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1.
Bioorg Med Chem Lett ; 108: 129803, 2024 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-38777280

RESUMO

Targeted delivery of radionuclides to tumors is significant in theranostics applications for precision medicine. Pre-targeting, in which a tumor-targeting vehicle and a radionuclide-loaded effector small molecule are administered separately, holds promise since it can reduce unnecessary internal radiation exposure of healthy cells and can minimize radiation decay. The success of the pre-targeting delivery requires an in vivo-stable tumor-targeting vehicle selectively binding to tumor antigens and an in vivo-stable small molecule effector selectively binding to the vehicle accumulated on the tumor. We previously reported a drug delivery system composed of a low-immunogenic streptavidin with weakened affinity to endogenous biotin and a bis-iminobiotin with high affinity to the engineered streptavidin. It was, however, unknown whether the bis-iminobiotin is stable in vivo when administered alone for the pre-targeting applications. Here we report a new in vivo-stable bis-iminobiotin derivative. The keys to success were the identification of the degradation site of the original bis-iminobiotin treated with mouse plasma and the structural modification of the degradation site. We disclosed the successful pre-targeting delivery of astatine-211 (211At), α-particle emitter, to the CEACAM5-positive tumor in xenograft mouse models.


Assuntos
Biotina , Estreptavidina , Animais , Estreptavidina/química , Camundongos , Biotina/química , Humanos , Sistemas de Liberação de Medicamentos , Linhagem Celular Tumoral , Mutação , Estrutura Molecular
2.
Cancer Sci ; 114(1): 321-338, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36136061

RESUMO

Important roles of humoral tumor immunity are often pointed out; however, precise profiles of dominant antigens and developmental mechanisms remain elusive. We systematically investigated the humoral antigens of dominant intratumor immunoglobulin clones found in human cancers. We found that approximately half of the corresponding antigens were restricted to strongly and densely negatively charged polymers, resulting in simultaneous reactivities of the antibodies to both densely sulfated glycosaminoglycans (dsGAGs) and nucleic acids (NAs). These anti-dsGAG/NA antibodies matured and expanded via intratumoral immunological driving force of innate immunity via NAs. These human cancer-derived antibodies exhibited acidic pH-selective affinity across both antigens and showed specific reactivity to diverse spectrums of human tumor cells. The antibody-drug conjugate exerted therapeutic effects against multiple cancers in vivo by targeting cell surface dsGAG antigens. This study reveals that intratumoral immunological reactions propagate tumor-oriented immunoglobulin clones and demonstrates a new therapeutic modality for the universal treatment of human malignancies.


Assuntos
Neoplasias , Ácidos Nucleicos , Humanos , Epitopos , Antígenos , Neoplasias/terapia , Anticorpos , Antígenos de Superfície , Concentração de Íons de Hidrogênio
3.
Cancer Sci ; 113(12): 4350-4362, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36121618

RESUMO

Antibody-mimetic drug conjugate is a novel noncovalent conjugate consisting of an antibody-mimetic recognizing a target molecule on the cancer cell surface and low-molecular-weight payloads that kill the cancer cells. In this study, the efficacy of a photo-activating antibody-mimetic drug conjugate targeting HER2-expressing tumors was evaluated in mice, by using the affibody that recognize HER2 (ZHER2:342 ) as a target molecule and an axially substituted silicon phthalocyanine (a novel potent photo-activating compound) as a payload. The first treatment with the photo-activating antibody-mimetic drug conjugates reduced the size of all HER2-expressing KPL-4 xenograft tumors macroscopically. However, during the observation period, relapsed tumors gradually appeared in approximately 50% of the animals. To evaluate the efficacy of repeated antibody-mimetic drug conjugate treatment, animals with relapsed tumors were treated again with the same regimen. After the second observation period, the mouse tissues were examined histopathologically. Unexpectedly, all relapsed tumors were eradicated, and all animals were diagnosed with pathological complete remission. After the second treatment, skin wounds healed rapidly, and no significant side effects were observed in other organs, except for occasional microscopic granulomatous tissues beneath the serosa of the liver in a few mice. Repeated treatments seemed to be well tolerated. These results indicate the promising efficacy of the repeated photo-activating antibody-mimetic drug conjugate treatment against HER2-expressing tumors.


