Cytokine storm and translating IL-6 biology into effective treatments for COVID-19 / 医学前沿

As of May 3, 2023, the Coronavirus disease 2019 (COVID-19) pandemic has resulted in more than 760 million confirmed cases and over 6.9 million deaths. Several patients have developed pneumonia, which can deteriorate into acute respiratory distress syndrome. The primary etiology may be attributed to cytokine storm, which is triggered by the excessive release of proinflammatory cytokines and subsequently leads to immune dysregulation. Considering that high levels of interleukin-6 (IL-6) have been detected in several highly pathogenic coronavirus-infected diseases, such as severe acute respiratory syndrome in 2002, the Middle East respiratory syndrome in 2012, and COVID-19, the IL-6 pathway has emerged as a key in the pathogenesis of this hyperinflammatory state. Thus, we review the history of cytokine storm and the process of targeting IL-6 signaling to elucidate the pivotal role played by tocilizumab in combating COVID-19.

Tocilizumab in patients with moderate or severe COVID-19: a randomized, controlled, open-label, multicenter trial / 医学前沿

Tocilizumab has been reported to attenuate the "cytokine storm" in COVID-19 patients. We attempted to verify the effectiveness and safety of tocilizumab therapy in COVID-19 and identify patients most likely to benefit from this treatment. We conducted a randomized, controlled, open-label multicenter trial among COVID-19 patients. The patients were randomly assigned in a 1:1 ratio to receive either tocilizumab in addition to standard care or standard care alone. The cure rate, changes of oxygen saturation and interference, and inflammation biomarkers were observed. Thirty-three patients were randomized to the tocilizumab group, and 32 patients to the control group. The cure rate in the tocilizumab group was higher than that in the control group, but the difference was not statistically significant (94.12% vs. 87.10%, rate difference 95% CI-7.19%-21.23%, P = 0.4133). The improvement in hypoxia for the tocilizumab group was higher from day 4 onward and statistically significant from day 12 (P = 0.0359). In moderate disease patients with bilateral pulmonary lesions, the hypoxia ameliorated earlier after tocilizumab treatment, and less patients (1/12, 8.33%) needed an increase of inhaled oxygen concentration compared with the controls (4/6, 66.67%; rate difference 95% CI-99.17% to-17.50%, P = 0.0217). No severe adverse events occurred. More mild temporary adverse events were recorded in tocilizumab recipients (20/34, 58.82%) than the controls (4/31, 12.90%). Tocilizumab can improve hypoxia without unacceptable side effect profile and significant influences on the time virus load becomes negative. For patients with bilateral pulmonary lesions and elevated IL-6 levels, tocilizumab could be recommended to improve outcome.

Potential role of aberrant mucosal immune response to SARS-CoV-2 in pathogenesis of IgA Nephropathy

Aberrant mucosal immunity has been suggested to play a pivotal role in pathogenesis of IgA nephropathy (IgAN), the most common form of glomerulonephritis worldwide. The outbreak of severe acute respiratory syndrome coronavirus (SARS-CoV-2), the causal pathogen of coronavirus disease 2019 (COVID-19), has become a global concern. However, whether the mucosal immune response caused by SARS-CoV-2 influences the clinical manifestations of IgAN patients remains unknown. Here we tracked the SARS-CoV-2 anti-receptor binding domain (RBD) antibody levels in a cohort of 88 COVID-19 patients. We found that 52.3% of the COVID-19 patients produced more SARS-CoV-2 anti-RBD IgA than IgG or IgM, and the levels of the IgA were stable during 4-41 days of infection. Among these IgA-dominated COVID-19 patients, we found a severe COVID-19 patient concurrent with IgAN. The renal function of the patient declined presenting with increased serum creatinine during the infection and till 7 months post infection. This patient predominantly produced anti-RBD IgA as well as total IgA in the serum compared to that of healthy controls. The analysis of the IgA-coated microbiota as well as proinflammatory cytokine IL-18, which was mainly produced in the intestine, reveals intestinal inflammation, although no obvious gastrointestinal symptom was reported. The mucosal immune responses in the lung are not evaluated due to the lack of samples from respiratory tract. Collectively, our work highlights the potential adverse effect of the mucosal immune response towards SARS-CoV-2, and additional care should be taken for COVID-19 patients with chronic diseases like IgAN.

