthy control group. Methods: Observational, with prospective inclusion. It included PLHIV >18 years and seronegative controls. All of them had their EAT measured in two axes by transthoracic echocardiogram, as well as the carotid intima-media thickness determined by color doppler ultrasound.Results: 75 patients, 58.7% male, age of 36 years (RIQ 22). 50.7% patients with HIV (CD4+ of 512 cells/mm3; and 80% undetectable). BMI was of 25.2 kg/m2 and waist circumference of 88.5 cm, without between-groups differences. PLHIV had lower HDL, higher C reactive protein, higher D-dimer and higher fasting blood glucose. EATT was higher in PLHIV (4.05 vs 3.49 mm, p=0.021), and this correlated with age, fasting blood glucose and D-dimer. In PLHIV, it correlated with insulinemia, HOMA2-IR index, HDL-c ; and D-dimer. Treatment with Efavirenz was associated with a higher EATT.Conclusion: PLHIV presented increased systemic inflammation of low grade and higher EATT than the seronegative control group. EATT was associated in PLHIV to insulin resistance
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Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Idoso , Ecocardiografia , Tecido Adiposo/metabolismo , HIV/metabolismo , Inflamação/patologiaRESUMO
OBJECTIVE: To investigate the association between early neonatal respiratory management in infants with bronchopulmonary dysplasia (BPD) and the degree of pulmonary ventilation perfusion-matching (V/Q) at term. METHODS: 30 preterm infants with a diagnosis of BPD who were initially treated with either controlled mechanical ventilation/continuous positive airway pressure (CMV/CPAP) (n = 14) or high-frequency oscillatory ventilation (HFOV) using a high lung-volume strategy (n = 16) were retrospectively included in this study. All infants underwent pulmonary V/Q single photon emission computed tomography at a median postmenstrual age of 37 weeks. RESULTS: Infants treated with HFOV had significantly larger proportion of the lung with matched V/Q as compared to infants treated with CMV/CPAP, median (interquartile range) 60.4% (55.5-66.0%) and 45.8% (37.8-53.1%) respectively (p = 0.01). CONCLUSIONS: In infants who needed mechanical ventilation the first week of life and later developed BPD an association was observed between treatment with a HFOV and better pulmonary V/Q matching at near-term age.
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Displasia Broncopulmonar , Infecções por Citomegalovirus , Recém-Nascido , Lactente , Humanos , Displasia Broncopulmonar/terapia , Recém-Nascido Prematuro , Estudos Retrospectivos , Perfusão , Ventilação PulmonarRESUMO
Objective: Successful preoperative image localisation of all parathyroid adenomas (PTA) in patients with primary hyperparathyroidism (pHPT) and multiglandular disease (MGD) remains challenging. We investigate whether a machine learning classifier (MLC) could predict the presence of overlooked PTA at preoperative localisation with 99mTc-Sestamibi-SPECT/CT in MGD patients. Design: This study is a retrospective study from a single tertiary referral hospital initially including 349 patients with biochemically confirmed pHPT and cured after surgical parathyroidectomy. Methods: A classification ensemble of decision trees with Bayesian hyperparameter optimisation and five-fold cross-validation was trained with six predictor variables: the preoperative plasma concentrations of parathyroid hormone, total calcium and thyroid-stimulating hormone, the serum concentration of ionised calcium, the 24-h urine calcium and the histopathological weight of the localised PTA at imaging. Two response classes were defined: patients with single-gland disease (SGD) correctly localised at imaging and MGD patients in whom only one PTA was localised on imaging. The data set was split into 70% for training and 30% for testing. The MLC was also tested on a subset of the original data based on CT image-derived PTA weights. Results: The MLC achieved an overall accuracy at validation of 90% with an area under the cross-validation receiver operating characteristic curve of 0.9. On test data, the MLC reached a 72% true-positive prediction rate for MGD patients and a misclassification rate of 6% for SGD patients. Similar results were obtained in the testing set with image-derived PTA weight. Conclusions: Artificial intelligence can aid in identifying patients with MGD for whom 99mTc-Sestamibi-SPECT/CT failed to visualise all PTAs.
