Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 3.015
Filtrar
1.
PLoS One ; 16(8): e0255976, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34411149

RESUMO

BACKGROUND: Cardiac injury associated with cytokine release frequently occurs in SARS-CoV-2 mediated coronavirus disease (COVID19) and mortality is particularly high in these patients. The mechanistic role of the COVID19 associated cytokine-storm for the concomitant cardiac dysfunction and associated arrhythmias is unclear. Moreover, the role of anti-inflammatory therapy to mitigate cardiac dysfunction remains elusive. AIMS AND METHODS: We investigated the effects of COVID19-associated inflammatory response on cardiac cellular function as well as its cardiac arrhythmogenic potential in rat and induced pluripotent stem cell derived cardiomyocytes (iPS-CM). In addition, we evaluated the therapeutic potential of the IL-1ß antagonist Canakinumab using state of the art in-vitro confocal and ratiometric high-throughput microscopy. RESULTS: Isolated rat ventricular cardiomyocytes were exposed to control or COVID19 serum from intensive care unit (ICU) patients with severe ARDS and impaired cardiac function (LVEF 41±5%; 1/3 of patients on veno-venous extracorporeal membrane oxygenation; CK 154±43 U/l). Rat cardiomyocytes showed an early increase of myofilament sensitivity, a decrease of Ca2+ transient amplitudes and altered baseline [Ca2+] upon exposure to patient serum. In addition, we used iPS-CM to explore the long-term effect of patient serum on cardiac electrical and mechanical function. In iPS-CM, spontaneous Ca2+ release events were more likely to occur upon incubation with COVID19 serum and nuclear as well as cytosolic Ca2+ release were altered. Co-incubation with Canakinumab had no effect on pro-arrhythmogenic Ca2+ release or Ca2+ signaling during excitation-contraction coupling, nor significantly influenced cellular automaticity. CONCLUSION: Serum derived from COVID19 patients exerts acute cardio-depressant and chronic pro-arrhythmogenic effects in rat and iPS-derived cardiomyocytes. Canakinumab had no beneficial effect on cellular Ca2+ signaling during excitation-contraction coupling. The presented method utilizing iPS-CM and in-vitro Ca2+ imaging might serve as a novel tool for precision medicine. It allows to investigate cytokine related cardiac dysfunction and pharmacological approaches useful therein.


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Arritmias Cardíacas , COVID-19 , Sinalização do Cálcio/efeitos dos fármacos , Miócitos Cardíacos , SARS-CoV-2/metabolismo , Adulto , Idoso , Animais , Arritmias Cardíacas/etiologia , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/patologia , COVID-19/complicações , COVID-19/tratamento farmacológico , COVID-19/metabolismo , COVID-19/patologia , Cálcio/metabolismo , Avaliação Pré-Clínica de Medicamentos , Feminino , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Pluripotentes Induzidas/patologia , Masculino , Pessoa de Meia-Idade , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Ratos , Ratos Sprague-Dawley , Disfunção Ventricular Esquerda/tratamento farmacológico , Disfunção Ventricular Esquerda/etiologia , Disfunção Ventricular Esquerda/metabolismo , Disfunção Ventricular Esquerda/patologia
4.
Oncology ; 99(9): 562-570, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34237736

