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1.
J Nucl Med ; 2021 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-34475235

RESUMO

This prospective non-randomized, multicenter clinical trial was performed to investigate efficacy and safety of 131I-labeled metuximab in adjuvant treatment of unresectable hepatocellular carcinoma. Methods: Patients were assigned to treatment with transcatheter arterial chemoembolization (TACE) combined with 131I-metuximab or TACE alone. The primary outcome was overall tumor recurrence. The secondary outcomes were safety and overall survival. Results: The median time to tumor recurrence was 6 months in the TACE+131I-metuximab group (n = 160) and 3 months in the TACE group (n = 160) (hazard ratio, 0.55; 95% confidence interval, 0.43 to 0.70; P < 0.001). The median overall survival was 28 months in the TACE+131I-metuximab group and 19 months in the TACE group (hazard ratio, 0.62; 95% confidence interval, 0.47 to 0.82; P = 0.001). Conclusion: TACE+131I-metuximab showed a greater anti-recurrence benefit, significantly improved the 5-year survival of patients with advanced hepatocellular carcinoma, and was well tolerated by patients.

2.
Signal Transduct Target Ther ; 6(1): 347, 2021 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-34564690

RESUMO

SARS-CoV-2 mutations contribute to increased viral transmissibility and immune escape, compromising the effectiveness of existing vaccines and neutralizing antibodies. An in-depth investigation on COVID-19 pathogenesis is urgently needed to develop a strategy against SARS-CoV-2 variants. Here, we identified CD147 as a universal receptor for SARS-CoV-2 and its variants. Meanwhile, Meplazeumab, a humanized anti-CD147 antibody, could block cellular entry of SARS-CoV-2 and its variants-alpha, beta, gamma, and delta, with inhibition rates of 68.7, 75.7, 52.1, 52.1, and 62.3% at 60 µg/ml, respectively. Furthermore, humanized CD147 transgenic mice were susceptible to SARS-CoV-2 and its two variants, alpha and beta. When infected, these mice developed exudative alveolar pneumonia, featured by immune responses involving alveoli-infiltrated macrophages, neutrophils, and lymphocytes and activation of IL-17 signaling pathway. Mechanistically, we proposed that severe COVID-19-related cytokine storm is induced by a "spike protein-CD147-CyPA signaling axis": Infection of SARS-CoV-2 through CD147 initiated the JAK-STAT pathway, which further induced expression of cyclophilin A (CyPA); CyPA reciprocally bound to CD147 and triggered MAPK pathway. Consequently, the MAPK pathway regulated the expression of cytokines and chemokines, which promoted the development of cytokine storm. Importantly, Meplazumab could effectively inhibit viral entry and inflammation caused by SARS-CoV-2 and its variants. Therefore, our findings provided a new perspective for severe COVID-19-related pathogenesis. Furthermore, the validated universal receptor for SARS-CoV-2 and its variants can be targeted for COVID-19 treatment.


Assuntos
Enzima de Conversão de Angiotensina 2/metabolismo , Anticorpos Monoclonais Humanizados/farmacologia , Basigina/antagonistas & inibidores , Basigina/metabolismo , COVID-19/tratamento farmacológico , COVID-19/metabolismo , Síndrome da Liberação de Citocina/tratamento farmacológico , SARS-CoV-2/metabolismo , Enzima de Conversão de Angiotensina 2/genética , Animais , Basigina/genética , COVID-19/genética , Chlorocebus aethiops , Síndrome da Liberação de Citocina/genética , Síndrome da Liberação de Citocina/metabolismo , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/genética , Camundongos , Camundongos Transgênicos , SARS-CoV-2/genética , Células Vero
3.
Ann Acad Med Singap ; 50(6): 456-466, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34195752