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Adenoma , Hiperparatireoidismo Primário , Neoplasias das Paratireoides , Adenoma/diagnóstico por imagem , Adenoma/cirurgia , Inteligência Artificial , Teorema de Bayes , Cálcio , Humanos , Hiperparatireoidismo Primário/diagnóstico por imagem , Hiperparatireoidismo Primário/cirurgia , Aprendizado de Máquina , Neoplasias das Paratireoides/patologia , Paratireoidectomia , Compostos Radiofarmacêuticos , Estudos Retrospectivos , Tecnécio Tc 99m Sestamibi , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Tomografia Computadorizada por Raios XRESUMO
The introduction of molecular complexity in an atom- and step-efficient manner remains an outstanding goal in modern synthetic chemistry. Artificial biosynthetic pathways are uniquely able to address this challenge by using enzymes to carry out multiple synthetic steps simultaneously or in a one-pot sequence1-3. Conducting biosynthesis ex vivo further broadens its applicability by avoiding cross-talk with cellular metabolism and enabling the redesign of key biosynthetic pathways through the use of non-natural cofactors and synthetic reagents4,5. Here we describe the discovery and construction of an enzymatic cascade to MK-1454, a highly potent stimulator of interferon genes (STING) activator under study as an immuno-oncology therapeutic6,7 (ClinicalTrials.gov study NCT04220866 ). From two non-natural nucleotide monothiophosphates, MK-1454 is assembled diastereoselectively in a one-pot cascade, in which two thiotriphosphate nucleotides are simultaneously generated biocatalytically, followed by coupling and cyclization catalysed by an engineered animal cyclic guanosine-adenosine synthase (cGAS). For the thiotriphosphate synthesis, three kinase enzymes were engineered to develop a non-natural cofactor recycling system in which one thiotriphosphate serves as a cofactor in its own synthesis. This study demonstrates the substantial capacity that currently exists to use biosynthetic approaches to discover and manufacture complex, non-natural molecules.
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Guanosina , Nucleotidiltransferases , Adenosina , Animais , Interferons , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Nucleotidiltransferases/metabolismo , Transdução de SinaisRESUMO
OBJECTIVE: Epidemiological studies indicate association between elevated air pollution and adverse health effects. Several mechanisms have been suggested, including translocation of inhaled ultrafine carbon (UFC) particles into the bloodstream. Previous studies in healthy subjects have shown no significant pulmonary translocation of UFC-particles. This study aimed to assess if UFC-particles translocate from damaged alveolar compartment in subjects suffering from chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). METHODS: Eleven COPD and nine IPF subjects were exposed to a 100 nm UFC-particle-aerosol labeled with Indium-111. Activity in the body was followed up for 10 days using gamma camera planar-imaging as well as in blood and urine samples. RESULTS: The pulmonary central to periphery activity ratio was significantly higher for COPD as compared to IPF subjects at exposure, 1.8 and 1.4, respectively and remained constant throughout the test period. Ten days after exposure, the estimated median pulmonary translocation of UFC particles was 22.8 and 25.8% for COPD and IPF, respectively. Bound activity was present in blood throughout the test period, peaking at 24-h postinhalation with a median concentration of 5.6 and 8.9 Bq/ml for the COPD and IPF, respectively. Median bound activity excreted in urine (% of inhaled) after 10 days was 1.4% in COPD and 0.7% in IPF. Activity accumulation in liver and spleen could not be demonstrated. CONCLUSIONS: Our results suggest that UFC particles leak through the damaged alveolar barrier to the bloodstream in COPD and IPF patients probably distributing in a wide spectrum of whole-body tissues.