RESUMO

BACKGROUND: Among patients with non-small cell lung cancer (NSCLC), the impact of first-line treatment on overall survival (OS) may be influenced by subsequent therapies. Thus, using patient-level data, we assessed the relationships of progression-free survival (PFS) and post-progression survival (PPS) with OS among patients with high-programmed death-ligand 1 (PD-L1) expression undergoing first-line pembrolizumab monotherapy for NSCLC. METHODS: We reviewed data from 133 patients with high PD-L1 expression undergoing first-line pembrolizumab monotherapy for NSCLC at 6 Japanese centers between February 2017 and December 2018. The correlations of PFS and PPS with OS were evaluated at the patient level. RESULTS: Linear regression analyses and Spearman's rank correlation coefficient revealed that PPS was strongly correlated with OS (r = 0.76, p < 0.05, R2 = 0.65), while PFS was only moderately correlated with OS (r = 0.71, p < 0.05, and R2 = 0.4). Furthermore, PPS was significantly associated with performance status at the end of pembrolizumab monotherapy, as well as the use of platinum-based combination chemotherapy after pembrolizumab monotherapy (both p < 0.05). CONCLUSIONS: Among patients with high PD-L1 expression undergoing first-line pembrolizumab monotherapy for NSCLC, PPS was more strongly correlated with OS, relative to the relationship between PFS and OS. Therefore, subsequent treatment appears to significantly influence OS in patients with disease progression following first-line pembrolizumab monotherapy.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/farmacologia , Antineoplásicos Imunológicos/farmacologia , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Análise de Sobrevida
5.
Nat Commun ; 12(1): 4172, 2021 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-34234141

RESUMO

Cell-free DNA (cfDNA) is attractive for many applications, including detecting cancer, identifying the tissue of origin, and monitoring. A fundamental task underlying these applications is SNV calling from cfDNA, which is hindered by the very low tumor content. Thus sensitive and accurate detection of low-frequency mutations (<5%) remains challenging for existing SNV callers. Here we present cfSNV, a method incorporating multi-layer error suppression and hierarchical mutation calling, to address this challenge. Furthermore, by leveraging cfDNA's comprehensive coverage of tumor clonal landscape, cfSNV can profile mutations in subclones. In both simulated and real patient data, cfSNV outperforms existing tools in sensitivity while maintaining high precision. cfSNV enhances the clinical utilities of cfDNA by improving mutation detection performance in medium-depth sequencing data, therefore making Whole-Exome Sequencing a viable option. As an example, we demonstrate that the tumor mutation profile from cfDNA WES data can provide an effective biomarker to predict immunotherapy outcomes.


Assuntos
DNA Tumoral Circulante/genética , Análise Mutacional de DNA/métodos , Inibidores de Checkpoint Imunológico/farmacologia , Neoplasias/genética , Sequenciamento Completo do Exoma/métodos , Adulto , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Biópsia , DNA Tumoral Circulante/sangue , Simulação por Computador , Conjuntos de Dados como Assunto , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Masculino , Pessoa de Meia-Idade , Mutação , Neoplasias/sangue , Neoplasias/tratamento farmacológico , Neoplasias/mortalidade , Polimorfismo de Nucleotídeo Único , Prognóstico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Intervalo Livre de Progressão , Sensibilidade e Especificidade
6.
Cell Rep ; 36(3): 109415, 2021 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-34270919

RESUMO

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants threatens efforts to contain the coronavirus disease 2019 (COVID-19) pandemic. The number of COVID-19 cases and deaths in India has risen steeply, and a SARS-CoV-2 variant, B.1.617, is believed to be responsible for many of these cases. The spike protein of B.1.617 harbors two mutations in the receptor binding domain, which interacts with the angiotensin converting enzyme 2 (ACE2) receptor and constitutes the main target of neutralizing antibodies. Therefore, we analyze whether B.1.617 is more adept in entering cells and/or evades antibody responses. B.1.617 enters two of eight cell lines tested with roughly 50% increased efficiency and is equally inhibited by two entry inhibitors. In contrast, B.1.617 is resistant against bamlanivimab, an antibody used for COVID-19 treatment. B.1.617 evades antibodies induced by infection or vaccination, although less so than the B.1.351 variant. Collectively, our study reveals that antibody evasion of B.1.617 may contribute to the rapid spread of this variant.