Assuntos
Imunoconjugados , Humanos , Animais , Camundongos , Imunoconjugados/farmacologia , Imunoconjugados/uso terapêutico , Receptor ErbB-2/metabolismo , Linhagem Celular Tumoral , Anticorpos
4.
Protein Expr Purif ; 192: 106043, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-34973460

RESUMO

Antibody-drug conjugates (ADCs) are a major therapeutic tool for the treatment of advanced cancer. Malignant cells in advanced cancer often display multiple genetic mutations and become resistant to monotherapy. Therefore, a therapeutic regimen that simultaneously targets multiple molecules with multiple payloads is desirable. However, the development of ADCs is hampered by issues in biopharmaceutical manufacturing and the complexity of the conjugation process of low-molecular-weight payloads to biologicals. Here, we report antibody mimetic-drug conjugates (AMDCs) developed by exploiting the non-covalent binding property of payloads based on high-affinity binding of mutated streptavidin and modified iminobiotin. Miniprotein antibodies were fused to a low immunogenic streptavidin variant, which was then expressed in Escherichia coli inclusion bodies, solubilized, and refolded into functional tetramers. The AMDC developed against human epidermal growth factor receptor 2 (HER2) effectively killed cultured cancer cells using bis-iminobiotin conjugated to photo-activating silicon phthalocyanine. The HER2-targeting AMDC was also effective in vivo against a mouse KPL-4 xenograft model. This AMDC platform provides rapid, stable, and high-yield therapeutics against multiple targets.


Assuntos
Escherichia coli/metabolismo , Expressão Gênica , Imunoconjugados/genética , Animais , Biotina/administração & dosagem , Biotina/análogos & derivados , Biotina/química , Biotina/genética , Biotina/imunologia , Linhagem Celular Tumoral , Clonagem Molecular , Escherichia coli/genética , Humanos , Imunoconjugados/administração & dosagem , Imunoconjugados/química , Imunoconjugados/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias/tratamento farmacológico , Dobramento de Proteína , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/genética , Receptor ErbB-2/imunologia , Estreptavidina/administração & dosagem , Estreptavidina/química , Estreptavidina/genética , Estreptavidina/imunologia
5.
Int J Mol Sci ; 22(3)2021 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-33498253

RESUMO

Ventricular arrhythmia induced by ischemia/reperfusion (I/R) injury is a clinical problem in reperfusion therapies for acute myocardial infarction. Ca2+ overload through reactive oxygen species (ROS) production is a major cause for I/R-induced arrhythmia. We previously demonstrated that canstatin, a C-terminal fragment of type IV collagen α2 chain, regulated Ca2+ handling in rat heart. In this study, we aimed to clarify the effects of canstatin on I/R-induced ventricular arrhythmia in rats. Male Wistar rats were subjected to I/R injury by ligating the left anterior descending artery followed by reperfusion. Ventricular arrhythmia (ventricular tachycardia and ventricular fibrillation) was recorded by electrocardiogram. Nicotinamide adenine dinucleotide phosphate oxidase (NOX) activity and ROS production in neonatal rat cardiomyocytes (NRCMs) stimulated with oxygen glucose deprivation/reperfusion (OGD/R) were measured by lucigenin assay and 2',7'-dichlorodihydrofluorescein diacetate staining, respectively. The H2O2-induced intracellular Ca2+ ([Ca2+]i) rise in NRCMs was measured by a fluorescent Ca2+ indicator. Canstatin (20 µg/kg) inhibited I/R-induced ventricular arrhythmia in rats. Canstatin (250 ng/mL) inhibited OGD/R-induced NOX activation and ROS production and suppressed the H2O2-induced [Ca2+]i rise in NRCMs. We for the first time demonstrated that canstatin exerts a preventive effect against I/R-induced ventricular arrhythmia, perhaps in part through the suppression of ROS production and the subsequent [Ca2+]i rise.