Tocilizumab treatment in severe COVID-19 patients attenuates the inflammatory storm incited by monocyte centric immune interactions revealed by single-cell analysis

ABSTRACTDespite the current devastation of the COVID-19 pandemic, several recent studies have suggested that the immunosuppressive drug Tocilizumab can powerfully treating inflammatory responses that occur in this disease. Here, by employing single-cell analysis of the immune cell composition of severe-stage COVID-19 patients and these same patients in post Tocilizumab-treatment remission, we have identified a monocyte subpopulation specific to severe disease that contributes to inflammatory storms in COVID-19 patients. Although Tocilizumab treatment attenuated the strong inflammatory immune response, we found that immune cells including plasma B cells and CD8+ T cells still exhibited an intense humoral and cell-mediated anti-virus immune response in COVID-19 patients after Tocilizumab treatment. Thus, in addition to providing a rich, very high-resolution data resource about the immune cell distribution at multiple stages of the COVID-19 disease, our work both helps explain Tocilizumab’s powerful therapeutic effects and defines a large number of potential new drug targets related to inflammatory storms.Competing Interest StatementJingwen Fang is the executive officer of HanGen BiotechView Full Text

Aberrant pathogenic GM-CSF+ T cells and inflammatory CD14+CD16+ monocytes in severe pulmonary syndrome patients of a new coronavirus

Pathogenic human coronavirus infections, such as severe acute respiratory syndrome CoV (SARS-CoV) and Middle East respiratory syndrome CoV (MERS-CoV), cause high morbidity and mortality 1,2. Recently, a severe pneumonia-associated respiratory syndrome caused by a new coronavirus was reported at December 2019 (2019-nCoV) in the city Wuhan, Hubei province, China3-5, which was also named as pneumonia-associated respiratory syndrome (PARS)6. Up to 9th of February 2020, at least 37, 251 cases have been reported with 812 fatal cases according to the report from China CDC. However, the immune mechanism that potential orchestrated acute mortality from patients of 2019-nCoV is still unknown. Here we show that after the 2019-nCoV infection, CD4+T lymphocytes are rapidly activated to become pathogenic T helper (Th) 1 cells and generate GM-CSF etc. The cytokines environment induces inflammatory CD14+CD16+ monocytes with high expression of IL-6 and accelerates the inflammation. These aberrant and excessive immune cells may enter the pulmonary circulation in huge numbers and play an immune damaging role to causing lung functional disability and quick mortality. Our results demonstrate that excessive non-effective host immune responses by pathogenic T cells and inflammatory monocytes may associate with severe lung pathology. Therefore, we suggest that monoclonal antibody that targets the GM-CSF or interleukin 6 receptor may potentially curb immunopathology caused by 2019-nCoV and consequently win more time for virus clearance.

Research progress on tumor-vessel associated extravascular tumor metastasis / 中华消化外科杂志

The occurrence of malignant tunors is increasing annually around the world.In every year,8.2 million patients died of malignant tumors in which about 90％ patients died of malignant tumors associated multiple organs metastases.Inhibiting tumor metastasis is the key event to prolong the survival time of patients.With the further research,tumor-vessel associated extravascular tumor metastasis is playing an increasingly important role in the clinical application.This paper summarizes the new developments of tumor-vessel associated extravascular tumor metastasis to provide possible ideas for the therapy of malignant tumors.

The value of dynamic contrast-enhanced MRI and diffusion tensor imaging in grading of glioma / 实用放射学杂志