RESUMO

INTRODUCTION: Melanomas in Asians have different clinicopathological characteristics and prognosis from melanomas in Caucasians. This study reviewed the epidemiology and treatment outcomes of cutaneous melanoma diagnosed at a tertiary referral dermatology centre in Singapore, which has a multiracial population. The study also determined whether Asians had comparable relapse-free and overall survival periods to Caucasians in Singapore. METHOD: This is a retrospective review of cutaneous melanoma cases in our centre between 1996 and 2015. RESULTS: Sixty-two cases of melanoma were diagnosed in 61 patients: 72.6% occurred in Chinese, 19.4% in Caucasians and 3.2% in Indians, with an over-representation of Caucasians. Superficial spreading melanoma, acral lentiginous melanoma and nodular melanoma comprised 37.1%, 35.5% and 22.6% of the cases, respectively. The median time interval to diagnosis was longer in Asians than Caucasians; median Breslow's thickness in Asians were significantly thicker than in Caucasians (2.6mm versus 0.9mm, P=0.018) and Asians tend to present at a later stage. The mortality rates for Asians and Caucasians were 52% and 0%, respectively. CONCLUSION: More physician and patient education on skin cancer awareness is needed in our Asian-predominant population for better outcomes.


Assuntos
Melanoma , Neoplasias Cutâneas , Humanos , Melanoma/epidemiologia , Melanoma/terapia , Prognóstico , Estudos Retrospectivos , Singapura/epidemiologia , Neoplasias Cutâneas/epidemiologia , Neoplasias Cutâneas/terapia , Resultado do Tratamento
4.
Medicine (Baltimore) ; 100(19): e25762, 2021 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-34106605

RESUMO

ABSTRACT: The aim of this study was to explore the association of rs1836724 single-nucleotide polymorphism (SNP) of ERBB4 with risk and prognosis of non-small cell lung cancer (NSCLC) in the Chinese Han population.The genotype of rs1836724 SNP of ERBB4 from 258 patients with NSCLC and 200 noncancer controls were detected the TaqMan-MGB probes real-time fluorescence polymerase chain reaction. The distribution of genotype and alleles between the 2 groups was compared, and the association between clinicopathological characteristic and rs1836724 SNP was analyzed. Prognosis and influencing factors were analyzed by Kaplan-Meier and Cox regression analysis.There were significant differences in the genotype and allele distribution of ERBB4 rs1836724 between the NSCLC group and control group (P < .05). And CC genotype of rs1836724 was associated with increased risk of NSCLC in the Chinese Han population. Rs1836724 SNP was associated with TNM stage and lymph nodal metastasis (P = .001, P = .007). The median follow-up was 29 months, and the progression-free survival and overall survival of 258 NSCLC patients were 27.91% and 31.39%, respectively. Patients with GG genotype of rs1836724 had poor progression-free survival and overall survival. Rs1836724 SNP was an independent prognostic marker of NSCLC patients, CC genotype had a high risk of poor prognosis (odds ratio = 1.587, 95% confidence interval: 1.079-2.335, P = .019).In Chinese Han populations, rs1836724 SNP of ERBB4 may contribute toward the increased risk and poor prognosis of NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Predisposição Genética para Doença , Neoplasias Pulmonares/genética , Polimorfismo de Nucleotídeo Único , Receptor ErbB-4/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Grupo com Ancestrais do Continente Asiático , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/etnologia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Estudos de Casos e Controles , China/epidemiologia , Feminino , Seguimentos , Genótipo , Técnicas de Genotipagem , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/etnologia , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de Risco , Análise de Sobrevida
5.
Mol Cancer ; 20(1): 79, 2021 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-34044846

