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INTRODUCTION: EGFR-mutated NSCLC is characterized by an immunosuppressive microenvironment that confers limited clinical effectiveness to anti-PD-1 or PD-L1 antibodies. Despite the discouraging outcomes of immunotherapy, novel immune checkpoints are constantly emerging, among which the specific vulnerability for therapeutic intervention in the context of EGFR-mutated NSCLC remains unresolved. METHODS: Data sets of patient- and cell line-levels were used for screening and mutual validation of association between EGFR mutation and a panel of immune checkpoint-related genes. Regulatory mechanism was elucidated through in vitro manipulation of EGFR signaling pathway and evaluated by immunoblot analysis, quantitative polymerase chain reaction, flow cytometry, immunofluorescence staining, and chromatin immunoprecipitation. In vivo investigation of different therapeutic strategies were conducted using both immunocompetent and immunodeficient mouse models. RESULTS: Among all screened immune checkpoints, CD47 emerged as the candidate most relevant to EGFR activation. Mechanistically, EGFR mutation constitutively activated downstream ERK and AKT pathways to respectively up-regulate the transcriptional factors c-Myc and NF-κB, both of which structurally bound to the promotor region of CD47 and actively transcribed this "don't eat me" signal. Impaired macrophage phagocytosis was observed on introduction of EGFR-sensitizing mutations in NSCLC cell line models, whereas CD47 blockade restored the phagocytic capacity and augmented tumor cell killing in both in vitro and in vivo models. Remarkably, the combination of anti-CD47 antibody with EGFR tyrosine kinase inhibitor revealed an additive antitumor activity compared with monotherapy of either antitumor agent in both immunocompetent and adaptive immunity-deficient mouse models. CONCLUSIONS: EGFR-sensitizing mutation facilitates NSCLC's escape from innate immune attack through up-regulating CD47. Combination therapy incorporating CD47 blockade holds substantial promise for clinical translation in developing more effective therapeutic approaches against EGFR-mutant NSCLC.
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Antígeno CD47 , Carcinoma Pulmonar de Células não Pequenas , Receptores ErbB , Neoplasias Pulmonares , Macrófagos , Mutação , Fagocitose , Regulação para Cima , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Antígeno CD47/genética , Humanos , Camundongos , Animais , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/imunologia , Receptores ErbB/genética , Macrófagos/metabolismo , Macrófagos/imunologia , Imunidade Inata , Evasão da Resposta Imune , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
In December 2019, a new type viral pneumonia cases occurred in Wuhan, Hubei Province; and then named "2019 novel coronavirus (2019-nCoV)" by the World Health Organization (WHO) on 12 January 2020. For it is a never been experienced respiratory disease before and with infection ability widely and quickly, it attracted the world's attention but without treatment and control manual. For the request from frontline clinicians and public health professionals of 2019-nCoV infected pneumonia management, an evidence-based guideline urgently needs to be developed. Therefore, we drafted this guideline according to the rapid advice guidelines methodology and general rules of WHO guideline development; we also added the first-hand management data of Zhongnan Hospital of Wuhan University. This guideline includes the guideline methodology, epidemiological characteristics, disease screening and population prevention, diagnosis, treatment and control (including traditional Chinese Medicine), nosocomial infection prevention and control, and disease nursing of the 2019-nCoV. Moreover, we also provide a whole process of a successful treatment case of the severe 2019-nCoV infected pneumonia and experience and lessons of hospital rescue for 2019-nCoV infections. This rapid advice guideline is suitable for the first frontline doctors and nurses, managers of hospitals and healthcare sections, community residents, public health persons, relevant researchers, and all person who are interested in the 2019-nCoV.