Assuntos
Antiarrítmicos/uso terapêutico , Colágeno Tipo IV/uso terapêutico , Traumatismo por Reperfusão Miocárdica/complicações , Fragmentos de Peptídeos/uso terapêutico , Taquicardia/prevenção & controle , Fibrilação Ventricular/prevenção & controle , Animais , Antiarrítmicos/farmacologia , Cálcio/metabolismo , Células Cultivadas , Colágeno Tipo IV/farmacologia , Masculino , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Fragmentos de Peptídeos/farmacologia , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Taquicardia/tratamento farmacológico , Taquicardia/etiologia , Fibrilação Ventricular/tratamento farmacológico , Fibrilação Ventricular/etiologia
6.
Int J Mol Sci ; 21(18)2020 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-32947968

RESUMO

Pulmonary arterial hypertension (PAH) is a progressive disease which causes right ventricular (RV) failure. Canstatin, a C-terminal fragment of type IV collagen α2 chain, is expressed in various rat organs. However, the expression level of canstatin in plasma and organs during PAH is still unclear. We aimed to clarify it and further investigated the protective effects of canstatin in a rat model of monocrotaline-induced PAH. Cardiac functions were assessed by echocardiography. Expression levels of canstatin in plasma and organs were evaluated by enzyme-linked immunosorbent assay and Western blotting, respectively. PAH was evaluated by catheterization. RV remodeling was evaluated by histological analyses. Real-time polymerase chain reaction was performed to evaluate RV remodeling-related genes. The plasma concentration of canstatin in PAH rats was decreased, which was correlated with a reduction in acceleration time/ejection time ratio and an increase in RV weight/body weight ratio. The protein expression of canstatin in RV, lung and kidney was decreased in PAH rats. While recombinant canstatin had no effect on PAH, it significantly improved RV remodeling, including hypertrophy and fibrosis, and prevented the increase in RV remodeling-related genes. We demonstrated that plasma canstatin is decreased in PAH rats and that administration of canstatin exerts cardioprotective effects.


Assuntos
Cardiotônicos/uso terapêutico , Colágeno Tipo IV/biossíntese , Colágeno Tipo IV/uso terapêutico , Hipertensão Pulmonar/metabolismo , Fragmentos de Peptídeos/uso terapêutico , Remodelação Ventricular/efeitos dos fármacos , Animais , Peso Corporal/efeitos dos fármacos , Colágeno Tipo IV/sangue , Colágeno Tipo IV/genética , Avaliação Pré-Clínica de Medicamentos , Ensaio de Imunoadsorção Enzimática , Fibrose , Ventrículos do Coração/efeitos dos fármacos , Hipertensão Pulmonar/induzido quimicamente , Hipertensão Pulmonar/genética , Hipertrofia , Rim/metabolismo , Pulmão/metabolismo , Pulmão/patologia , Masculino , Monocrotalina/toxicidade , Tamanho do Órgão/efeitos dos fármacos , Ratos , Ratos Wistar , Proteínas Recombinantes/uso terapêutico
7.
Molecules ; 25(17)2020 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-32867091

RESUMO

Chiral tertiary α-hydroxyketones were synthesized with high enantiopurity by asymmetric decarboxylative chlorination and subsequent nucleophilic substitution. We recently reported the asymmetric decarboxylative chlorination of ß-ketocarboxylic acids in the presence of a chiral primary amine catalyst to obtain α-chloroketones with high enantiopurity. Here, we found that nucleophilic substitution of the resulting α-chloroketones with tetrabutylammonium hydroxide yielded the corresponding α-hydroxyketones without loss of enantiopurity. The reaction proceeded smoothly even at a tertiary carbon. The proposed method would be useful for the preparation of chiral tertiary alcohols.


Assuntos
Cetonas/síntese química , Álcoois/síntese química , Catálise , Halogenação , Estrutura Molecular , Fenômenos de Química Orgânica
8.
Proc Jpn Acad Ser B Phys Biol Sci ; 95(10): 602-611, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31827018

RESUMO

In advanced cancer patients, malignant cells invade and disseminate within normal cells and develop resistance to therapy with additional genetic mutations, which makes radical cure very difficult. Precision medicine against advanced cancer is hampered by the lack of systems aimed at multiple target molecules within multiple loci. Here, we report the development of a versatile diagnostic and therapeutic system for advanced cancer, named the Cupid and Psyche system. Based on the strong non-covalent interaction of streptavidin and biotin, a low immunogenic mutated streptavidin, Cupid, and a modified artificial biotin, Psyche, have been designed. Cupid can be fused with various single-chain variable fragment antibodies and forms tetramer to recognize cancer cells precisely. Psyche can be conjugated to a wide range of diagnostic and therapeutic agents against malignant cells. The Cupid and Psyche system can be used in pre-targeting therapy as well as photo-immunotherapy effectively in animal models supporting the concept of a system for precision medicine for multiple targets within multiple loci.