Assuntos
Enzima de Conversão de Angiotensina 2/farmacologia , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Antivirais/farmacologia , COVID-19/tratamento farmacológico , Ésteres/farmacologia , Guanidinas/farmacologia , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Anticorpos Monoclonais Humanizados/imunologia , Anticorpos Antivirais/imunologia , COVID-19/imunologia , Linhagem Celular , Humanos , Inibidores de Proteases/farmacologia , Ligação Proteica , SARS-CoV-2/genética , SARS-CoV-2/patogenicidade , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/genética , Vacinação
7.
Int J Mol Sci ; 22(14)2021 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-34299325

RESUMO

Extramammary Paget's disease (EMPD) is a rare skin cancer arising in the apocrine gland-rich areas. Most EMPD tumors are dormant, but metastatic lesions are associated with poor outcomes owing to the lack of effective systemic therapies. Trophoblast cell surface antigen 2 (Trop2), a surface glycoprotein, has drawn attention as a potential therapeutic target for solid tumors. Sacituzumab govitecan, an antibody-drug conjugate of Trop2, has recently entered clinical use for the treatment of various solid cancers. However, little is known about the role of Trop2 in EMPD. In this study, we immunohistochemically examined Trop2 expression in 116 EMPD tissue samples and 10 normal skin tissues. In normal skin, Trop2 was expressed in the epidermal keratinocytes, inner root sheaths, and infundibulum/isthmus epithelium of hair follicles, eccrine/apocrine glands, and sebaceous glands. Most EMPD tissues exhibited homogeneous and strong Trop2 expression, and high Trop2 expression was significantly associated with worse disease-free survival (p = 0.0343). These results suggest the potential use of Trop2-targeted therapy for EMPD and improve our understanding of the skin-related adverse effects of current Trop2-targeted therapies such as sacituzumab govitecan.


Assuntos
Antígenos de Neoplasias/biossíntese , Moléculas de Adesão Celular/biossíntese , Doença de Paget Extramamária/metabolismo , Neoplasias Cutâneas/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/farmacologia , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/metabolismo , Glândulas Apócrinas/metabolismo , Biomarcadores Tumorais , Camptotecina/análogos & derivados , Camptotecina/farmacologia , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/metabolismo , Feminino , Expressão Gênica/genética , Regulação da Expressão Gênica/genética , Folículo Piloso/metabolismo , Humanos , Imunoconjugados/farmacologia , Queratinócitos/metabolismo , Masculino , Glicoproteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Doença de Paget Extramamária/tratamento farmacológico , Doença de Paget Extramamária/genética , Doença de Paget Extramamária/patologia , Glândulas Sebáceas/metabolismo , Pele/metabolismo , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia
8.
Ann Clin Transl Neurol ; 8(8): 1738-1744, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34240579

RESUMO

We evaluated the effect of DMTs on Covid-19 severity in patients with MS, with a pooled-analysis of two large cohorts from Italy and France. The association of baseline characteristics and DMTs with Covid-19 severity was assessed by multivariate ordinal-logistic models and pooled by a fixed-effect meta-analysis. 1066 patients with MS from Italy and 721 from France were included. In the multivariate model, anti-CD20 therapies were significantly associated (OR = 2.05, 95%CI = 1.39-3.02, p < 0.001) with Covid-19 severity, whereas interferon indicated a decreased risk (OR = 0.42, 95%CI = 0.18-0.99, p = 0.047). This pooled-analysis confirms an increased risk of severe Covid-19 in patients on anti-CD20 therapies and supports the protective role of interferon.


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , COVID-19/fisiopatologia , Fatores Imunológicos/farmacologia , Interferons/farmacologia , Esclerose Múltipla/tratamento farmacológico , Rituximab/farmacologia , Adulto , Anticorpos Monoclonais Humanizados/efeitos adversos , COVID-19/epidemiologia , Feminino , França/epidemiologia , Humanos , Fatores Imunológicos/efeitos adversos , Interferons/efeitos adversos , Itália/epidemiologia , Masculino , Metanálise como Assunto , Pessoa de Meia-Idade , Esclerose Múltipla/epidemiologia , Análise Multivariada , Fatores de Proteção , Estudos Retrospectivos , Fatores de Risco , Rituximab/efeitos adversos , Índice de Gravidade de Doença
9.
Int J Mol Sci ; 22(13)2021 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-34201664