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Betacoronavirus , Infecções por Coronavirus , Infecção Hospitalar , Controle de Infecções , Programas de Rastreamento , Equipamento de Proteção Individual , Pneumonia Viral , Antibacterianos/uso terapêutico , Antivirais/uso terapêutico , Betacoronavirus/isolamento & purificação , Betacoronavirus/patogenicidade , COVID-19 , Teste para COVID-19 , Técnicas de Laboratório Clínico , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/terapia , Infecções por Coronavirus/transmissão , Infecção Hospitalar/prevenção & controle , Diagnóstico Diferencial , Medicamentos de Ervas Chinesas , Medicina Baseada em Evidências , Hidratação , Humanos , Controle de Infecções/normas , Pulmão/diagnóstico por imagem , Epidemiologia Molecular , Cuidados de Enfermagem , Pneumonia Viral/diagnóstico , Pneumonia Viral/epidemiologia , Pneumonia Viral/etiologia , Pneumonia Viral/terapia , Pneumonia Viral/transmissão , SARS-CoV-2 , Tratamento Farmacológico da COVID-19RESUMO
OBJECTIVE: To compare the observation of high-grade glioma (HGG) based on intraoperative multiplane ultrasonography (US) images and preoperative reconstructive coplanar T1-weighted enhanced magnetic resonance imaging (MRI) using volume navigation (V Nav) fusion image technology. METHODS: We retrospectively evaluated intraoperative data obtained from 16 patients diagnosed with HGG (grade III and IV). Overall, 18 nodules observed in 15 patients were examined. HGG images from US and contrast-enhanced US (CEUS) were compared with those from preoperative reconstructive coplanar enhanced T1-weighted MRI using automatic V Nav fusion image technology. RESULTS: All HGG tumors were detected. Images of 13 of 18 tumors (72.2%) with obscure margins using B-mode US were improved with clear tumor boundaries using CEUS imaging. The relative difference in tumor area between CEUS and enhanced MRI modalities in 14 mainly solid component lesions was considered statistically significant (P value < 0.05). There was a perfect correlation of the enhanced area between coplanar CEUS and enhanced MRI. CONCLUSIONS: The V Nav fusion image system combining intraoperative real-time US imaging with reconstructive preoperative coplanar MRI is valuable for image-guided HGG resection. It is suitable for neurosurgeons who lack the expertise in US technology to discern the brain structure and allows better recognition of tumor and edema tissues compared with reconstructive preoperative coplanar-enhanced MRI in real time and in multiplane from different angles. In addition, CEUS combined with B-mode US could improve tumor detection and resection control in neurosurgery, even in single US-guided operations.
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Neoplasias Encefálicas/cirurgia , Glioma/cirurgia , Procedimentos Neurocirúrgicos/métodos , Adulto , Idoso , Meios de Contraste , Feminino , Gadolínio , Humanos , Cuidados Intraoperatórios/métodos , Imagem por Ressonância Magnética Intervencionista/métodos , Masculino , Microbolhas , Pessoa de Meia-Idade , Imagem Multimodal/métodos , Cuidados Pré-Operatórios/métodos , Estudos Retrospectivos , Hexafluoreto de Enxofre , Cirurgia Assistida por Computador/métodos , Resultado do Tratamento , Ultrassonografia de Intervenção/métodosRESUMO
OBJECTIVES: The aim of study is to evaluate the general performance and efficiency of the using real time intraoperative ultrasound system with Volume Navigation system technology in glioma. Compare glioma intraoperative ultrasound and contrast agent ultrasound images to obtained preoperative MRI with fusion image in a real-time. PATIENTS AND METHODS: Fifteen patients had been performed fusion imaging involved intraoperative real-time ultrasound and contrast agent ultrasound with preoperative MR imaging including preoperative gadolinium-enhanced MRI from March 2017 to December 2017. The number of tumor was counted online fusion imaging in real time ultrasound with and without preoperative MR. We analyzed ultrasound coplanar MR modalities in real time including tumor location, margin (obscure or defined). In addition, intraoperative ultrasound enhancement pattern was analyzed compare it to preoperative reconstruction gadolinium-enhanced T1-weighted MRI. Two radiologists who made planning ultrasound assessment for the focus lesion based on a 4 scoring system according to the degree of confidence. RESULTS: Thirteen of fifteen patients whose automatically registration successful intraoperative neurosurgery accepted preoperative MR examination. Seven of fifteen fine-tuning registration phase were performed and satisfactory with fusion image substantially. Intraoperatively, 73.3% (11/15) glioma nodules were definite on conventional B-mode US by a radiologist who doesn't know the MR result before fusion US with MRI. However, 100% tumors were detected on fusion B-mode ultrasound imaging with MRI. Two radiologists evaluated the score between fusion B-mode ultrasound and CEUS with coplanar MRI and had a result that score was upgraded in 69.2% (9/13) and 84.6% (11/13) patients. Inter-observer agreement was significant (kappa value = 1.0, p < 0.001) in B-mode ultrasound fusion image with MRI. Inter-observer agreement was moderate (kappa value = 0. 0.618, p < 0.001) in CEUS fusion image with MRI. CONCLUSION: Fusion imaging is very useful to detect poor sonographic visibility tumor on fusion B-mode US imaging with MR images. Fusion image may demonstrate multiplane images including same standard and nonstandard MRI and US images to help localize tumor. The additional real time fusion CEUS mode image with MR is a safe method for neurosurgery and the use of CEUS should be considered when fusion B-mode ultrasound imaging alone is not satisfactory for margin.