Assuntos
Antineoplásicos/química , Biotina/química , Neoplasias/diagnóstico , Neoplasias/tratamento farmacológico , Estreptavidina/química , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos , Humanos , Imunoterapia , Medicina de Precisão , Anticorpos de Cadeia Única/química
9.
J Comput Assist Tomogr ; 42(5): 767-770, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29613995

RESUMO

Perforation of a peptic ulcer into the ventricle is uncommon, and the definitive diagnosis is difficult in living patients. We herein report a case of perforation of a peptic ulcer in a hiatal hernia into the left ventricle with systemic air and food embolism. This is the first case report of the perforation diagnosed by computed tomography and confirmed by autopsy. Computed tomography was useful for the diagnosis of perforation into the ventricle.


Assuntos
Embolia/complicações , Ventrículos do Coração/diagnóstico por imagem , Ventrículos do Coração/lesões , Hérnia Hiatal/complicações , Úlcera Péptica/complicações , Perfuração Espontânea/complicações , Idoso , Autopsia , Embolia/diagnóstico por imagem , Embolia Aérea/complicações , Embolia Aérea/diagnóstico por imagem , Evolução Fatal , Feminino , Alimentos , Hérnia Hiatal/diagnóstico por imagem , Humanos , Úlcera Péptica/diagnóstico por imagem , Perfuração Espontânea/diagnóstico por imagem , Tomografia Computadorizada por Raios X/métodos
10.
Int J Mol Sci ; 19(3)2018 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-29509663

RESUMO

Myofibroblasts contribute to the healing of infarcted areas after myocardial infarction through proliferation, migration, and production of extracellular matrix (ECM). Expression of endostatin, a cleaved fragment of type XVIII collagen, increases in the heart tissue of an experimental myocardial infarction model. In the present study, we examined the effect of endostatin on the function of myofibroblasts derived from an infarcted area. The myocardial infarction model was created by ligating the left anterior descending artery in rats. Two weeks after the operation, α-smooth muscle actin (α-SMA)-positive myofibroblasts were isolated from the infarcted area. Endostatin significantly increased the proliferation and migration of myofibroblasts in vitro. On the other hand, endostatin had no effect on the production of type I collagen, a major ECM protein produced by myofibroblasts. Endostatin activated Akt and extracellular signal-regulated kinase (ERK), and the pharmacological inhibition of these signaling pathways suppressed the endostatin-induced proliferation and migration. A knockdown of the COL18A1 gene in the myocardial infarction model rats using small interference RNA (siRNA) worsened the cardiac function concomitant with wall thinning and decreased the α-SMA-positive myofibroblasts and scar formation compared with that of control siRNA-injected rats. In summary, we demonstrated for the first time that endostatin might be an important factor in the healing process after myocardial infarction through the activation of myofibroblasts.


Assuntos
Movimento Celular , Proliferação de Células , Endostatinas/farmacologia , Infarto do Miocárdio/metabolismo , Miofibroblastos/efeitos dos fármacos , Animais , Células Cultivadas , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Masculino , Miofibroblastos/metabolismo , Miofibroblastos/fisiologia , Ratos , Ratos Wistar
11.
J Biol Chem ; 291(5): 2319-30, 2016 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-26627827

RESUMO

Epiregulin (EPR) is a ligand of the epidermal growth factor (EGF) family that upon binding to its epidermal growth factor receptor (EGFR) stimulates proliferative signaling, especially in colon cancer cells. Here, we describe the three-dimensional structure of the EPR antibody (the 9E5(Fab) fragment) in the presence and absence of EPR. Among the six complementarity-determining regions (CDRs), CDR1-3 in the light chain and CDR2 in the heavy chain predominantly recognize EPR. In particular, CDR3 in the heavy chain dramatically moves with cis-trans isomerization of Pro(103). A molecular dynamics simulation and mutational analyses revealed that Arg(40) in EPR is a key residue for the specific binding of 9E5 IgG. From isothermal titration calorimetry analysis, the dissociation constant was determined to be 6.5 nm. Surface plasmon resonance analysis revealed that the dissociation rate of 9E5 IgG is extremely slow. The superimposed structure of 9E5(Fab)·EPR on the known complex structure of EGF·EGFR showed that the 9E5(Fab) paratope overlaps with Domains I and III on the EGFR, which reveals that the 9E5(Fab)·EPR complex could not bind to the EGFR. The 9E5 antibody will also be useful in medicine as a neutralizing antibody specific for colon cancer.