RESUMO

The paradigm of psoriasis as a Th17-driven disease has evolved in the last years towards a much deeper knowledge of the complex pathways, mechanisms, cells, and messengers involved, highlighting the crucial role played by the IL-17 family of cytokines. All IL-17 isoforms signal through IL-17R. Five subunits of IL-17R have been described to date, which couple to form a homo- or hetero-receptor complex. Characteristically, IL-17RA is a common subunit in all hetero-receptors. IL-17RA has unique structural-containing a SEFIR/TILL domain-and functional-requiring ACT-1 for signaling-properties, enabling Th17 cells to act as a bridge between innate and adaptive immune cells. In psoriasis, IL-17RA plays a key role in pathogenesis based on: (a) IL-17A, IL-17F, and other IL-17 isoforms are involved in disease development; and (b) IL-17RA is essential for signaling of all IL-17 cytokines but IL-17D, whose receptor has not been identified to date. This article reviews current evidence on the biology and role of the IL-17 family of cytokines and receptors, with focus on IL-17RA, in psoriasis and some related comorbidities, and puts them in context with current and upcoming treatments.


Assuntos
Psoríase/tratamento farmacológico , Psoríase/etiologia , Receptores de Interleucina-17/fisiologia , Anticorpos Monoclonais Humanizados/farmacologia , Humanos , Interleucina-17/imunologia , Interleucina-17/metabolismo , Isoformas de Proteínas
10.
Indian J Pharmacol ; 53(3): 226-228, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34169908

RESUMO

Although many potent drugs have been used for cytokine storm, mortality is high for patients with coronavirus disease-2019 (COVID-19), which is followed up in the intensive care unit. Interferons (IFNs) are the major cytokines of the antiviral defense system released from many cell types. However, IFN-γ plays a key role in both primary and secondary cytokine storms. If the cytokine storm is not treated urgently, it will be fatal; therefore, it should be treated immediately. Anakinra, an interleukin-1 (IL-1) antagonist, tocilizumab, an IL-6 antagonist, and Janus kinase (JAK) inhibitors are successfully used in cytokine storm caused by COVID-19. However, sometimes, despite these treatments, the patient's clinical course does not improve. Emapalumab (Eb) is the human immunoglobulin G1 monoclonal antibody and is a potent and noncompetitive antagonist of IFN-γ. Eb can be life saving for cytokine storm caused by COVID-19, which is resistant to anakinra, tocilizumab, and JAK inhibitors.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Anticorpos Neutralizantes/uso terapêutico , COVID-19/tratamento farmacológico , Síndrome da Liberação de Citocina/tratamento farmacológico , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Inibidores de Janus Quinases/uso terapêutico , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Neutralizantes/farmacologia , Antirreumáticos/farmacologia , Antirreumáticos/uso terapêutico , COVID-19/epidemiologia , COVID-19/imunologia , Síndrome da Liberação de Citocina/epidemiologia , Síndrome da Liberação de Citocina/imunologia , Progressão da Doença , Farmacorresistência Viral , Humanos , Interferon gama/antagonistas & inibidores , Interferon gama/imunologia , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Interleucinas/antagonistas & inibidores , Interleucinas/imunologia , Inibidores de Janus Quinases/farmacologia , Recidiva
11.
Medicine (Baltimore) ; 100(25): e26471, 2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34160456