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Fibrose Pulmonar Idiopática , Doença Pulmonar Obstrutiva Crônica , Carbono/metabolismo , Humanos , Fibrose Pulmonar Idiopática/diagnóstico por imagem , Fibrose Pulmonar Idiopática/metabolismo , Pulmão/metabolismo , Material Particulado/metabolismo , Material Particulado/toxicidadeRESUMO
OBJECTIVES: To investigate the incremental value of Sestamibi SPECT combined with a non-enhanced and contrast-enhanced CT, using SPECT/CT, for the preoperative localisation of small parathyroid adenomas (PTA). METHODS: Retrospectively, 147 patients surgically cured from primary hyperparathyroidism, as verified by biochemistry 6 months postoperatively, were included. All patients had preoperatively undergone a dual time 99mTechnetium-Sestamibi SPECT (S) with multiphase CT including native (N), arterial (A) and venous (V) phases. Independently, two radiologists blinded from both the surgical and the preoperative imaging reports, sequentially performed PTA localisation starting with either [A] or [V], thereafter [A + N] or [V + N] and finally with the complete [A + N + S] or [V + N + S]. PTA localisation was reported for each image-set. The readers results were combined and the diagnostic performance for each image set was determined. Sensitivity was also calculated for the different quartiles of PTA weight distribution. RESULTS: The median adenoma weight was 315 mg. No statistically significant differences in diagnostic performance between arterial and venous based image sets were found. The net effect of adding [N] was to increase specificity. Sestamibi SPECT significantly increased the overall diagnostic accuracy for arterial- and venous-based image sets, p = 0.0008 and p = 0.001, respectively. [A + N + S] was found to have the highest diagnostic performance with 86.5% sensitivity and 94.9% overall accuracy. [A + N + S] was particularly advantageous for locating PTA in the lower weight quartiles. CONCLUSIONS: Native CT-phase and dual time point Sestamibi SPECT increase specificity and sensitivity, respectively. These, in combination with a single contrast-enhanced CT-phase is the most optimal examination protocol for preoperative localisation of PTA using SPECT/CT.
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PURPOSE: The aim of this study was to assess the value of intravenously contrast-enhanced CT in conjunction with Tc-MIBI SPECT for preoperative localization of parathyroid adenoma. METHODS: One hundred ninety-two patients with primary hyperparathyroidism were enrolled in the study between May 2015 and May 2017. The patients underwent a preoperative "one-stop shop" examination with Tc-MIBI SPECT/CT by using dual time-point (10 and 90 minutes) protocol and both nonenhanced CT and contrast-enhanced CT acquisition in the arterial and venous phase, 35 and 75 seconds, respectively, after contrast medium injection start. For 149 patients, the imaging results could be correlated to those at surgery and histopathology. RESULTS: The median adenoma weight was 330 mg. The addition of contrast-enhanced CT increased the sensitivity from 81.1% to 89.9% (P = 0.003). The specificity of nonenhanced SPECT/CT was similar to contrast-enhanced CT (96.1% vs 97.9%; P = 0.077). For patients with uniglandular disease (n = 140, 94.0%), the sensitivity increased from 86.4% to 93.6% (P = 0.021) and the specificity from 96.2% to 97.9% (P = 0.118) by adding contrast-enhanced CT. In patients with multiglandular disease (n = 9, 6.0%), adding contrast-enhanced CT improved detection sensitivity from 42.1% to 63.2%. However, these patients were few and significance was not reached (P = 0.125). CONCLUSIONS: In this cohort, with generally small parathyroid adenomas, the sensitivity in preoperative localization was greatly improved by adding contrast-enhanced CT to Tc-MIBI SPECT/CT.
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Adenoma/diagnóstico por imagem , Meios de Contraste/química , Iodo/química , Neoplasias das Paratireoides/diagnóstico por imagem , Período Pré-Operatório , Tomografia Computadorizada com Tomografia Computadorizada de Emissão de Fóton Único/métodos , Adenoma/patologia , Adenoma/cirurgia , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias das Paratireoides/patologia , Neoplasias das Paratireoides/cirurgia , Sensibilidade e Especificidade , Tecnécio Tc 99m Sestamibi , Carga TumoralRESUMO
AIM: The ratio of ventilation to blood flow is an important determinant for regional gas exchange in the lung and hypoxemia is one of the clinical hallmarks in infants with bronchopulmonary dysplasia (BPD). We have previously demonstrated ventilation/perfusion ratio (V/Q) abnormalities in infants with BPD at 36 weeks postconceptional age. The status of V/Q matching in older children with a history of BPD in infancy is unknown. In this study, we examined if 10-year-old children with a history of BPD had V/Q impairments. METHODS: Three-dimensional V/Q-scintigraphy (SPECT) was performed in 26 children. RESULTS: In the BPD group, lung volume with mismatch, (V>Q) was larger compared to areas with reverse mismatch (Q>V), 26.2% and 11.8%, respectively, implying that perfusion defects contribute more than ventilation defects in the V/Q mismatch. Also, the mean fractional distribution of V and Q to V/Q in children with BPD was reduced compared to healthy children, 31% and 51% compared to 64% and 89%, respectively (P < 0.01). CONCLUSION: At 10 years of age children with a history of BPD had ventilation/perfusion abnormalities, with prominent perfusion defects. These V/Q abnormalities suggest the presence of residual alveolar-capillary impairment.