Assuntos
Anticorpos Monoclonais Humanizados/química , Anticorpos Monoclonais/química , Anticorpos Monoclonais/imunologia , Epirregulina/química , Animais , Anticorpos Monoclonais Humanizados/imunologia , Calorimetria , Análise Mutacional de DNA , Espectroscopia de Ressonância de Spin Eletrônica , Humanos , Imunoglobulina G/química , Camundongos , Simulação de Dinâmica Molecular , Mutagênese Sítio-Dirigida , Mutação , Ligação Proteica , Estrutura Terciária de Proteína , Proteínas Recombinantes/química , Ressonância de Plasmônio de Superfície
12.
Biol Pharm Bull ; 40(12): 2050-2060, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29199230

RESUMO

The extracellular matrix (ECM), which contributes to structural homeostasis as well as to the regulation of cellular function, is enzymatically cleaved by proteases, such as matrix metalloproteinases and cathepsins, in the normal and diseased heart. During the past two decades, matricryptins have been defined as fragments of ECM with a biologically active cryptic site, namely the 'matricryptic site,' and their biological activities have been initially identified and clarified, including anti-angiogenic and anti-tumor effects. Thus, matricryptins are expected to be novel anti-tumor drugs, and thus widely investigated. Although there are a smaller number of studies on the expression and function of matricryptins in fields other than cancer research, some matricryptins have been recently clarified to have biological functions beyond an anti-angiogenic effect in heart. This review particularly focuses on the expression and function of basement membrane-derived matricryptins, including arresten, canstatin, tumstatin, endostatin and endorepellin, during cardiac diseases leading to heart failure such as cardiac hypertrophy and myocardial infarction.


Assuntos
Proteínas Angiostáticas/metabolismo , Membrana Basal/metabolismo , Matriz Extracelular/metabolismo , Insuficiência Cardíaca/patologia , Miocárdio/metabolismo , Animais , Cardiomegalia/patologia , Colágeno Tipo IV/metabolismo , Humanos , Metaloproteinases da Matriz/metabolismo , Infarto do Miocárdio/patologia , Fragmentos de Peptídeos/metabolismo
13.
Biochem Biophys Res Commun ; 465(4): 725-31, 2015 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-26296461

RESUMO

SET domain, bifurcated 1 (SETDB1) is a histone methyltransferase that methylates lysine 9 on histone H3. Although it is important to know the localization of proteins to elucidate their physiological function, little is known of the subcellular localization of human SETDB1. In the present study, to investigate the subcellular localization of hSETDB1, we established a human cell line constitutively expressing enhanced green fluorescent protein fused to hSETDB1. We then generated a monoclonal antibody against the hSETDB1 protein. Expression of both exogenous and endogenous hSETDB1 was observed mainly in the cytoplasm of various human cell lines. Combined treatment with the nuclear export inhibitor leptomycin B and the proteasome inhibitor MG132 led to the accumulation of hSETDB1 in the nucleus. These findings suggest that hSETDB1, localized in the nucleus, might undergo degradation by the proteasome and be exported to the cytosol, resulting in its detection mainly in the cytosol.


Assuntos
Proteínas Metiltransferases/metabolismo , Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Sequência de Aminoácidos , Linhagem Celular , Núcleo Celular/metabolismo , Citoplasma/metabolismo , Ácidos Graxos Insaturados/farmacologia , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Células HEK293 , Células HeLa , Células Hep G2 , Histona-Lisina N-Metiltransferase , Humanos , Carioferinas/antagonistas & inibidores , Leupeptinas/farmacologia , Dados de Sequência Molecular , Complexo de Endopeptidases do Proteassoma/metabolismo , Inibidores de Proteassoma/farmacologia , Proteínas Metiltransferases/genética , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Deleção de Sequência , Frações Subcelulares/metabolismo , Proteína Exportina 1
14.
Opt Express ; 23(11): 15057-64, 2015 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-26072862

RESUMO

We have developed a 1 kHz repetition picosecond laser system dedicated for intense terahertz (THz) pulse generation. The system comprises a chirped pulse amplification laser equipped with a Yb:YAG thin-disk amplifier. At room temperature, the Yb:YAG thin-disk regenerative amplifier provides pulses having energy of over 10 mJ and spectral bandwidth of 1.2 nm. The pulse duration achieved after passage through a diffraction grating pair compressor was 1.3 ps. By employing this picosecond laser as a pump source, THz pulses having a peak frequency of 0.3 THz and 4 µJ of energy were generated by means of optical rectification in an Mg-doped LiNbO3 crystal.