RESUMO

RATIONALE: Advanced hepatocellular carcinoma (HCC) remains a deadly disease in part due to decades of limited therapeutic options. With recent advances in our understanding of the tumor biology, several promising treatment strategies involving targeted and immunotherapies have emerged. However, enhancing their modest efficacy in HCC and other gastrointestinal malignancies is essential to improving survival. PATIENT CONCERNS: A man in his late 50s with a history of type 2 diabetes mellitus and morbid obesity initially presented with progressive abdominal pain and anorexia prompting an abdominal computed tomography scan that revealed a large solitary liver mass with extensive local involvement. DIAGNOSES: Although there were features consistent with a primary gastric tumor on subsequent endoscopic evaluation leading to early diagnostic uncertainty, his clinical picture, including a dominant liver mass, immunohistochemical staining profile, and significantly elevated alpha fetoprotein ultimately favored HCC. INTERVENTIONS: The patient received palliative systemic therapy with infusional fluorouracil for a presumed gastric primary, however restaging scans after 3 cycles demonstrated disease progression. The consensus from a multidisciplinary discussion was that his pathology was more consistent with primary HCC. He was subsequently started on nivolumab with a partial response, although after 5 months, he progressed prompting initiation of second-line atezolizumab and bevacizumab with a favorable response. OUTCOMES: The addition of atezolizumab and bevacizumab led to a sustained biochemical and radiographic response that appeared to overcome the resistance to nivolumab monotherapy. Aside from several mild immune-related adverse effects, his quality of life has greatly improved and he has tolerated treatment well to date. LESSONS: Our findings suggest that vascular endothelial growth factor inhibition can overcome resistance to checkpoint inhibition in advanced HCC by resulting in a unique synergy that has never before been described in patients. The biological rationale for this response is likely attributable to the immunomodulatory effects of antiangiogenic agents, promoting an immunostimulatory microenvironment that can be exploited by immune checkpoint inhibitors for more effective antitumor activity. Given the considerable benefit patients may derive following progression on first-line treatment, it is important to consider this strategic combination of therapies which can ultimately lead to improved patient outcomes.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Hepáticas/tratamento farmacológico , Inibidores da Angiogênese/farmacologia , Inibidores da Angiogênese/uso terapêutico , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Bevacizumab/farmacologia , Bevacizumab/uso terapêutico , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/imunologia , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Fígado/diagnóstico por imagem , Fígado/patologia , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/imunologia , Masculino , Pessoa de Meia-Idade , Nivolumabe/farmacologia , Nivolumabe/uso terapêutico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores
13.
Cancer Sci ; 112(8): 2984-2992, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34107132

RESUMO

Delta-like canonical Notch ligand 3 (DLL3) is a member of the Delta/Serrate/Lag2 (DSL) Notch receptor ligand family and plays a crucial role in Notch signaling, which influences various cellular processes including differentiation, proliferation, survival, and apoptosis. DLL3 is expressed throughout the presomitic mesoderm and is localized to the rostral somatic compartments; mutations in DLL3 induce skeletal abnormalities such as spondylocostal dysostosis. Recently, DLL3 has attracted interest as a novel molecular target due to its high expression in neuroendocrine carcinoma of the lung. Moreover, a DLL3-targeting Ab-drug conjugate, rovalpituzumab tesirine (ROVA-T), has been developed as a new treatment with proven antitumor activity. However, the development of ROVA-T was suspended because of shorter overall survival compared to topotecan, the second-line standard treatment. Thus, several studies on the mechanism and function of DLL3 in several malignancies are underway to find a new strategy for targeting DLL3. In this review, we discuss the roles of DLL3 in various malignancies and the future perspectives of DLL3-related research, especially as a therapeutic target.


Assuntos
Antineoplásicos/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas de Membrana/genética , Neoplasias/tratamento farmacológico , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/uso terapêutico , Benzodiazepinonas/farmacologia , Benzodiazepinonas/uso terapêutico , Ensaios Clínicos como Assunto , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Imunoconjugados/farmacologia , Imunoconjugados/uso terapêutico , Peptídeos e Proteínas de Sinalização Intracelular/efeitos dos fármacos , Masculino , Proteínas de Membrana/efeitos dos fármacos , Terapia de Alvo Molecular , Mutação , Neoplasias/genética
14.
Front Immunol ; 12: 611256, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34079536