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Displasia Broncopulmonar/fisiopatologia , Pulmão/fisiopatologia , Relação Ventilação-Perfusão , Displasia Broncopulmonar/diagnóstico por imagem , Estudos de Casos e Controles , Criança , Feminino , Humanos , Pulmão/diagnóstico por imagem , Masculino , Ventilação Pulmonar , Volume de Ventilação Pulmonar , Tomografia Computadorizada de Emissão de Fóton Único , Cintilografia de Ventilação/PerfusãoRESUMO
PURPOSE: The aim of this study was to analyse the characteristics of patients with IE in three groups of age and to assess the ability of age and the Charlson Comorbidity Index (CCI) to predict mortality. METHODS: Prospective cohort study of all patients with IE included in the GAMES Spanish database between 2008 and 2015.Patients were stratified into three age groups:<65â¯years,65 to 80â¯years,andâ¯≥â¯80â¯years.The area under the receiver-operating characteristic (AUROC) curve was calculated to quantify the diagnostic accuracy of the CCI to predict mortality risk. RESULTS: A total of 3120 patients with IE (1327â¯<â¯65â¯years;1291 65-80â¯years;502â¯≥â¯80â¯years) were enrolled.Fever and heart failure were the most common presentations of IE, with no differences among age groups.Patients ≥80â¯years who underwent surgery were significantly lower compared with other age groups (14.3%,65â¯years; 20.5%,65-79â¯years; 31.3%,≥80â¯years). In-hospital mortality was lower in the <65-year group (20.3%,<65â¯years;30.1%,65-79â¯years;34.7%,≥80â¯years;pâ¯<â¯0.001) as well as 1-year mortality (3.2%, <65â¯years; 5.5%, 65-80â¯years;7.6%,≥80â¯years; pâ¯=â¯0.003).Independent predictors of mortality were ageâ¯≥â¯80â¯years (hazard ratio [HR]:2.78;95% confidence interval [CI]:2.32-3.34), CCIâ¯≥â¯3 (HR:1.62; 95% CI:1.39-1.88),and non-performed surgery (HR:1.64;95% CI:11.16-1.58).When the three age groups were compared,the AUROC curve for CCI was significantly larger for patients aged <65â¯years(pâ¯<â¯0.001) for both in-hospital and 1-year mortality. CONCLUSION: There were no differences in the clinical presentation of IE between the groups. Ageâ¯≥â¯80â¯years, high comorbidity (measured by CCI),and non-performance of surgery were independent predictors of mortality in patients with IE.CCI could help to identify those patients with IE and surgical indication who present a lower risk of in-hospital and 1-year mortality after surgery, especially in the <65-year group.
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Fatores Etários , Comorbidade , Endocardite/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Área Sob a Curva , Bases de Dados Factuais , Endocardite/etiologia , Feminino , Insuficiência Cardíaca/mortalidade , Mortalidade Hospitalar , Humanos , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos Prospectivos , Curva ROC , Fatores de Risco , Espanha/epidemiologia , Infecções Estafilocócicas/mortalidadeRESUMO
BACKGROUND: In most parts of the world, curatively intended treatment for esophageal cancer includes neoadjuvant therapy, either with chemoradiotherapy or chemotherapy alone, followed by esophagectomy. Currently 18F-FDG positron emission tomography/computed tomography (PET/CT) is used for preoperative disease staging, but is not well established in the evaluation of neoadjuvant treatment. PURPOSE: To evaluate changes in PET parameters in relation to the histological primary tumor response in the surgical specimen in patients randomized to neoadjuvant chemoradiotherapy or chemotherapy. MATERIAL AND METHODS: Patients were randomized between either neoadjuvant chemotherapy or chemoradiotherapy followed by esophagectomy.18F-FDG PET/CT exams were conducted at baseline and following neoadjuvant treatment. Standardized uptake ratio (SUR) values were measured in the primary tumor and compared as regards histological responders and non-responders as well as different treatment arms. RESULTS: Seventy-nine patients were enrolled and 51 were available for analysis. A significant rate of SUR reduction was observed ( P = 0.02) in the primary tumor in histological responders compared to non-responders. Changes in SUR were significantly greater in responders following chemoradiotherapy ( P = 0.02), but not following chemotherapy alone ( P = 0.49). There was no statistically significant difference in SUR in patients with a complete histological response compared to those with a subtotal response. CONCLUSION: Our results are similar to those of previous studies and show that changes in the rate of SUR can be used reliably to differentiate histological responders from non-responders after neoadjuvant treatment with either chemoradiotherapy or chemotherapy. Limitations of current PET technology are likely to restrict the possibility of accurately ruling out limited residual disease.