RESUMO

BACKGROUND: Somatic mutations are involved in hepatocellular carcinoma (HCC) progression, but the genetic mechanism associated to hepatocarcinogenesis remains poorly understood. We report that Eyes absent homolog 2 (EYA2) suppresses the HCC progression, while EYA2(A510E) mutation identified by exome sequencing attenuates the tumor-inhibiting effect of EYA2. METHODS: Whole-exome sequencing was performed on six pairs of human HCC primary tumors and matched adjacent tissues. Focusing on EYA2, expression level of EYA2 in human HCC samples was evaluated by quantitative real-time PCR, western blot and immunohistochemistry. Loss- and gain-of-function studies, hepatocyte-specific deletion of EYA2 (Eya2-/-) in mice and RNA sequencing analysis were used to explore the functional effect and mechanism of EYA2 on HCC cell growth and metastasis. EYA2 methylation status was evaluated using Sequenom MassARRAY and publicly available data analysis. RESULTS: A new somatic mutation p.Ala510Glu of EYA2 was identified in HCC tissues. The expression of EYA2 was down-regulated in HCC and associated with tumor size (P = 0.001), Barcelona Clinic Liver Cancer stage (P = 0.016) and tumor differentiation (P = 0.048). High level of EYA2 was correlated with a favorable prognosis in HCC patients (P = 0.003). Results from loss-of-function and gain-of-function experiments suggested that knockdown of EYA2 enhanced, while overexpression of EYA2 attenuated, the proliferation, clone formation, invasion, and migration of HCC cells in vitro. Delivery of EYA2 gene had a therapeutic effect on inhibition of orthotopic liver tumor in nude mice. However, EYA2(A510E) mutation led to protein degradation by unfolded protein response, thus weakening the inhibitory function of EYA2. Hepatocyte-specific deletion of EYA2 in mice dramatically promoted diethylnitrosamine-induced HCC development. EYA2 was also down-regulated in HCC by aberrant CpG methylation. Mechanically, EYA2 combined with DACH1 to transcriptionally regulate SOCS3 expression, thus suppressing the progression of HCC via SOCS3-mediated blockade of the JAK/STAT signaling pathway. CONCLUSIONS: In our study, we identified and validated EYA2 as a tumor suppressor gene in HCC, providing a new insight into HCC pathogenesis.

6.
Signal Transduct Target Ther ; 6(1): 194, 2021 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-34001849

RESUMO

Recent evidence suggests that CD147 serves as a novel receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Blocking CD147 via anti-CD147 antibody could suppress the in vitro SARS-CoV-2 replication. Meplazumab is a humanized anti-CD147 IgG2 monoclonal antibody, which may effectively prevent SARS-CoV-2 infection in coronavirus disease 2019 (COVID-19) patients. Here, we conducted a randomized, double-blinded, placebo-controlled phase 1 trial to evaluate the safety, tolerability, and pharmacokinetics of meplazumab in healthy subjects, and an open-labeled, concurrent controlled add-on exploratory phase 2 study to determine the efficacy in COVID-19 patients. In phase 1 study, 59 subjects were enrolled and assigned to eight cohorts, and no serious treatment-emergent adverse event (TEAE) or TEAE grade ≥3 was observed. The serum and peripheral blood Cmax and area under the curve showed non-linear pharmacokinetic characteristics. No obvious relation between the incidence or titer of positive anti-drug antibody and dosage was observed in each cohort. The biodistribution study indicated that meplazumab reached lung tissue and maintained >14 days stable with the lung tissue/cardiac blood-pool ratio ranging from 0.41 to 0.32. In the exploratory phase 2 study, 17 COVID-19 patients were enrolled, and 11 hospitalized patients were involved as concurrent control. The meplazumab treatment significantly improved the discharged (P = 0.005) and case severity (P = 0.021), and reduced the time to virus negative (P = 0.045) in comparison to the control group. These results show a sound safety and tolerance of meplazumab in healthy volunteers and suggest that meplazumab could accelerate the recovery of patients from COVID-19 pneumonia with a favorable safety profile.


Assuntos
Anticorpos Monoclonais Humanizados , COVID-19/tratamento farmacológico , COVID-19/metabolismo , Pulmão/metabolismo , SARS-CoV-2/metabolismo , Adolescente , Adulto , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/farmacocinética , COVID-19/patologia , Método Duplo-Cego , Feminino , Humanos , Pulmão/patologia , Pulmão/virologia , Masculino , Pessoa de Meia-Idade
7.
Eur J Med Chem ; 216: 113355, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33721668

RESUMO

We describe the use of natural product combretastatin A4 (CA4) as a versatile new payload for the construction of antibody-drug conjugates (ADCs). Cetuximab conjugates consisting of CA4 derivatives were site-specially prepared by disulfide re-bridging approach using cleavable and non-cleavable linkers. These ADCs retained antigen binding and internalization efficiency and exhibited high potencies against cancer cell lines in vitro. The conjugates also demonstrated significant antitumor activities in EGFR-positive xenograft models without observed toxicities. CA4 appears to be a viable payload option for ADCs research and development.