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Neoplasias Encefálicas/diagnóstico por imagem , Sistemas Computacionais , Glioma/diagnóstico por imagem , Monitorização Neurofisiológica Intraoperatória/métodos , Procedimentos Neurocirúrgicos/métodos , Ultrassonografia de Intervenção/métodos , Adulto , Idoso , Neoplasias Encefálicas/cirurgia , Feminino , Glioma/cirurgia , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
A carotid body tumor (CBT) is a rare, non-chromaffin paraganglioma, and its diagnosis mainly depends on imaging modalities. The aim of this study was to investigate the ability of color Doppler ultrasound (CDU) in the diagnosis and assessment of CBT based on computed tomography (CT). We retrospectively reviewed the CDU and CT features of 49 consecutive CBTs and 23 schwannomas from 67 patients and compared these findings with surgical resection specimens. The mean size of CBT lesions on ultrasound scans and CT angiography (CTA) was 3.24 cm ± 0.82 cm (range, 1.6-5.2 cm) and 3.84 cm ± 1.08 cm (range, 1.8-6.8 cm), respectively, which had statistically significant difference (t = 9.815, p = 0.000). The vascularity of CBT lesions was richer than that of schwannoma lesions (p < 0.05). Intra-lesional vascularities feeding CBT mostly arose from the external carotid artery and had spectrum characteristics including low velocity and resistance. Peak systolic velocity (PSV) and resistance index (RI) of the vasa vasorum were 39.8 cm/s ± 19.8 cm/s and 0.54 ± 0.06, respectively. There was the correlation between CTA and CDU in identifying Shamblin type I CBT lesions, while CTA technique was superior for CDU, identifying Shamblin type II and III CBT lesions. Accuracy, specificity and sensitivity of CDU in diagnosing CBTs were 87.5% (63 of 72), 82.6% (19 of 23) and 89.8% (44 of 49), respectively. Both accuracy and sensitivity of CTA in diagnosing CBTs were 100%. CDU can be useful for assessment of Shamblin's type and intra-lesional blood flow of CBTs before its metastases, while CT imaging can reveal the relationship between lesions and adjacent arteries, as well as the involvement of the skull base. CDU combined with CT imaging can be used as an optimal detection modality for the assessment and management of CBT.
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Artéria Carótida Primitiva/diagnóstico por imagem , Tumor do Corpo Carotídeo/diagnóstico por imagem , Angiografia por Tomografia Computadorizada/métodos , Ultrassonografia Doppler em Cores/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Estudos RetrospectivosRESUMO
OBJECTIVE: The main purpose of this work was to investigate the effect of berberine hydrochloride (BH) on the proliferation, apoptosis, migration, and invasion of CNE-1 nasopharyngeal carcinoma cells. Our results shed light on the functional components of traditional Chinese herbs for potential use in modern medicine. METHODS: The CNE-1 cell line was treated with different concentrations of BH and effects on cell viability and proliferation were evaluated using the Cell Counting Kit-8 (CCK-8) assay. Anti-migratory and anti-invasive actions of BH were investigated using wound healing assays and the Millicell Hanging cell culture insert system, respectively. Expression of the epithelial-mesenchymal transition (EMT)-related gene twist (Twist) was analyzed by real-time PCR and Western blotting. Apoptosis was estimated with an annexin-V fluorescein (FITC) apoptosis detection kit, as well as with reference to levels of activated caspase-3 of CNE-1 cells before and after treatment with BH utilizing fluorescence spectroscopy. RESULTS: BH was capable of reducing proliferation and viability of CNE-1 cells in a dose- and time-dependent manner, also demonstrating anti-migratory and anti-invasive capacities which correlated with reduction in expression of Twist. Finally, BH was able to induce significant amounts of apoptosis in CNE-1 cells, as demonstrated by an increase in the activity of caspase-3 and in annexin-V staining following treatment. CONCLUSION: BH extracted from rhizoma coptidis demonstrated an ability to block proliferation, induce apoptosis, and impair the migration and invasion of the CNE-1 cell line Considering these properties, our results suggest that BH could be an important compound for consideration in the treatment of nasopharyngeal carcinoma.