15.
Biosci Biotechnol Biochem ; 79(4): 640-2, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25560769

RESUMO

The streptavidin/biotin interaction has been widely used as a useful tool in research fields. For application to a pre-targeting system, we previously developed a streptavidin mutant that binds to an iminobiotin analog while abolishing affinity for natural biocytin. Here, we design a bivalent iminobiotin analog that shows 1000-fold higher affinity than before, and determine its crystal structure complexed with the mutant protein.


Assuntos
Biotina/análogos & derivados , Estreptavidina/química , Biotina/síntese química , Biotina/química , Cristalografia por Raios X , Desenho de Fármacos , Modelos Moleculares , Mutação , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas
16.
Dig Endosc ; 27(6): 704-7, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25630914

RESUMO

Placement of a self-expandable metallic stent (SEMS) is recognized as a safe and effective procedure for patients with malignant severe colonic stenosis. However, reports of this stent for right-sided colonic stenosis are limited, possibly as a result of technical difficulties. We report a new method for delivering SEMS to the site of right-sided colonic stenosis in four patients with malignant right-sided colonic stenosis. Technical success was obtained with sequential use of a double-balloon endoscope and ultrathin endoscope, while we also injected non-ionic contrast agent into the submucosal layer as a marker for stenting under fluoroscopy. There were no adverse events noted during the procedure and clinical improvement was seen in all four cases. In conclusion, SEMS placement for right-sided malignant colonic stenosis with our newly developed method appears to be safe and effective, and can be used for decompression of the right colon.


Assuntos
Neoplasias do Colo/complicações , Colonoscópios , Enteroscopia de Duplo Balão/métodos , Obstrução Intestinal/terapia , Stents Metálicos Autoexpansíveis , Idoso , Idoso de 80 Anos ou mais , Neoplasias do Colo/patologia , Dilatação/instrumentação , Dilatação/métodos , Feminino , Seguimentos , Humanos , Obstrução Intestinal/etiologia , Obstrução Intestinal/patologia , Masculino , Desenho de Prótese , Estudos de Amostragem , Resultado do Tratamento
17.
Front Immunol ; 15: 1412918, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39238641

RESUMO

Patients undergoing hemodialysis are particularly vulnerable to severe outcomes of SARS-CoV-2 infection, with mortality rates higher than that of the general population. Vaccination reduces the risk of adverse outcomes, with booster doses being particularly beneficial. However, limited data are available on the effectiveness of subsequent vaccinations or their effect on increasing antibody levels. This single-center study aimed to investigate changes in SARS-CoV-2 IgG antibody titers following the fourth vaccination among 28 patients undergoing hemodialysis. Blood tests were conducted at various intervals post-vaccination, with a focus on identifying factors associated with antibody levels. The IgG antibody levels rapidly increased by Day 7 post-vaccination, with a median time to peak of 11 days. Antibody titers tended to be higher in male patients than in female patients. This study sheds light on the immune response to the fourth vaccination in patients undergoing hemodialysis. As this study included a small sample size, with a short observation period, further research is warranted to comprehensively understand the effectiveness of vaccination and the benefits of additional doses of vaccine.


Assuntos
Anticorpos Antivirais , Vacina BNT162 , COVID-19 , Imunoglobulina G , Diálise Renal , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Vacina BNT162/imunologia , Vacina BNT162/administração & dosagem , COVID-19/imunologia , COVID-19/prevenção & controle , População do Leste Asiático , Imunização Secundária , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Japão/epidemiologia , Glicoproteína da Espícula de Coronavírus/imunologia , Vacinação
18.
Vaccine X ; 20: 100553, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39309610