Objective To explore the value of dynamic contrast-enhanced MRI (DCE-MRI)and diffusion tensor imaging(DTI)in grading of glioma.Methods 3.0T DCE-MRI and DTI scans were performed in 31 patients with glioma confirmed by pathology.Capacity volume transfer constant (Ktrans ),extravascular extracellular volume fraction (Ve ),exchange rate constant (Kep ),initial area under the gadolinium concentration-time curve (iAUC),and relative fractional anisotropy (rFA)were measured in the low grade glioma (LGG)and the high grade glioma (HGG).The correlation between parameters of DCE-MRI and rFA with microvessel denisity (MVD)and microvessel structure (MVS)were performed by Spearman rank correlation analysis.Results The MVD and MVS were positive correlation with the grading of glioma.Ktrans ,Kep ,Ve ,iAUC and rFA values of the LGG were (0.02±0.01)min-1 ,1.82 (0.18-8.54)min-1 ,0.05±0.03, 2.47±1.66 and 0.55±0.22,respectively.Ktrans ,Kep ,Ve ,iAUC and rFA values of the HGG were (0.1 1±0.02)min-1 ,1.31 (0.12-7.58)min-1 ,0.28±0.10,10.84 ±6.46 and 0.28 ±0.08,respectively.The differences of all parameters between the LGG and the HGG were statistically significant,except for Kep (P <0.05 ).Ktrans ,Ve and iAUC values were positive correlation with MVD and MVS (P <0.05),and rFA values were negative correlation with MVD and MVS (P <0.01).Conclusion The quantitative parameters of DCE-MRI and DTI have important values in grading of glioma and evaluating tumor angiogenesis and microvessel structure.

Expressions and significances of prognosis by MiR-451a in nasopharyngeal carcinoma in Guangxi / 实用医学杂志

Objective To investigate the expression level and the significances of prognosis by miR-451a in nasopharyngeal carcinoma (NPC) in Guangxi. Methods The expressions of miR-451a in 89 cases of nasopharyngeal carcinoma were detected by real time RT-PCR. The relation among the expression level , the clinicopathologic features of NPC and its prognosis were analyzed. Results The expression of miR-451a were found in all of nasopharyngeal carcinoma. The expression level of miR-451a in nasopharyngeal carcinoma was negative correlated to overall survival and disease free survival (P = 0.01,P = 0.04). Conclusions miR-451a may play a key role in detection of nasopharyngeal carcinoma with poor prognosis.

Acoustic Radiation Force Impulse Imaging for the Assessment of Renal Histopathology in Chronic Glomerulonephritis / 中国医学影像学杂志

Purpose To observe the change of renal parenchyma elasticity in patients with chronic glomerulonephritis (CGN), and to explore the value of acoustic radiation force impulse (ARFI) in the assessment of renal histological damages in CGN. Materials and Methods 123 patients with CGN and 27 healthy volunteers were enrolled, CGN patients were divided into three groups according to renal histologic scores: mildly, moderately, and severely impaired. Shear wave velocities (SWV) of the renal parenchyma were measured and compared in different groups, the correlation between the SWV measurements and renal fibrosis Katafuchi scores, serum creatinine (Scr) and estimated glomerular filtration rate (e-GFR) was accessed, and receiver operating characteristic (ROC) curves analyses were also performed to assess the value of ARFI for the diagnosis of pathology impairment degree in CGN. Results There were statistically significant differences in SWV measurements between each CGN patient group and the control group (F=16.592, P<0.01); the mean SWV in patients with severe kidney impairment was significant lower than that of mildly impaired, moderately impaired, and the control groups (P<0.001). SWV measurements correlated significantly with renal fibrosis Katafuchi scores (r=-0.481, P<0.01), Scr (r=-0.441, P<0.01), and e-GFR (r=0.546, P<0.01); ROC analyses indicated that the sensitivity was 63.4%, 71.4%, 93.8%, specificity was 77.8%, 71.3%, 79.9%, and the area under the curve was 0.730, 0.738 and 0.870, when using the optimal cut-off value of 2.65 m/s for the diagnosis of mildly impaired kidneys, 2.50 m/s for moderately impaired kidneys, and 2.34 m/s for severely impaired kidneys, respectively. Conclusion ARFI is expected to become an effective tool for non-invasive evaluating of renal histological fibrosis in CGN patients.