Assuntos
Cetuximab/química , Imunoconjugados/química , Estilbenos/química , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Dissulfetos , Desenho de Fármacos , Humanos , Imunoconjugados/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos NOD , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Transplante Heterólogo
8.
Signal Transduct Target Ther ; 6(1): 64, 2021 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-33589597

RESUMO

Genomic sequencing analysis of tumors provides potential molecular therapeutic targets for precision medicine. However, identifying a key driver gene or mutation that can be used for hepatocellular carcinoma (HCC) treatment remains difficult. Here, we performed whole-exome sequencing on genomic DNA obtained from six pairs of HCC and adjacent tissues and identified two novel somatic mutations of UBE2S (p. Gly57Ala and p. Lys63Asn). Predictions of the functional effects of the mutations showed that two amino-acid substitutions were potentially deleterious. Further, we observed that wild-type UBE2S, especially in the nucleus, was significantly higher in HCC tissues than that in adjacent tissues and closely related to the clinicopathological features of patients with HCC. Functional assays revealed that overexpression of UBE2S promoted the proliferation, invasion, metastasis, and G1/S phase transition of HCC cells in vitro, and promoted the tumor growth significantly in vivo. Mechanistically, UBE2S interacted with TRIM28 in the nucleus, both together enhanced the ubiquitination of p27 to facilitate its degradation and cell cycle progression. Most importantly, the small-molecule cephalomannine was found by a luciferase-based sensitive high-throughput screen (HTS) to inhibit UBE2S expression and significantly attenuate HCC progression in vitro and in vivo, which may represent a promising strategy for HCC therapy.

9.
Perfusion ; 36(2): 122-129, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32522095

RESUMO

BACKGROUND: Periprocedural myocardial infarction is a common complication following percutaneous coronary intervention. The present study was conducted with an aim to compare the safety and efficacy of loading doses of ticagrelor versus clopidogrel in preventing periprocedural myocardial infarction in Asian patients with acute coronary syndrome undergoing elective percutaneous coronary intervention. METHODS: A total of 114 patients with acute coronary syndrome undergoing elective percutaneous coronary intervention were assigned to clopidogrel group (n = 57, the loading and maintenance doses were 300 and 75 mg qd for clopidogrel, and 300 and 100 mg qd for aspirin), or ticagrelor group (n = 57, the loading and maintenance doses were 180 and 90 mg bid for ticagrelor, and 300 and 100 mg qd for aspirin). Cardiac biomarkers were measured before, 8 hours, and 24 hours after percutaneous coronary intervention. The percutaneous coronary intervention-related periprocedural myocardial infarction was defined according to the fourth universal definition of myocardial infarction (2018). RESULTS: The overall incidence of percutaneous coronary intervention-related periprocedural myocardial infarction was 21.1%. The ticagrelor group showed a significantly lower incidence of periprocedural myocardial infarction (12.3% vs 29.8%, p = 0.022) and numerically lower bleeding events (3.5% vs 8.8%, p = 0.242) as compared with clopidogrel group. No patient had major adverse cardiovascular events during the 1-month follow-up. The levels of high-sensitivity C-reactive protein did not differ significantly between the two groups (p > 0.05), indicating that the benefits of ticagrelor were not from its anti-inflammatory effects. Multivariable analysis showed that the use of ticagrelor (odds ratio: 0.50; 95% confidence interval: 0.29-0.87; p = 0.014) and number of stents (odds ratio: 2.75; 95% confidence interval: 1.25-6.06; p = 0.012) were independent predictors of periprocedural myocardial infarction. CONCLUSION: Pretreatment with a loading dose of ticagrelor seems to be superior in reducing the incidence of percutaneous coronary intervention-related periprocedural myocardial infarction in Asian patients with acute coronary syndrome as compared with clopidogrel.