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Neoplasias Esofágicas/terapia , Fluordesoxiglucose F18 , Terapia Neoadjuvante/métodos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Compostos Radiofarmacêuticos , Adulto , Idoso , Junção Esofagogástrica/diagnóstico por imagem , Esôfago/diagnóstico por imagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Noruega , SuéciaRESUMO
BACKGROUND: In 2006, we reported a "forme frustrée" of hammock valve involving the posterior mitral leaflet resulting in restricted leaflet motion and mitral regurgitation. The purpose of this retrospective report is to describe the surgical techniques and long-term outcome of 23 patients with partial hammock valve who underwent successful repaired over a 22-year period (1995 to 2017). METHODS: Partial hammock valve is defined as anomalous papillary muscles that have hypertrophied and fused together. There are three or four papillary muscles implanted high on the posterior wall, forming a palisade under the posterior leaflet. Twenty-three patients were operated on, 19 adults and 4 children. In all but 3 patients, repair consisted of posterior leaflet enlargement of the P2 and P3 segments with a semilunar patch of bovine pericardium. The fused papillary muscles were split longitudinally, and some secondary chordae were cut. All adult patients received a prosthetic ring. RESULTS: A satisfactory repair was achieved in all patients. Mean age at the time of operation was 62 ± 11 years (range, 6 days to 79 years). Hospital mortality occurred in 1 patient (1 of 23; 4.3%). Mean follow-up was 7 years (range, 1 to 22). Actuarial survival rate at 7 years was 70%. At last echocardiogram, all survivors were free from mitral regurgitation grade II or higher. There was no reoperation. CONCLUSIONS: Partial hammock valve is a rare congenital anomaly resulting in mitral regurgitation. Patch enlargement of the posterior leaflet achieves long-term repair. It is safe and reliable.
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Valva Mitral/anormalidades , Valva Mitral/cirurgia , Músculos Papilares/anormalidades , Músculos Papilares/cirurgia , Idoso , Idoso de 80 Anos ou mais , Procedimentos Cirúrgicos Cardíacos/métodos , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de TempoRESUMO
BACKGROUND: Gallium-68-labeled prostate-specific antigen positron emission tomography/computed tomography imaging (Ga68-PSMA-11-PET/CT) has emerged as a potential gold standard for prostate cancer (PCa) diagnosis. However, the imaging limitations of this technique at the early state of PCa recurrence/metastatic spread are still not well characterized. The aim of this study was to determine the quantitative properties and the fundamental imaging limits of Ga68-PSMA-11-PET/CT in localizing small PCa cell deposits. METHODS: The human PCa LNCaP cells (PSMA expressing) were grown and collected as single cell suspension or as 3D-spheroids at different cell numbers and incubated with Ga68-PSMA-11. Thereafter, human HCT116 cells (PSMA negative) were added to a total cell number of 2 × 105 cells per tube. The tubes were then pelleted and the supernatant aspirated. A whole-body PET/CT scanner with a clinical routine protocol was used for imaging the pellets inside of a cylindrical water phantom with increasing amounts of background activity. The actual activity bound to the cells was also measured in an automatic gamma counter. Imaging detection limits and activity recovery coefficients as a function of LNCaP cell number were obtained. The effect of Ga68-PSMA-11 mass concentration on cell binding was also investigated in samples of LnCaP cells incubated with increasing concentrations of radioligand. RESULTS: A total of 1 × 104 LNCaP cells mixed in a pellet of 2 × 105 cells were required to reach a 50% detection probability with Ga68-PSMA-11-PET/CT without background. With a background level of 1 kBq/ml, between 4 × 105 and 1 × 106 cells are required. The radioligand equilibrium dissociation constant was 27.05 nM, indicating high binding affinity. Hence, the specific activity of the radioligand has a profound effect on image quantification. CONCLUSIONS: Ga68-PSMA-11-PET detects a small number of LNCaP cells even when they are mixed in a population of non-PSMA expressing cells and in the presence of background. The obtained image detection limits and characteristic quantification properties of Ga68-PSMA-11-PET/CT are essential hallmarks for the individualization of patient management. The use of the standardized uptake value for Ga68-PSMA-11-PET/CT image quantification should be precluded.