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Apoptose/efeitos dos fármacos , Berberina/farmacologia , Neoplasias Nasofaríngeas/tratamento farmacológico , Proteínas Nucleares/biossíntese , Proteína 1 Relacionada a Twist/biossíntese , Anexina A5/biossíntese , Carcinoma , Caspase 3/biossíntese , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Humanos , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/patologia , Invasividade NeoplásicaRESUMO
OBJECTIVE: The aim of this study was to evaluate the feasibility and therapeutic effectiveness of ultrasonography (US)-guided percutaneous microwave ablation (PMA) in the treatment of peripheral lung cancer. METHODS: From December 2002 to September 2003, 12 Chinese patients with 16 histologically proven lung malignant tumors (6 primary and 10 metastatic) were treated with US-guided PMA. All tumors were located at the peripheral portions of the lung where the tumors were in direct contact with visceral pleura and visualized on US. A total of 21 insertions with 25 applications was administered to the 16 tumors. There was no radiation or chemotherapy combined with PMA. RESULTS: Based on the follow-up period of 6-40 months (average=20 months), seven patients survived without serious complications and five patients died from metastasis after PMA. The size of treated tumors was decreased in all cases (10 tumors with moderate to remarkable area reduction and 6 tumors with mild area reduction). Blood flow in the tumors became either invisible or diminished on color Doppler flow imaging, which showed 9 tumors with no enhancement and 7 tumors with partially decreased enhancement on contrast-enhanced computed tomography after PMA. All patients experienced improvement of clinical symptoms after PMA treatment. CONCLUSIONS: Ultrasonography-guided PMA, a mildly invasive procedure, is an effective, safe, and feasible method for treating peripheral lung tumors. Percutaneous microwave ablation provides an alternative therapy for patients with inoperable peripheral lung cancer as well as for patients who refuse radiation or chemotherapy.
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Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/terapia , Micro-Ondas/uso terapêutico , Terapia Assistida por Computador/métodos , Ultrassonografia/métodos , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
AIM: To study the effect of angelica sinensis polysaccharide (ASP) on immunological colon injury and its mechanisms in rats. METHODS: Immunological colitis model of rats was induced by intracolon enema with 2, 4, 6-trinitrobenzene sulfonic acid (TNBS) and ethanol. The experimental animals were randomly divided into normal control, model control, 5-aminosalicylic acid therapy groups and three doses of ASP therapy groups. The 6 groups were treated intracolonically with normal saline, normal saline, 5-aminosalicylic acid (100 mg.kg(-1)), and ASP daily (8:00 am) at the doses of 200, 400 and 800 mg.kg(-1) respectively for 21 days 7 d following induction of colitis. The rat colon mucosa damage index (CMDI), the histopathological score (HS), the score of occult blood test (OBT), and the colonic MPO activity were evaluated. The levels of SOD, MDA, NO, TNF-alpha, IL-2 and IL-10 in colonic tissues were detected biochemically and immunoradiometrically. The expressions of TGF-beta and EGF in colonic tissues were also determined immunochemically. RESULTS: Enhanced colonic mucosal injury, inflammatory response and oxidative stress were observed in colitis rats, which manifested as significant increases of CMDI, HS, OBT, MPO activity, MDA and NO contents, as well as the levels of TNF-alpha and IL-2 in colonic tissues, although colonic TGF-beta protein expression, SOD activity and IL-10 content were significantly decreased compared with the normal control (P<0.01). However, these parameters were found to be significantly ameliorated in colitis rats treated intracolonically with ASP at the doses of 400 and 800 mg.kg(-1) (P<0.05-0.01). Meantime, colonic EGF protein expression in colitis rats was remarkably up-regulated. CONCLUSION: ASP has a protective effect on immunological colon injury induced by TNBS and ethanol enema in rats, which was probably due to the mechanism of antioxidation, immunomodulation and promotion of wound repair.
