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1.
Biochem Biophys Res Commun ; 638: 28-35, 2023 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-36436339

RESUMO

Over the last decade, 64Cu-labeling of monoclonal antibody (mAb) via inverse electron demand Diels-Alder click chemistry (IEDDA) have received much attention. Despite the tetrazine-transcyclooctene (Tz-TCO) click chemistry's convenience and efficiency in mAb labeling, there is limited information about the ideal parameters in the development of click chemistry mediated (radio)immunoconjugates. This encourages us to conduct a systematic optimization while concurrently determining the physiochemical characteristics of the model mAb, trastuzumab, and TCO conjugates. To accomplish this, we investigated a few critical parameters, first, we determined the degree of conjugations with varying molar equivalents (eq.) of TCO (3, 5, 10, and 15 eq.). Through analytical techniques like size exclusion chromatography, dynamic light scattering, and zeta potential, qualitative analysis were performed to determine the purity, degree of aggregation and net charge of the conjugates. We found that as the degree of conjugation increased the purity of intact mAb fraction is compromised and net charge of conjugates became less positive. Next, all trastuzumab-PEG4-TCO conjugates with varying molar ratio and quantity (30, 50, 100, 200, 250 µg) were radiolabeled with 64Cu-NOTA-PEG4-Tz via IEDDA click chemistry and radiochemical yields were determined by radio-thin layer chromatography. The radiochemical yields of trastuzumab conjugates improved with increased amount and molar ratio. Next, we investigated the effect of the radioprotectant ascorbic acid (AA) of varied concentrations (0.25, 0.5, 0.75, 1 mM) on radiochemical yields and subsequent pharmacokinetics. A concentration of 0.25 mM of AA was found to be optimal for click reaction and in vivo biodistribution. Finally, we investigated the indirect influence of bioconjugation buffers on radiochemical yields and biodistribution in NIH3T6.7 tumor models that resulted approximately ∼11 %ID/g tumor uptake.


Assuntos
Radioisótopos de Cobre , Neoplasias , Humanos , Trastuzumab , Química Click/métodos , Distribuição Tecidual , Anticorpos Monoclonais , Compostos Radiofarmacêuticos/farmacocinética , Linhagem Celular Tumoral
2.
Eur J Nucl Med Mol Imaging ; 49(12): 4073-4087, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35680737

RESUMO

PURPOSE: Hydrogen sulfide (H2S) plays important roles in brain pathophysiology. However, nuclear imaging probes for the in vivo detection of brain H2S in living animals have not been developed. Here, we report the first nuclear imaging probe that enables in vivo imaging of endogenous H2S in the brain of live mice. METHODS: Utilizing a bis(thiosemicarbazone) backbone, a fluorescent ATSM-FITC conjugate was synthesized. Its copper complex, Cu(ATSM-FITC) was thoroughly tested as a biosensor for H2S. The same ATSM-FITC ligand was quantitatively labeled with [64Cu]CuCl2 to obtain a radioactive [64Cu][Cu(ATSM-FITC)] imaging probe. Biodistribution and positron emission tomography (PET) imaging studies were performed in healthy mice and neuroinflammation models. RESULTS: The Cu(ATSM-FITC) complex reacts instantly with H2S to release CuS and becomes fluorescent. It showed excellent reactivity, sensitivity, and selectivity to H2S. Endogenous H2S levels in living cells were successfully detected by fluorescence microscopy. Exceptionally high brain uptake of [64Cu][Cu(ATSM-FITC)] (> 9% ID/g) was observed in biodistribution and PET imaging studies. Subtle changes in brain H2S concentrations in live mice were accurately detected by quantitative PET imaging. Due to its dual modality feature, increased H2S levels in neuroinflammation models were characterized at the subcellular level by fluorescence imaging and at the whole-body scale by PET imaging. CONCLUSION: Our biosensor can be readily utilized to study brain H2S function in live animal models and shows great potential as a novel imaging agent for diagnosing brain diseases.