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Disulfide bond formation is critical for maintaining structure stability and function of many peptides and proteins. Mass spectrometry has become an important tool for the elucidation of molecular connectivity. However, the interpretation of the tandem mass spectral data of disulfide-linked peptides has been a major challenge due to the lack of appropriate tools. Developing proper data analysis software is essential to quickly characterize disulfide-linked peptides. A thorough and in-depth understanding of how disulfide-linked peptides fragment in mass spectrometer is a key in developing software to interpret the tandem mass spectra of these peptides. Two model peptides with inter- and intra-chain disulfide linkages were used to study fragmentation behavior in both collisional-activated dissociation (CAD) and electron-based dissociation (ExD) experiments. Fragments generated from CAD and ExD can be categorized into three major types, which result from different S-S and C-S bond cleavage patterns. DiSulFinder is a computer algorithm that was newly developed based on the fragmentation observed in these peptides. The software is vendor neutral and capable of quickly and accurately identifying a variety of fragments generated from disulfide-linked peptides. DiSulFinder identifies peptide backbone fragments with S-S and C-S bond cleavages and, more importantly, can also identify fragments with the S-S bond still intact to aid disulfide linkage determination. With the assistance of this software, more comprehensive disulfide connectivity characterization can be achieved. Graphical Abstract á .
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Dissulfetos/análise , Peptídeos/química , Espectrometria de Massas em Tandem/métodos , Algoritmos , Sequência de Aminoácidos , Animais , Análise de Dados , Humanos , Insulina/química , Neuropeptídeos/química , Software , Fluxo de TrabalhoRESUMO
We report herein the design and synthesis of a series of orally active, liver-targeted hypoxia-inducible factor prolyl hydroxylase (HIF-PHD) inhibitors for the treatment of anemia. In order to mitigate the concerns for potential systemic side effects, we pursued liver-targeted HIF-PHD inhibitors relying on uptake via organic anion transporting polypeptides (OATPs). Starting from a systemic HIF-PHD inhibitor (1), medicinal chemistry efforts directed toward reducing permeability and, at the same time, maintaining oral absorption led to the synthesis of an array of structurally diverse hydroxypyridone analogues. Compound 28a was chosen for further profiling, because of its excellent in vitro profile and liver selectivity. This compound significantly increased hemoglobin levels in rats, following chronic QD oral administration, and displayed selectivity over systemic effects.
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OBJECTIVE: This study aims to determine the diagnostic test accuracy (DTA) of 11C-methionine (MET) PET in the discrimination between recurrent tumor and radiation-induced injury in neuropathologically confirmed cases. METHODS: A retrospective cohort of 30 patients with previously irradiated intracranial tumors (23 gliomas, 6 metastases, and 1 meningioma) was included. All patients underwent a preoperative MET PET and postoperative neuropathological analysis. Maximum and mean standardized uptake values (SUV) were obtained in the lesion, in the contralateral mirror region, and in the contralateral frontal cortex. Lesion-to-background SUV ratios (SUR mirror and SUR cortex) were then calculated. The Mann-Whitney U test was used to evaluate differences in SUV ratios between confirmed recurrent tumor and radiation injury. DTA was determined through receiver operating characteristic (ROC) analysis. RESULTS: Twenty-one patients had recurrent tumor and nine had radiation injury. The area under the ROC curve (AUC) was 0.89 for SURmaxmirror and 0.88 for SURmaxcortex. The mean (SD) of SURmaxmirror was 2.37 (0.58) in tumor recurrence and 1.57 (0.40) in radiation necrosis (P ≤ 0.001). The corresponding values for SURmaxcortex were 2.13 (0.50) and 1.45 (0.37) (P = 0.001). Clinically relevant cutoffs were SURmaxmirror ≥ 1.99 giving a specificity of 100% for tumor recurrence with a sensitivity of 76% and SURmaxcortex ≥ 1.58 giving a sensitivity and specificity of 90 and 78%, respectively. CONCLUSIONS: Based on neuropathologically confirmed cases, the DTA of SURmaxmirror and SURmaxcortex from 11C-methionine PET was high when discriminating recurrent tumor from radiation injury.