RESUMO

Ulcerative colitis (UC) is a chronic relapsing disorder of the colonic tract, characterized by a dysregulated innate and adaptive immune response to gut microbiota that contributes to the perpetuation of intestinal inflammatory processes. The Interleukin (IL) 23/IL17 axis has been reported to play a key role in UC pathogenesis promoting Th17 cells and cytokines-related immune response. Recently, the blockade of IL23/IL17 pathways has been raised enormous interest in the treatment o several chronic inflammatory disorders. In this review, we summarize the emerging results from clinical trials that evoked both promise and discouragement in IL23/IL17 axis in the treatment of UC. Targeting IL23 p40 through Ustekinumab results safe and effective to induce and maintain clinical remission, low inflammatory indexes, mucosal healing, and a better quality of life. Studies targeting IL23 p19 through Mirikizumab, Risankizumab, Brazikumab and Guselkumab are still ongoing. To date, no clinical studies targeting IL17 pathway are ongoing in UC. IL-17 targeting is thought to have a context-dependent biological effect, based on whether cytokine is selectively targeted or if its function is dampened by the upstream block of IL23.


Assuntos
Colite Ulcerativa/imunologia , Colite Ulcerativa/metabolismo , Imunomodulação/efeitos dos fármacos , Interleucina-17/metabolismo , Interleucina-23/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Colite Ulcerativa/diagnóstico , Colite Ulcerativa/tratamento farmacológico , Gerenciamento Clínico , Suscetibilidade a Doenças , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/imunologia , Humanos , Terapia de Alvo Molecular , Resultado do Tratamento , Ustekinumab/farmacologia , Ustekinumab/uso terapêutico
15.
Nat Commun ; 12(1): 3343, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-34099693

RESUMO

In the absence of a prophylactic vaccine, the use of antiretroviral therapy (ART) as pre-exposure prophylaxis (PrEP) to prevent HIV acquisition by uninfected individuals is a promising approach to slowing the epidemic, but its efficacy is hampered by incomplete patient adherence and ART-resistant variants. Here, we report that competitive inhibition of HIV Env-CCR5 binding via the CCR5-specific antibody Leronlimab protects rhesus macaques against infection following repeated intrarectal challenges of CCR5-tropic SHIVSF162P3. Injection of Leronlimab weekly at 10 mg/kg provides significant but partial protection, while biweekly 50 mg/kg provides complete protection from SHIV acquisition. Tissue biopsies from protected macaques post challenge show complete CCR5 receptor occupancy and an absence of viral nucleic acids. After Leronlimab washout, protected macaques remain aviremic, and adoptive transfer of hematologic cells into naïve macaques does not transmit viral infection. These data identify CCR5 blockade with Leronlimab as a promising approach to HIV prophylaxis and support initiation of clinical trials.


Assuntos
Receptores CCR5/metabolismo , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/transmissão , Vírus da Imunodeficiência Símia/imunologia , Animais , Anticorpos Monoclonais Humanizados/farmacologia , Linfócitos T CD4-Positivos , Linfócitos T CD8-Positivos , Feminino , Anticorpos Anti-HIV/farmacologia , Infecções por HIV , Humanos , Macaca mulatta , Masculino , Membrana Mucosa , Profilaxia Pré-Exposição , Carga Viral
16.
Mol Immunol ; 135: 320-328, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33971510

RESUMO

Using antibody drug conjugates (ADC) which can exclusively bind to their target cells and upon internalization release their toxic agent, is one of the most effective methods for killing tumor cells. Therefore, increasing the internalization rate is an important factor for tumor treatment in this case. The aim of the present study was to develop a new variant of pertuzumab (an anti-ErbB2 humanized antibody) with higher internalization rate that can be a good candidate for the production of ADC. To this end, the Human Immunodeficiency Virus TAT Protein Transduction Domain (TAT-PTD) was replaced into the structure of the pertuzumab. At first, the best site in antibody heavy chain constant region for the replacement of TAT-PTD was predicted through computational methods. Then, the resulting recombinant antibody, of which TAT-PTD was located at amino acid position 130-140 and named Tatibody, was produced in CHO-S cell line. Finally, its physicochemical properties and biological activities were evaluated and compared with pertuzumab. Results showed that the binding ability of Tatibody to the ErbB2 receptor is similar to that of pertuzumab, but its internalization potency is 3.6 fold higher and can be used as a good candidate for ADC construction.