RESUMO

Background: Understanding the waning of immunity after booster vaccinations is important to identify which immune-low populations should be prioritized. Methods: We investigated longitudinal cellular and humoral immunity after the third vaccine dose in both high- and low-cellular and humoral immunity groups at the peak immunity phase after the booster vaccination in a large community-based cohort. Blood samples were collected from 1045 participants at peak (T1: median 54 days post-third dose) and decay (T2: median 145 days post-third dose) phases to assess IgG(S), neutralizing activity, and ELISpot responses. Participants were categorized into high/low ELISpot/IgG(S) groups at T1. Cellular and humoral responses were tracked for approximately five months after the third vaccination. Results: In total, 983 participants were included in the cohort. IgG(S) geometric mean fold change between timepoints revealed greater waning in the >79 years age group (T2/T1 fold change: 0.27) and higher IgG(S) fold change in the low-ELISpot group at T1 (T2/T1 fold change: 0.32-0.33) than in the other groups, although ELISpot geometric mean remained stable. Conclusions: Antibody level of those who did not respond well to third dose vaccination waned rapidly than those who responded well. Evidence-based vaccine strategies are essential in preventing potential health issues caused by vaccines, including side-effects.

19.
PLOS Digit Health ; 3(5): e0000497, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38701055

RESUMO

As we learned during the COVID-19 pandemic, vaccines are one of the most important tools in infectious disease control. To date, an unprecedentedly large volume of high-quality data on COVID-19 vaccinations have been accumulated. For preparedness in future pandemics beyond COVID-19, these valuable datasets should be analyzed to best shape an effective vaccination strategy. We are collecting longitudinal data from a community-based cohort in Fukushima, Japan, that consists of 2,407 individuals who underwent serum sampling two or three times after a two-dose vaccination with either BNT162b2 or mRNA-1273. Using the individually reconstructed time courses of the vaccine-elicited antibody response based on mathematical modeling, we first identified basic demographic and health information that contributed to the main features of the antibody dynamics, i.e., the peak, the duration, and the area under the curve. We showed that these three features of antibody dynamics were partially explained by underlying medical conditions, adverse reactions to vaccinations, and medications, consistent with the findings of previous studies. We then applied to these factors a recently proposed computational method to optimally fit an "antibody score", which resulted in an integer-based score that can be used as a basis for identifying individuals with higher or lower antibody titers from basic demographic and health information. The score can be easily calculated by individuals themselves or by medical practitioners. Although the sensitivity of this score is currently not very high, in the future, as more data become available, it has the potential to identify vulnerable populations and encourage them to get booster vaccinations. Our mathematical model can be extended to any kind of vaccination and therefore can form a basis for policy decisions regarding the distribution of booster vaccines to strengthen immunity in future pandemics.

20.
Biochem Biophys Res Commun ; 441(4): 1011-7, 2013 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-24239549

RESUMO

Growth factors are implicated in several processes essential for cancer progression. Specifically, epidermal growth factor (EGF) family members, including epiregulin (EREG), are important prognostic factors in many epithelial cancers, and treatments targeting these molecules have recently become available. Here, we constructed and expressed humanized anti-EREG antibodies by variable domain resurfacing based on the three-dimensional (3D) structure of the Fv fragment. However, the initial humanized antibody (HM0) had significantly decreased antigen-binding affinity. Molecular modeling results suggested that framework region (FR) residues latently important to antigen binding included residue 49 of the light chain variable region (VL). Back mutation of the VL49 residue (tyrosine to histidine) generated the humanized version HM1, which completely restored the binding affinity of its murine counterpart. Importantly, only one mutation in the framework may be necessary to recover the binding capability of a humanized antibody. Our data support that HM1 exerts potent antibody-dependent cellular cytotoxicity (ADCC). Hence, this antibody may have potential for further development as a candidate therapeutic agent and research tool.


Assuntos
Anticorpos Monoclonais Humanizados/biossíntese , Fator de Crescimento Epidérmico/imunologia , Sequência de Aminoácidos , Anticorpos Monoclonais Humanizados/química , Anticorpos Monoclonais Humanizados/imunologia , Fator de Crescimento Epidérmico/antagonistas & inibidores , Epirregulina , Células HCT116 , Humanos , Região Variável de Imunoglobulina/biossíntese , Região Variável de Imunoglobulina/química , Região Variável de Imunoglobulina/imunologia , Células Jurkat , Luciferases/biossíntese , Modelos Moleculares , Dados de Sequência Molecular , Fatores de Transcrição NFATC/metabolismo , Engenharia de Proteínas , Receptores de IgG/biossíntese
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