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Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/radioterapia , Metionina , Tomografia por Emissão de Pósitrons , Transporte Biológico , Neoplasias Encefálicas/patologia , Diagnóstico Diferencial , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Masculino , Pessoa de Meia-Idade , Neoplasias Induzidas por Radiação/diagnóstico por imagem , Recidiva , Sensibilidade e EspecificidadeRESUMO
OBJECTIVES: Anomalous aortic origin of a coronary artery is uncommon but potentially clinically significant. Manifestations vary from asymptomatic patients to those who present with angina pectoris, myocardial infarction, heart failure, syncope, arrhythmias, and sudden death. We describe our experience with surgical reimplantation and results at midterm follow-up. METHODS: Between February 2003 and July 2016, a total of 13 patients with anomalous origin of the right coronary artery (RCA) from the left sinus underwent surgical reimplantation. RESULTS: Mean age was 39 years (range, 11-72 years). Eight patients presented with dyspnea and angina, two with acute myocardial infarction, and the remaining three were studied for atypical chest pain and ventricular premature contractions. Definitive diagnosis was achieved with coronary angiography in eight cases and with computed tomography scan in five. In all cases, the anomalous origin of the RCA from the left sinus had an intramural course except one case with interarterial (but not intramural) course. At operation, the RCA was dissected at the takeoff from the intramural course and reimplanted into the right sinus of Valsalva. There was no mortality. One patient had associated atherosclerotic coronary artery disease that required stent placement postoperatively. After a mean follow-up of 65 months (maximum 12 years), all patients are asymptomatic and have returned to exercise without limitations. CONCLUSIONS: The reimplantation technique provides a good physiological and anatomical repair, eliminates a slit-like ostium, avoids compression of the coronary artery between the aorta and the pulmonary artery, and gives similar results to the unroofing technique.
Assuntos
Procedimentos Cirúrgicos Cardíacos/métodos , Seio Coronário/anormalidades , Anomalias dos Vasos Coronários/cirurgia , Vasos Coronários/cirurgia , Reimplante/métodos , Adolescente , Adulto , Idoso , Anastomose Cirúrgica/métodos , Criança , Angiografia Coronária , Seio Coronário/diagnóstico por imagem , Seio Coronário/cirurgia , Anomalias dos Vasos Coronários/diagnóstico , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Tempo , Tomografia Computadorizada por Raios X , Adulto JovemRESUMO
PURPOSES: The aims of this study were to assess the performance of Tc-sestamibi SPECT/CT, with diagnostic CT quality, compared with SPECT alone for preoperative localization of parathyroid adenomas and to assess the influence of adenoma weight on the correct adenoma lateralization with SPECT/CT and with SPECT alone. METHODS: Two hundred forty-nine consecutive patients, biochemically diagnosed with primary hyperparathyroidism, were examined with a combined SPECT/CT scanner. Subsequently, 200 patients with confirmed histopathology and biochemical cure after parathyroidectomy were included in this study (16 with multiglandular disease). For each patient, the SPECT-alone data were analyzed first. Thereafter, the CT information was added, and a new evaluation was performed with the combined data. In addition, for each patient, the diagnostic confidence with each method was graded on a scale based on the presence of different image features. The preoperative diagnostic findings were then compared with the surgical and histopathologic reports. RESULTS: The distribution of adenoma weights showed a peak at 210 mg, with a median at 338 mg. The sensitivity and specificity (multiglandular disease included) for correct classification of adenomas were significantly higher for SPECT/CT, 83% and 96%, respectively, than for SPECT alone, 80% and 93% (P < 0.01). Below 210 mg, the differences between SPECT/CT and SPECT alone in accurate adenoma lateralization were more prominent. Sixty-seven percent of all adenomas were graded with the highest confidence score with SPECT/CT compared with 53% with SPECT. CONCLUSIONS: SPECT/CT yields fewer false-positive findings than SPECT alone. The advantage of SPECT/CT over SPECT alone was most apparent for correct lateralization of small adenomas (<210 mg).