Assuntos
Complexos de Coordenação , Sulfeto de Hidrogênio , Compostos Organometálicos , Tiossemicarbazonas , Animais , Encéfalo/diagnóstico por imagem , Cobre , Fluoresceína-5-Isotiocianato , Corantes Fluorescentes , Ligantes , Camundongos , Doenças Neuroinflamatórias , Distribuição Tecidual
3.
J Clin Densitom ; 24(3): 414-421, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33846060

RESUMO

Despite the potential roles of sphingosine 1-phosphate (S1P) as a biomarker of osteoporotic fracture (OF), independent of bone mineral density (BMD) and clinical risk factors (CRFs), its association with bone microarchitecture, a key determinant of bone quality, have not been studied yet. We here investigated the association of S1P with the trabecular bone score (TBS), an index of the bone microarchitecture. The plasma S1P concentrations, TBS, and BMD were measured in the 339 postmenopausal women. The S1P level was inversely correlated with the TBS (γ=-0.096, p=0.049) and BMD at the femur neck (FN-BMD: γ=-0.122, p=0.025) and tended to be inversely correlated the BMD at the total hip (TH-BMD: γ=-0.096, p=0.079), but not at the lumbar spine (LS-BMD). After adjusting for fracture risk assessment tool probabilities of major OF from CRFs, the S1P level was inversely associated with the TBS (ß=-0.096, p=0.049) and FN-BMD (ß=-0.118, p=0.025) and tended to be inversely associated with the TH-BMD (ß=-0.092, p=0.083). Compared with subjects in the lowest S1P tertile, those in the highest S1P tertile had a significantly lower TBS (p=0.032) and BMD at femur (p=0.004-0.036). These findings indicated that a high S1P level in postmenopausal women was inversely associated with the both bone mass and microarchitecture, reflecting the compromised bone strength.


Assuntos
Densidade Óssea , Fraturas por Osteoporose , Absorciometria de Fóton , Osso Esponjoso/diagnóstico por imagem , Feminino , Humanos , Vértebras Lombares/diagnóstico por imagem , Lisofosfolipídeos , Fraturas por Osteoporose/diagnóstico por imagem , Pós-Menopausa , Esfingosina/análogos & derivados
4.
Calcif Tissue Int ; 107(4): 362-370, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32719936

RESUMO

Circulating sphingosine 1-phosphate (S1P) levels may be a biomarker for osteoporotic fracture (OF). This study assessed whether the addition of S1P levels to the fracture risk assessment tool (FRAX) could improve predictability of OF risk. Plasma S1P concentrations and FRAX variables were measured in 81 subjects with and 341 subjects without OF. S1P levels were higher in subjects with than those without OF (3.11 ± 0.13 µmol/L vs. 2.65 ± 0.61 µmol/L, P = 0.001). Higher S1P levels were associated with a higher likelihood of OF (odds ratio [OR] = 1.33, 95% confidence interval [CI] = 1.05-1.68), even after adjusting for FRAX probabilities. Compared with the lowest S1P tertile, subjects in the middle (OR = 3.37, 95% CI = 1.58-7.22) and highest (OR = 3.65, 95% CI = 1.66-8.03) S1P tertiles had higher rates of OF after adjustment. The addition of S1P levels to FRAX probabilities improved the area under the receiver-operating characteristics curve (AUC) for OF, from 0.708 to 0.769 (P = 0.013), as well as enhancing category-free net reclassification improvement (NRI = 0.504, 95% CI = 0.271-0.737, P < 0.001) and integrated discrimination improvement (IDI = 0.044, 95% CI = 0.022-0.065, P < 0.001). Adding S1P levels to FRAX probabilities especially in 222 subjects with osteopenia having a FRAX probability of 3.66-20.0% markedly improved the AUC for OF from 0.630 to 0.741 (P = 0.012), as well as significantly enhancing category-free NRI (0.571, 95% CI = 0.221-0.922, P = 0.001) and IDI (0.060, 95% CI = 0.023-0.097, P = 0.002). S1P is a consistent and significant risk factor of OF independent of FRAX, especially in subjects with osteopenia and low FRAX probability.


Assuntos
Lisofosfolipídeos/sangue , Fraturas por Osteoporose/diagnóstico , Medição de Risco , Esfingosina/análogos & derivados , Densidade Óssea , Humanos , Fraturas por Osteoporose/sangue , Fatores de Risco , Esfingosina/sangue
5.
J Cardiothorac Vasc Anesth ; 26(6): 1055-9, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22883445

RESUMO

OBJECTIVE: The aim of this study was to determine whether the epidural administration of magnesium during the perioperative period decreased the incidence of chronic postoperative pain (CPOP) at 3 months after video-assisted thoracic surgery. DESIGN: Prospective, randomized, and blinded. SETTING: A university hospital. PARTICIPANTS: Patients. INTERVENTIONS: Before the induction of anesthesia, the patients were assigned randomly to receive normal saline, 5 mL, (group C, n = 72) or magnesium sulfate, 100 mg (group M, n = 72), epidurally. At the end of surgery, group C received a continuous infusion of a mixture of 0.2% ropivacaine, 226 mL, and fentanyl, 1,200 µg, through a patient-controlled epidural analgesia pump for 48 hours. In group M, magnesium sulfate, 500 mg, was added to the infusion. MEASUREMENTS AND MAIN RESULTS: The incidence and severity of CPOP were assessed by a telephone survey 3 months after surgery. Patients were asked whether they experienced pain and to rank the severity of the pain using a 3-point scale (1, mild; 2, moderate; 3, severe). The incidences of CPOP were 42.4% in group C and 49.1% in group M. The severities of pain in the patients with CPOP were 1.0 (1-2) in group C and 1.0 (1-2) in group M. The incidence and severity of CPOP did not differ between the 2 groups. CONCLUSIONS: The epidural administration of magnesium from before the induction of anesthesia to 48 hours postoperatively did not decrease significantly the incidence or severity of CPOP in patients undergoing video-assisted thoracic surgery.