Assuntos
Anticorpos Monoclonais Humanizados/genética , Anticorpos Monoclonais Humanizados/farmacologia , Antineoplásicos Imunológicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Proteínas Recombinantes/genética , Produtos do Gene tat do Vírus da Imunodeficiência Humana/genética , Animais , Anticorpos Monoclonais Humanizados/imunologia , Afinidade de Anticorpos/imunologia , Células CHO , Linhagem Celular Tumoral , Cricetulus , Feminino , Humanos , Cadeias Pesadas de Imunoglobulinas/genética , Cadeias Pesadas de Imunoglobulinas/imunologia , Simulação de Acoplamento Molecular , Conformação Proteica , Transporte Proteico/genética , Transporte Proteico/fisiologia , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/imunologia , Proteínas Recombinantes/imunologia
17.
Lung ; 199(3): 239-248, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34050796

RESUMO

BACKGROUND: To date, only dexamethasone has been shown to reduce mortality in coronavirus disease-19 (COVID-19) patients. Tocilizumab has been recently added to the treatment guidelines for hospitalized COVID-19 patients, but data remain conflicting. STUDY DESIGN AND METHODS: Electronic databases such as MEDLINE, EMBASE, and Cochrane central were searched from March 1, 2020, until March 10, 2021, for randomized controlled trials evaluating the efficacy of tocilizumab in hospitalized COVID-19 patients. The outcomes assessed were all-cause mortality, mechanical ventilation, and time to discharge. RESULTS: Nine studies (with 6490 patients) were included in the analysis. In total, 3358 patients received tocilizumab, and 3132 received standard care/placebo. Pooled analysis showed a significantly decreased risk of all-cause mortality (RR 0.89, 95% CI 0.80-0.98, p = 0.02) and progression to mechanical ventilation (RR 0.80, 95% CI 0.71-0.89, p < 0.0001) in the tocilizumab arm compared to standard therapy or placebo. In addition, there was a trend towards improved median time to hospital discharge (RR 1.28, 95% CI 1.12-1.45, p = 0.0002). CONCLUSIONS: Tocilizumab therapy improves outcomes of mortality and need for mechanical ventilation, in hospitalized patients with COVID-19 infection compared with standard therapy or placebo. Our findings suggest the efficacy of tocilizumab therapy in hospitalized COVID-19 patients and strengthen the concept that tocilizumab is a promising therapeutic intervention to improve mortality and morbidity in COVID-19 patients.


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , COVID-19 , Receptores de Interleucina-6/antagonistas & inibidores , COVID-19/tratamento farmacológico , COVID-19/imunologia , COVID-19/mortalidade , Humanos , Fatores Imunológicos/farmacologia , Avaliação de Resultados em Cuidados de Saúde , SARS-CoV-2
18.
Sci Rep ; 11(1): 10220, 2021 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-33986382

RESUMO

The urgent need for a treatment of COVID-19 has left researchers with limited choice of either developing an effective vaccine or identifying approved/investigational drugs developed for other medical conditions for potential repurposing, thus bypassing long clinical trials. In this work, we compared the sequences of experimentally verified SARS-CoV-2 neutralizing antibodies and sequentially/structurally similar commercialized therapeutic monoclonal antibodies. We have identified three therapeutic antibodies, Tremelimumab, Ipilimumab and Afasevikumab. Interestingly, these antibodies target CTLA4 and IL17A, levels of which have been shown to be elevated during severe SARS-CoV-2 infection. The candidate antibodies were evaluated further for epitope restriction, interaction energy and interaction surface to gauge their repurposability to tackle SARS-CoV-2 infection. Our work provides candidate antibody scaffolds with dual activities of plausible viral neutralization and immunosuppression. Further, these candidate antibodies can also be explored in diagnostic test kits for SARS-CoV-2 infection. We opine that this in silico workflow to screen and analyze antibodies for repurposing would have widespread applications.