10.
Nitric Oxide ; 107: 1-10, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33246103

RESUMO

Phenotypic modulation of Corpus Cavernosum Smooth Muscle Cells (CCSMCs) is an important step in the development and progression of bilateral cavernous nerve injury induced erectile dysfunction (BCNI-ED). To investigate the effect of exogenous hydrogen sulfide (H2S) on the phenotypic modulation of CCSMCs in BCNI-ED rats, a total of 18 male Sprague-Dawley rats were equally divided into 3 groups, including sham-operated (Sham) group, BCNI group and BCNI treated with NaHS (BCNI + NaHS) group. The treated group received intraperitoneal injection of NaHS (100 µmol kg-1day-1) for 4 weeks starting day 1 postoperatively. Erectile function was measured by the ratio of intracavernous pressure (ICP)/mean arterial pressure (MAP), and relevant tissues were harvested for Immunohistochemistry, Hematoxylin and eosin (H&E), Masson's trichrome staining, H2S fluorescent probe WSP-1 and Western blot. The primary CCSMCs were isolated and pretreatment with NaHS before exposed to PDGF-BB (platelet-derived growth factor). Relative expression mRNA and protein of phenotypic biomarkers, RhoA, ROCK-1 and cell cycle proteins were detected. Cystathionine-ß-synthase (CBS) and cystathionine-γ-lyase (CSE), 3-mercaptopyruvate sulfurtransferase (3-MST) and H2S levels in penile tissue was significantly decreased in the BCNI group compared with the Sham group. Compared with the BCNI group, administration of NaHS significantly increased the ratio of ICP/MAP, ratio of smooth muscle to collagen, expressions of a-SMA, calponin and decreased the expression of OPN, collagen-I, RhoA, ROCK1 in the penile tissue. PDGF-BB-treated CCSMCs exhibited higher expression of OPN, RhoA, ROCK1, and lower α-SMA, calponin, which were attenuated by NaHS pretreatment. NaHS suppressed RhoA/ROCK activity and decreased the expression of CDK2, Cyclin E1, while increased the expression of P27kip1 induced by PDGF-BB in CCSMCs. Taken together, this study indicated that exogenous H2S inhibited the phenotypic modulation of CCSMCs by suppressing RhoA/ROCK1 signaling and affecting its downstream factor, CDK2, Cyclin E1, P27kip1, thereby improved BCNI rat erectile function.

11.
Signal Transduct Target Ther ; 5(1): 283, 2020 12 04.
Artigo em Inglês | MEDLINE | ID: mdl-33277466

RESUMO

In face of the everlasting battle toward COVID-19 and the rapid evolution of SARS-CoV-2, no specific and effective drugs for treating this disease have been reported until today. Angiotensin-converting enzyme 2 (ACE2), a receptor of SARS-CoV-2, mediates the virus infection by binding to spike protein. Although ACE2 is expressed in the lung, kidney, and intestine, its expressing levels are rather low, especially in the lung. Considering the great infectivity of COVID-19, we speculate that SARS-CoV-2 may depend on other routes to facilitate its infection. Here, we first discover an interaction between host cell receptor CD147 and SARS-CoV-2 spike protein. The loss of CD147 or blocking CD147 in Vero E6 and BEAS-2B cell lines by anti-CD147 antibody, Meplazumab, inhibits SARS-CoV-2 amplification. Expression of human CD147 allows virus entry into non-susceptible BHK-21 cells, which can be neutralized by CD147 extracellular fragment. Viral loads are detectable in the lungs of human CD147 (hCD147) mice infected with SARS-CoV-2, but not in those of virus-infected wild type mice. Interestingly, virions are observed in lymphocytes of lung tissue from a COVID-19 patient. Human T cells with a property of ACE2 natural deficiency can be infected with SARS-CoV-2 pseudovirus in a dose-dependent manner, which is specifically inhibited by Meplazumab. Furthermore, CD147 mediates virus entering host cells by endocytosis. Together, our study reveals a novel virus entry route, CD147-spike protein, which provides an important target for developing specific and effective drug against COVID-19.