Assuntos
Analgesia Epidural/métodos , Analgésicos/administração & dosagem , Dor Crônica/tratamento farmacológico , Sulfato de Magnésio/administração & dosagem , Dor Pós-Operatória/tratamento farmacológico , Cirurgia Torácica Vídeoassistida/efeitos adversos , Adolescente , Adulto , Criança , Dor Crônica/epidemiologia , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Medição da Dor/efeitos dos fármacos , Medição da Dor/métodos , Dor Pós-Operatória/epidemiologia , Estudos Prospectivos , Adulto Jovem
6.
Cancer Res Treat ; 53(3): 829-836, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33421987

RESUMO

PURPOSE: The study aimed to evaluate the diagnostic accuracy of polymerase chain reaction ‒based high-risk human papillomavirus (HPV) assays on self-collected vaginal and urine samples for detection of precancerous cervical lesions in referral population. MATERIALS AND METHODS: Women referred for colposcopy following abnormal cytology, were included this study. A total of 314 matched urine, vaginal, and cervical samples were collected. All samples were tested for HPV DNA using the RealTime HR-S HPV and Anyplex II HPV 28 assays. Primary endpoints were sensitivity for cervical intraepithelial neoplasia (CIN) 2+/CIN3+ and specificity for

Assuntos
Alphapapillomavirus/isolamento & purificação , Detecção Precoce de Câncer/métodos , Infecções por Papillomavirus/diagnóstico , Displasia do Colo do Útero/diagnóstico , Neoplasias do Colo do Útero/prevenção & controle , Adulto , Alphapapillomavirus/genética , Colo do Útero/patologia , Colo do Útero/virologia , Colposcopia/estatística & dados numéricos , DNA Viral/isolamento & purificação , Detecção Precoce de Câncer/estatística & dados numéricos , Feminino , Humanos , Pessoa de Meia-Idade , Infecções por Papillomavirus/patologia , Infecções por Papillomavirus/urina , Infecções por Papillomavirus/virologia , Reação em Cadeia da Polimerase/estatística & dados numéricos , Encaminhamento e Consulta/estatística & dados numéricos , Sensibilidade e Especificidade , Manejo de Espécimes/métodos , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/virologia , Displasia do Colo do Útero/patologia , Displasia do Colo do Útero/urina , Displasia do Colo do Útero/virologia
7.
Korean J Pain ; 26(3): 270-6, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23862001

RESUMO

BACKGROUND: Ketamine, an N-methyl-D-aspartate receptor antagonist, might play a role in postoperative analgesia, but its effect on postoperative pain after caesarean section varies with study design. We investigated whether the preemptive administration of low-dose intravenous ketamine decreases postoperative opioid requirement and postoperative pain in parturients receiving intravenous fentanyl with patient-controlled analgesia (PCA) following caesarean section. METHODS: Spinal anesthesia was performed in 40 parturients scheduled for elective caesarean section. Patients in the ketamine group received a 0.5 mg/kg ketamine bolus intravenously followed by 0.25 mg/kg/h continuous infusion during the operation. The control group received the same volume of normal saline. Immediately after surgery, the patients were connected to a PCA device set to deliver 25-µg fentanyl as an intravenous bolus with a 15-min lockout interval and no continuous dose. Postoperative pain was assessed using the cumulative dose of fentanyl and visual analog scale (VAS) scores at 2, 6, 24, and 48 h postoperatively. RESULTS: Significantly less fentanyl was used in the ketamine group 2 h after surgery (P = 0.033), but the difference was not significant at 6, 12, and 24 h postoperatively. No significant differences were observed between the VAS scores of the two groups at 2, 6, 12, and 24 h postoperatively. CONCLUSIONS: Intraoperative low-dose ketamine did not have a preemptive analgesic effect and was not effective as an adjuvant to decrease opioid requirement or postoperative pain score in parturients receiving intravenous PCA with fentanyl after caesarean section.

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