Assuntos
Anticorpos Monoclonais/farmacologia , Anticorpos Neutralizantes/farmacologia , COVID-19/tratamento farmacológico , Reposicionamento de Medicamentos , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais Humanizados/imunologia , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Neutralizantes/imunologia , COVID-19/imunologia , Reposicionamento de Medicamentos/métodos , Epitopos/imunologia , Humanos , Ipilimumab/imunologia , Ipilimumab/farmacologia , Simulação de Acoplamento Molecular , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia
19.
Clin Immunol ; 227: 108728, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33878452

RESUMO

OBJECTIVE: To investigate the relationship between lncRNA PVT1(PVT1) level and PD-L1 expression and their functions in cisplatin resistant epithelial ovarian cancer (CREOC). METHODS: PVT1 and PD-L1 in ovarian cancer tissues were detected and analyzed. The cells proliferation, apoptosis, invasion abilities and potential mechanism were detected by cell functional experiments and western-blot assay, respectively. RESULTS: The average expressions of PVT1 and PD-L1 in CREOC tissues were significantly higher. The expression of PVT1 is positively associated with PD-L1 in CREOC. Higher expressions of PVT1 and PD-L1 indicated more malignant clinical behavior and shorter PFS and OS. Knockdown of PVT1 inhibited the proliferation and invasion and promote apoptosis for A2780cis cells, which may be related to decrease the expression of PD-L1 via repressing JAK2/STAT3 pathway. CONCLUSIONS: The synergistic therapeutic strategy using LncRNA PVT1-targeted therapy and immune checkpoint blockade of PD-L1 warrant study further for ovarian cancer patients with cisplatin resistant recurrence.


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Antígeno B7-H1/genética , Carcinoma Epitelial do Ovário/genética , Inibidores de Checkpoint Imunológico/farmacologia , Janus Quinase 2/efeitos dos fármacos , Neoplasias Ovarianas/genética , RNA Longo não Codificante/genética , Fator de Transcrição STAT3/efeitos dos fármacos , Adulto , Idoso , Antineoplásicos , Apoptose/efeitos dos fármacos , Apoptose/genética , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/metabolismo , Carcinoma Epitelial do Ovário/tratamento farmacológico , Carcinoma Epitelial do Ovário/metabolismo , Estudos de Casos e Controles , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Cisplatino , Resistencia a Medicamentos Antineoplásicos , Feminino , Técnicas de Silenciamento de Genes , Humanos , Janus Quinase 2/metabolismo , Pessoa de Meia-Idade , Invasividade Neoplásica , Recidiva Local de Neoplasia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Intervalo Livre de Progressão , RNA Longo não Codificante/antagonistas & inibidores , RNA Longo não Codificante/metabolismo , RNA Interferente Pequeno , Reação em Cadeia da Polimerase em Tempo Real , Estudos Retrospectivos , Fator de Transcrição STAT3/metabolismo
20.
Int J Mol Sci ; 22(6)2021 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-33802761

RESUMO

Among patients suffering from coronavirus disease 2019 (COVID-19) syndrome, one of the worst possible scenarios is represented by the critical lung damage caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-induced cytokine storm, responsible for a potentially very dangerous hyperinflammatory condition. Within such a context, interleukin-6 (IL-6) plays a key pathogenic role, thus being a suitable therapeutic target. Indeed, the IL-6-receptor antagonist tocilizumab, already approved for treatment of refractory rheumatoid arthritis, is often used to treat patients with severe COVID-19 symptoms and lung involvement. Therefore, the aim of this review article is to focus on the rationale of tocilizumab utilization in the SARS-CoV-2-triggered cytokine storm, as well as to discuss current evidence and future perspectives, especially with regard to ongoing trials referring to the evaluation of tocilizumab's therapeutic effects in patients with life-threatening SARS-CoV-2 infection.


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , COVID-19/tratamento farmacológico , Síndrome da Liberação de Citocina/tratamento farmacológico , SARS-CoV-2/imunologia , Anticorpos Monoclonais Humanizados/química , COVID-19/complicações , COVID-19/imunologia , COVID-19/fisiopatologia , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/fisiopatologia , Humanos , Interleucina-6/antagonistas & inibidores , Interleucina-6/fisiologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...