Assuntos
Basigina/genética , COVID-19/genética , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Animais , Basigina/imunologia , COVID-19/imunologia , COVID-19/patologia , COVID-19/virologia , Interações Hospedeiro-Patógeno/imunologia , Humanos , Pulmão/imunologia , Pulmão/patologia , Pulmão/virologia , Camundongos , Pandemias , Ligação Proteica/imunologia , Domínios Proteicos/genética , Domínios Proteicos/imunologia , SARS-CoV-2/patogenicidade , Glicoproteína da Espícula de Coronavírus/genética , Internalização do Vírus
12.
Bioorg Med Chem ; 28(23): 115793, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-33039798

RESUMO

Methods that site-specifically attach payloads to an antibody with controlled DAR (Drug-Antibody Ratio) are highly desirable for the generation of homogeneous antibody-drug conjugates (ADCs). We describe the use of N-phenyl-divinylsulfonamide scaffold as a linker platform to site-specifically construct homogeneous DAR four ADCs through a disulfide re-bridging approach. Several monomethyl auristatin E (MMAE)-linkers were synthesized and the drug-linkers that contain electron-donating groups on the phenyl of the linker showed high stability. Her2-targeted MMAE-linker-herceptin and EGFR targeted MMAE-linker-cetuximab conjugates were prepared. The conjugates demonstrated high efficacy and selectivity for killing target-positive cancer cells in vitro. The EGFR-targeted conjugates also showed significant antitumor activities in vivo.


Assuntos
Imunoconjugados/química , Sulfonamidas/química , Aminobenzoatos/química , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cetuximab/química , Reação de Cicloadição , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Imunoconjugados/farmacologia , Imunoconjugados/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Neoplasias/tratamento farmacológico , Oligopeptídeos/química , Transplante Heterólogo , Trastuzumab/química
13.
Anal Chem ; 92(20): 13702-13710, 2020 10 20.
Artigo em Inglês | MEDLINE | ID: mdl-32955856

RESUMO

We describe an efficient decision tree searching strategy (DTSS) to boost the identification of cross-linked peptides. The DTSS approach allows the identification of a wealth of complementary information to facilitate the construction of more protein-protein interaction networks for human cell lysate, which was tested by the use of a recently reported cross-linking data set (ACS Cent. Sci. 2019, 5, 1514-1522). A variant of the PhoX-linker, named pDSPE, was synthesized and applied to cross-link Escherichia coli cell lysate to demonstrate that the acquisition of doubly charged ions can significantly improve identification results. The method can be seamlessly integrated to other search engines to maximize the number of identified cross-links.


Assuntos
Reagentes para Ligações Cruzadas/química , Árvores de Decisões , Espectrometria de Massas/métodos , Peptídeos/análise , Cromatografia Líquida de Alta Pressão , Escherichia coli/metabolismo , Peptídeos/química , Peptídeos/metabolismo , Ácidos Fosforosos/química , Mapas de Interação de Proteínas
15.
Eur J Med Chem ; 190: 112080, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-32018094

RESUMO

Disulfide re-bridging strategy has demonstrated significant advantages in the construction of homogeneous antibody drug conjugates (ADCs). However, a major issue that disulfide scrambling at the hinge region of antibody leads to the formation of "half-antibody" has appeared for many re-bridging linkers. We present bis(vinylsulfonyl)piperazines (BVP) as efficient linkers to selectively re-bridge disulfides at the antigen-binding fragment (Fab) regions and produce highly homogeneous conjugates with a loading of two drugs without disulfide scrambling. We also found that optically active (S)-configuration linkers led to more sufficient conjugation compared with (R)-configuration. The BVP-linked ADCs demonstrated superior efficacy and antigen-selectivity in vitro cytotoxicity.