Expression of bone morphogenetic protein and its receptors in different stages of hypertrophic scar / 中国组织工程研究

BACKGROUND:Bone morphogenetic proteins are associated with the formation and development of scars. Fibroblasts are closely related to the proliferation and maturation of scars. However, the expression of bone morphogenetic proteins in fibroblasts in different stage of hypertrophic scars remains poorly understood. OBJECTIVE:To observe the expression of bone morphogenetic protein 2/4, bone morphogenetic protein 7, bone morphogenetic protein receptor IA in fibroblasts in different stage of hypertrophic scars. METHODS:The immunohistochemical SP method was employed to detect the expression of bone morphogenetic protein 2/4, bone morphogenetic protein 7, bone morphogenetic protein receptor IA in fibroblasts in 20 cases of proliferative stage hypertrophic scar and 20 cases of maturation stage hypertrophic scar. Al samples were obtained from the Department of Plastic and Aesthetic Surgery, the People’s Hospital of Guangxi Zhuang Autonomous Region, China. RESULTS AND CONCLUSION:The expression of bone morphogenetic protein 2/4 in fibroblasts in proliferative hypertrophic scars significantly elevated compared with mature hypertrophic scars (P0.05). Results demonstrated that bone morphogenetic protein 2/4 expression down-regulated during the development from proliferative stage to maturation stages in fibroblasts in hypertrophic scars. However, there was no change in the expression of bone morphogenetic protein 7 and bone morphogenetic protein receptor IA.

Effect of p53 gene therapy on the local immunity and the efficacy of patients with nasopharyngeal carcinoma / 临床耳鼻咽喉头颈外科杂志

OBJECTIVE@#To investigate the tumor regression and local immune function in nasopharyngeal carcinoma patients treated with p53 gene therapy.@*METHOD@#The two-step immunohistochemical was done to detect the expression of tumor-infiltrating lymphocytes (TIL) T-cell receptor-CD3, CD4, CD8 and B cell receptor-CD20 in the primary tumor tissue of nasopharyngeal carcinoma. Nasal endoscopy with MRI or CT was used for evaluation of tumor size.@*RESULT@#The expression of CD3, CD4, CD8 was significantly increased after p53 gene treatment (P 0.05). In conventional treatment group, CD3, CD4, CD8 and CD20 (P > 0.05) did not show any significant difference. In gene therapy group at 3 months after treatment, 20 patients had achieved CR, 10 PR, 1 SD, 1 PD. In conventional treatment group, 11 patients had achieved CR, 12 PR,5 SD,3 PD. The response rate between treatment group and control group (CR+PR) was different (P < 0.05). CD3 and CD4 expression was correlated with tumor regression rate (P < 0.05, P < 0.01), and CD8 expression was correlated with the CR rate (P < 0.05).@*CONCLUSION@#T cells are the most proliferative cell of TII. in NPC patients after p53 gene therapy The local cellular immune status is positively correlated with tumor regression rate.

The expression and significance of IGF-1R in nasal polyp and its relationship with allergic rhinitis / 临床耳鼻咽喉头颈外科杂志

OBJECTIVE@#To study the expression of insulin-like growth factor-1 receptor(IGF-1R) in nasal polyps and its relationship with allergic rhinitis.@*METHOD@#The mRNA and protein expression of IGF-1R in 40 cases (20 cases with allergic rhinitis and 20 cases without) nasal polyps tissue (the CRSWNP group) and 20 middle turbinate tissue samples (the control group) were examined by fluorescence quantitative polymerase chain reaction (FQ-PCR) and immunohistochemistry.@*RESULT@#The positive staining rate of IGF-1R protein of nasal polyps tissue is 70.8% and that of control is 12.3%, the expression of IGF-1R mRNA of nasal polyp is 0.748 +/- 0.111,which is significant higher than that of the control group is 0.107 +/- 0.208 (P < 0.01). No significant difference of the expression of IGF-1R mRNA between with and without allergic rhinitis cases and between with and without endoscopy sinus surgery history cases in the CRSWNP group.@*CONCLUSION@#The overexpression of IGF-1R maybe play important roles in the formation of nasal polyp. Hypersensitivity reaction type I mediated by IgE has no contribution to the overexpression of the IGF-1R.