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Colite/induzido quimicamente , Colite/prevenção & controle , Doenças do Colo/imunologia , Doenças do Colo/prevenção & controle , Medicamentos de Ervas Chinesas/química , Fitoterapia , Polissacarídeos/farmacologia , Ferimentos e Lesões/prevenção & controle , Angelica sinensis , Animais , Colite/imunologia , Doenças do Colo/fisiopatologia , Modelos Animais de Doenças , Feminino , Interleucina-10/sangue , Interleucina-2/sangue , Masculino , Malondialdeído/análise , Óxido Nítrico/análise , Peroxidase/análise , Ratos , Ratos Sprague-Dawley , Superóxido Dismutase/análise , Fator de Necrose Tumoral alfa/análise , Ferimentos e Lesões/imunologia , Ferimentos e Lesões/fisiopatologiaRESUMO
AIM: To investigate the ameliorative effects of sodium ferulate (SF) on acetic acid-induced colitis and their mechanisms in rats. METHODS: The colitis model of Sprague-Dawley rats was induced by intracolon enema with 8% (V/V) of acetic acid. The experimental animals were randomly divided into model control, 5-aminosalicylic acid therapy group and three dose of SF therapy groups. The 5 groups were treated intracolonically with normal saline, 5-aminosalicylic acid (100 mg x kg(-1)), and SF at the doses of 200, 400 and 800 mg x kg(-1) respectively and daily (8:00 am) for 7 days 24 h following the induction of colitis. A normal control group of rats clystered with normal saline instead of acetic acid was also included in the study. Pathological changes of the colonic mucosa were evaluated by the colon mucosa damage index (CMDI) and the histopathological score (HS). The insulted colonic mucosa was sampled for a variety of determinations at the end of experiment when the animals were sacrificed by decapitation. Colonic activities of myeloperoxidase (MPO) and superoxide dismutase (SOD), and levels of malondialdehyde (MDA) and nitric oxide (NO) were assayed with ultraviolet spectrophotometry. Colonic contents of prostaglandin E2 (PGE2) and thromboxane B2 (TXB2) were determined by radioimmunoassay. The expressions of inducible nitric oxide synthase (iNOS), cyclo-oxygenase-2 (COX-2) and nuclear factor kappa B (NF-kappaB) p65 proteins in the colonic tissue were detected with immunohistochemistry. RESULTS: Enhanced colonic mucosal injury, inflammatory response and oxidative stress were observed in the animals clystered with acetic acid, which manifested as the significant increase of CMDI, HS, MPO activities, MDA and NO levels, PGE2 and TXB2 contents, as well as the expressions of iNOS, COX-2 and NF-kappaB p65 proteins in the colonic mucosa, although the colonic SOD activity was significantly decreased compared with the normal control (CMDI: 2.9+/-0.6 vs 0.0+/-0.0; HS: 4.3+/-0.9 vs 0.7+/-1.1; MPO: 98.1+/-26.9 vs 24.8+/-11.5; MDA: 57.53+/-12.36 vs 9.21+/-3.85; NO: 0.331+/-0.092 vs 0.176+/-0.045; PGE2: 186.2+/-96.2 vs 42.8+/-32.8; TXB2: 34.26+/-13.51 vs 8.83+/-3.75; iNOS: 0.365+/-0.026 vs 0.053+/-0.015; COX-2: 0.296+/-0.028 vs 0.034+/-0.013; NF-kappaB p65: 0.314+/-0.026 vs 0.039+/-0.012; SOD: 28.33+/-1.17 vs 36.14+/-1.91; P<0.01). However, these parameters were found to be significantly ameliorated in rats treated locally with SF at the given dose protocols, especially at 400 mg x kg(-1) and 800 mg x kg(-1) doses (CMDI: 1.8+/-0.8, 1.6+/-0.9; HS: 3.3+/-0.9, 3.1+/-1.0; MPO: 63.8+/-30.5, 36.2+/-14.2; MDA: 41.84+/-10.62, 37.34+/-8.58; NO: 0.247+/-0.042; 0.216+/-0.033; PGE2: 77.2+/-26.9, 58.4+/-23.9; TXB2: 18.07+/-14.83; 15.52+/-8.62; iNOS:0.175+/-0.018, 0.106+/-0.019; COX-2: 0.064+/-0.018, 0.056+/-0.014; NF-kappaBp65: 0.215+/-0.019,0.189+/-0.016; SOD: 32.15+/-4.26, 33.24+/-3.69; P<0.05-0.01). Moreover, a therapeutic dose protocol of 800 mg x kg(-1) SF was observed as effective as 100 mg x kg(-1) of 5-ASA in the amelioration of colonic mucosal injury as evaluated by CMDI and HS. CONCLUSION: Administration of SF intracolonically may have significant therapeutic effects on the rat model of colitis induced by acetic acid enema, which was probably due to the mechanism of antioxidation, inhibition of arachidonic acid metabolism and NF-kappaB expression.