Assuntos
Imunoconjugados/farmacologia , Piperazinas/farmacologia , Sulfonas/farmacologia , Compostos de Vinila/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/toxicidade , Linhagem Celular Tumoral , Dissulfetos/química , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Imunoconjugados/química , Imunoconjugados/toxicidade , Piperazinas/síntese química , Piperazinas/toxicidade , Sulfonas/síntese química , Sulfonas/toxicidade , Compostos de Vinila/síntese química , Compostos de Vinila/toxicidade
16.
Front Cell Dev Biol ; 7: 233, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31681766

RESUMO

Chimeric antigen receptor T cell (CAR-T) therapy to hematological malignancies has demonstrated tremendous clinical outcomes. However, the therapeutic efficacy of CAR-T cells in solid tumors remains limited due to the scarcity of tumor-specific antigen targets and the poor infiltration of CAR-T cells into tumor tissue. In this study, we developed a novel inducible CAR-T cell system which targets CD147, a tumor-associated antigen for hepatocellular carcinoma (HCC). To minimize potential toxicities of CAR-T cell therapy, the Tet-On 3G system was introduced to induce CD147CAR expression in the right place at the right time. Specifically, Tet-CD147CAR lentiviral vector (LV-Tet-CD147CAR) was constructed, which comprised CD147CAR controlled by the Tet-On system. Tet-CD147CART cells were successfully generated from activated T cells by infection with LV-Tet-CD147CAR. Proliferation, cytotoxicity, and cytokine secretion of Tet-CD147CART cells were significantly increased against CD147-positive cancer cells in the presence of doxycycline (Dox) compared to Tet-CD147CART cells in the absence of Dox and PBMCs. Consistently, in vivo studies indicated that the tumor growth in nude mice was significantly inhibited by (Dox+) Tet-CD147CART cells through multiple intratumoral administration. Taken together, our results indicated that the expression and activity of CD147CAR were controlled by Dox both in vitro and in vivo, which facilitated decreased toxicity and adverse effects to CAR-T cell therapy. Moreover, this study provides viable evidence in support of the potential benefits and translation of this strategy of CAR-T cells targeting CD147 for the treatment of patients with HCC.

17.
Dermatol Ther (Heidelb) ; 9(3): 601-611, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31376063

RESUMO

INTRODUCTION: Keloids are a prevalent chronic skin disorder with significant psychosocial morbidity. Intralesional corticosteroid injections are the first-line treatment but are painful and require repeated injections by medical professionals. Dissolving microneedles are a novel method of cutaneous drug delivery that induces minimal/no pain and can be self-administered. The objective of the study was to evaluate the efficacy and safety of triamcinolone-embedded dissolving microneedles in treatment of keloids. METHODS: This was a single-blind, intra-individual controlled two-phase clinical trial of 8-week duration each. Two keloids per subject were selected for (1) once-daily 2-min application with microneedles for 4 weeks, followed by no treatment for the next 4 weeks, or (2) non-intervention as control. Primary outcome was change in keloid volume as assessed by a high-resolution 3D scanner. RESULTS: There was significant reduction in keloid volume compared with controls after 4 weeks of treatment. This reduction was greater with a higher dosage of triamcinolone used. CONCLUSIONS: Once-daily application of dissolving triamcinolone-embedded microneedles significantly reduced the volume of keloids. The treatment was safe, can be self-administered and can serve as an alternative for patients unsuitable for conventional treatments. TRIAL REGISTRATION: Trial Registry: Health Science Authority (Singapore) Clinical Trials Register Registration number: 2015/00440.

18.
Artigo em Inglês | MEDLINE | ID: mdl-31279678

RESUMO

This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal.