Study for the histopathologic change of ethmoid bone in patients with chronic rhinosinusitis and its correlation factors / 临床耳鼻咽喉头颈外科杂志

OBJECTIVE@#To investigate the histopathologic changes of ethmoid bone and its correlation with clinical types of chronic rhinosinusitis (CRS).@*METHOD@#All ethmoid bones and mucosa from 180 patients with CRS after endoscopic sinus surgery were collected for histopathologic detection with HE staining. The number and the rate of cases were counted according to different histopathologic types. To analyze the correlation between ethmoid bones and clinical types of CRS, mucosal pathologic change, the CT-scanning types of sinusitis, the course of disease as well as operational history.@*RESULT@#The ethmoid bone of all patients had varying degrees of histopathologic changes. There were 5 cases (2.78%) in stage I, 38 cases (21.11%) in stage II, 71 cases (39.44%) in stage III, and 66 cases (36.67%) in stage NIV. The histopathologic changes of ethmoid bone varied in different clinical types. In type I, there were 5 cases (8.33%) in stage I, 33 cases (55.00%) in stage II, 15 cases (25.00%) in stage III, and 7 cases (11.67%) in stage NV. In type I, there were 5 cases (8.33%) in stage II, 37 cases (61.67%) in stage mI, and 18 cases (30.00%) in stage NV. In type III, there were 19 cases (31.67%) in stage III, and 41 cases (68.33%) in stage NV. All histopathologic changes of ethmoid bone were statistically correlated (P < 0.01) with clinical types of CRS, pathologic mucosal change, the CT-scanning types of sinusitis, the course of disease as well as operational history.@*CONCLUSION@#Almost all patients with CRS manifest different-degrees of histopathologic changes, which are correlated with the clinical types of CRS, pathologic mucosal change, the CT-scanning types, the course of disease as well as operational history.

A case of nasal keratoacanthoma (a case report and literatures review) / 临床耳鼻咽喉头颈外科杂志

OBJECTIVE@#To investigate the clinical characteristics and therapy methods of Keratoacanthoma.@*METHOD@#We reported a 39 years old man with nasal keratoacanthoma, and reviewed the literatures.@*RESULT@#The nasal neoplasms was expected, and the patient had a rhinoplasty. No recurrence happened in the half of one year follow up.@*CONCLUSION@#Keratoacanthoma is a kind of low malignant potential cutaneous neoplasms which grow rapidly with special clinical and histopathologic characteristics and is similar to squamous carcinoma cell.

Study on the liver injuries induced by cisplatin and carboplatin in mice / 中国基层医药

Objective To study the time the liver injuries appeared,the different level of liver injury induced by injecting Cisplatin and Carboplatin in mice and the possible mechanisms of the liver injury.Methods Mice were intravenously given,Cisplatin(17 mg/kg),Carboplatin(67 mg/kg) respectively.In the 3th,7th,11 th and 14th day after injecting the medicines,the serum biochemistry parameters,oxidation and antioxidation parameters of liver and histopathologic change in hepatic tissue were observed.Results HE stain showed that fatty degeneration of hepatocyte in the two experiment groups in the 3th day after injecting medicines,and hepatocellular spotty necrosis,and infiltration of inflammatory cells arroud the necrotic liver were found in,Cisplatin group.The level of aspartate aminotransferase and alkaline phosphatase in the two experiment groups increased significantly compared with those in the control (group P＜0.01),and alanine aminotransferase in Cisplatin group increased significantly(P＜0.01),compared with that in the control group and Carboplatin group.Conclusion Hepatic injury was observed in the 3th day after injecting medicines,the level of liver injury in Cisplatin group was heavier than that in Carboplatin group.

The histomorphological changes of the nasal mucosa in nasopharyngeal carcinoma patients postradiotherapy / 临床耳鼻咽喉头颈外科杂志

OBJECTIVE@#To study the histomorphology at the nasal mucosa in the nasopharyngeal carcinoma (NPC) patients postradiotherapy.@*METHOD@#Forty-seven specimens from the nasal mucosa of NPC patients postradiotherapy were observed under light microscope. The changes of the mucosal histomorphology include cells and cilia in epithelium, basal layer, glandular and glandular cells in lamina propria. Six specimens were observed under electron microscope, including the changes of the cilia and ciliated columnar epithelial cells in epithelium.@*RESULT@#The histomorphology of the 47 specimens were normal before radiotherapy. In the 47 specimens, six specimens had no changes but 41 specimens were found various changes postradiotherapy. The mucosal changes of epithelium and cilia desquamating, basal layer thickening, decrease of the serous glands and increase of the mucous glands in lamina propria were observed under light microscope. We found the cilia structural abnormalities and the abnormal phenomena of the epithelium under scanning electron microscope (SEM) and transmission electron microscope (TEM) respectively.@*CONCLUSION@#We found that the various extent of destruction of the nasal mucosa may be the pathological basis of complicating nasal or sinusitis in NPC patients postradiotherapy.