19.
Medicine (Baltimore) ; 98(27): e15970, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31277089

RESUMO

Shunt-dependent hydrocephalus is a common complication of aneurysmal subarachnoid hemorrhage (aSAH) which indicated intensive care unit stay and unfavorable outcome. Our aim is to study the risk factors of shunt-dependent hydrocephalus after aneurysmal subarachnoid space hemorrhage. Patients with intracranial aneurysms treated in our department from January 2014 to October 2018 were included in the study. Patients' age, gender, history of hypertension and diabetes, location of aneurysms, Glasgow coma scale (GCS) score, Hunt-Hess grading, intraventricular hemorrhage, therapeutic option, shunt placement, clinical outcome, length of stay were analyzed. The follow-up period was 1 to 5 years. Statistics included Chi-squared, Student t test, 1-way analysis of variance, Pearson correlation coefficient, and multivariate logistic regression. About 845 cases with intracranial aneurysms treated in our department were included in the study. The mean age was 52.19 ±â€Š9.51 years and the sex ratio was 317/528. About 14.3% (121/845) of the patients developed shunt-dependent hydrocephalus in the follow-up period. According to our results, older than 60, Hunt-Hess grading, GCS, coma, posterior circulation aneurysm, external ventricular drainage, and decompress craniotomy were risk factors of shunt dependency (P < .05). Moreover, older than 60, GCS 3 to 8, Hunt-Hess 3 to 5, and posterior circulation aneurysm were the independent risk factors of shunt dependency. Moreover, shunt dependency was related to longer hospital stay and unfavorable outcome (P < .05). In conclusion, patients older than 60, GCS 3 to 8, Hunt-Hess 3 to 5, and posterior circulation aneurysm need more strict observation and longer follow-up. Timely and appropriate treatment may benefit patients in recovery, while further exploration is still needed in the future.


Assuntos
Derivações do Líquido Cefalorraquidiano/efeitos adversos , Hidrocefalia/etiologia , Aneurisma Intracraniano/complicações , Hemorragia Subaracnóidea/etiologia , Adulto , Fatores Etários , Estudos de Casos e Controles , Feminino , Escala de Coma de Glasgow , Humanos , Hidrocefalia/diagnóstico por imagem , Aneurisma Intracraniano/cirurgia , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de Doença , Hemorragia Subaracnóidea/diagnóstico por imagem , Tomografia Computadorizada por Raios X
20.
Am J Pathol ; 189(8): 1637-1653, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31345467

RESUMO

Cholangiocarcinoma (CCA) is a malignant cancer that is associated with high mortality rates. The relationship between laminin γ 2 chain gene (LAMC2) and epidermal growth factor receptor (EGFR) has been previously documented in gastric cancer and oral squamous cell carcinoma. This study investigates the role of LAMC2 in epithelial-mesenchymal transition (EMT) and angiogenesis in CCA and explores the underlying mechanism(s). Differentially expressed genes related to CCA were initially screened using a microarray analysis, and the interaction between LAMC2 and the EGFR signaling pathway was identified. To determine the regulatory effects of LAMC2 on CCA progression, LAMC2 was silenced or overexpressed and the EGFR signaling pathway was activated or blocked. Subsequently, the regulation effects of LAMC2 were evaluated on the expression of EMT markers, invasion and migration of CCA cells, as well as microvessel density in nude mice. Microarray analysis demonstrated that highly expressed LAMC2 is linked to CCA development, which involves the EGFR signaling pathway. When LAMC2 expression was increased, the EGFR signaling pathway and EMT were activated in CCA tissues. Silencing of LAMC2 as well as EGFR signaling pathway inhibition led to suppression of EMT, cell invasion, and migration abilities in vitro, as well as angiogenesis in vivo. This study demonstrates that LAMC2 silencing suppresses the activity of the EGFR signaling pathway, thus functioning as a tumor suppressor in CCA.


Assuntos
Neoplasias dos Ductos Biliares , Colangiocarcinoma , Transição Epitelial-Mesenquimal , Laminina/metabolismo , Neovascularização Patológica/metabolismo , Transdução de Sinais , Proteínas Supressoras de Tumor/metabolismo , Adulto , Idoso , Animais , Neoplasias dos Ductos Biliares/irrigação sanguínea , Neoplasias dos Ductos Biliares/metabolismo , Neoplasias dos Ductos Biliares/patologia , Linhagem Celular Tumoral , Colangiocarcinoma/irrigação sanguínea , Colangiocarcinoma/metabolismo , Colangiocarcinoma/patologia , Receptores ErbB/metabolismo , Feminino , Inativação Gênica , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Neovascularização Patológica/patologia
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