Analysis for the correlation between skin prick test and clinical characteristics in patients with chronic sinusitis with nasal polyps / 中国耳鼻咽喉头颈外科

OBJECTIVE To investigate the relationship between the skin prick test and clinical characteristics in patients with chronic sinusitis with nasal polyps(CRSwNP).METHODS Sixty cases with CRSwNP and 40 control samples underwent skin prick test with standardized allergens provided by AllergoPhamar Company,the results and their clinical characteristics are analyzed.RESULTS The positive rate of skin prick test was 81.7% and 17.5% in CRSwNP group and control group respectively(?2 =40.104,?

Expression and correlation of COX-2 and VEGF-C in nasopharyngeal carcinoma / 中国耳鼻咽喉头颈外科

OBJECTIVE To investigate vascular endothelial growth factor-C (VEGF-C) and cyclooxyegense-2(COX-2) expression in nasopharyngeal carcinoma. METHODS The expression of COX-2 and VEGF-C were stained respectively in nasopharyngeal carcinoma tissues of 45 patients using immunohistochemical method,and were analyzed with clinical data. RESULTS The positive expression rates of COX-2 and VEGF-C were 68.9 % and 53.3 % respectively in nasopharyngeal carcinoma tissue. The expression of COX-2 was positively correlated with VEGF-C (r=0.334,P

Expression of transcription factor T-bet/GATA3 in lung cancer patients and its interference by the traditional Chinese herbal medicine / 中华肿瘤杂志

<p><b>OBJECTIVE</b>To study the relation between the expression of transcription factor T-bet/GATA3 and Th1/Th2 type cytokines in peripheral blood mononuclear cells (PBMC) from lung cancer patients and their interference by the traditional Chinese herbal medicine.</p><p><b>METHODS</b>The gene expression of Th1/Th2 type cytokine IFN gamma, IL-2, IL-4, IL-6, IL-10, transcription factor T-bet/GATA3 and tumor tissue specific mRNA CEA, CK19 in PBMC from lung cancer patients were detected by reverse transcription-polymerase chain reaction RT-PCR. Meanwhile, the change of IFN gamma, IL-4, T-bet and GATA3 in PBMC before and after being cultured with the traditional Chinese herbal medicine-Astragulus and Tetramethylpyrazine was also observed.</p><p><b>RESULTS</b>Predominant expression of Th2 type cytokines was detected in 42 lung cancer patients. The positive rates of IL-4, IL-6, IL-10, IFN gamma and IL-2 were 27/42, 24/42, 31/42, 4/42 and 5/42, respectively. But, the positive rates of transcription factor T-bet and GATA3 were 16/42 and 34/42. Moreover, the expression intensity of T-bet was lower in the CEA and CK19 positive patients than the negative ones. On the contrary, the expression intensity of GATA3 was significantly higher in the same patients.</p><p><b>CONCLUSION</b>Predominant expression of Th2 type cytokines may be related to lower expression of T-bet or higher expression of GATA3. This condition can be interfered by the traditional Chinese herbal medicine-Astragulus and Tetramethylpyrazine.</p>

NK cells are involved in OVA induced asthma in murine / 中国免疫学杂志

Objective:To investigate the changes of lung lymphocytes in OVA induced murine asthma model,and study the involvement of NK cells in this process.Methods:C57BL/6J(B6) mice were induced to develop asthma by intrapenitoneal injection of OVA with alum as adjuvant, and then inhalation of nebulized OVA. After collecting serum and Bronchoalveolar Lavage Fluid(BALF),IL-4 level was determined by ELISA. The kinetics of pulmonary lymphocyte recruitment and cytokine release were detected by flow cytometry.Results:IL-4 expression increased in BALF after OVA nebulization, while there was no significant difference in serum. IFN-?,IL-4+NK cells accumulation in lung parenchymal tissues,and exhibited an evident NK2 shift in mice with asthma.Conclusion:NK cell involved in OVA-induced mouse asthma and NK2 shift accompany with Th2, indicating that NK2 played an important role in this process.