The most important biomarker associated with coagulation and inflammation among COVID-19 patients.

Coronavirus disease 2019 (COVID-19) induced by SARS-Cov-2 can be related to coagulopathy. Also, the infection-induced inflammatory changes are found in patients with disseminated intravascular coagulopathy (DIC). The lack of previous immunity to COVID-19 has caused infection of a large number of patients worldwide and unpredictability regarding the management of the complications that appear in the course of this viral illness. Lungs are the most important target organ of the SARS-COV-2. In COVID-19 patients, acute lung injury leads to respiratory failure. However, multiorgan failure can also occur in these patients. The primary coagulopathy of COVID-19 is marked by a considerable elevation of D-dimer, ferritin, and fibrinogen degradation products. In comparison, abnormalities in platelet count, prothrombin time, and partial thromboplastin time are partly uncommon in initial presentations. Inflammatory biomarkers including CRP, LDH, and IL-6 are significantly elevated in the early stages of the disease. In this regard, inflammation-associated biomarkers and coagulation test screening, including the assessment of IL-6, CRP, LDH, D-dimer, platelet count, PT&PTT time, ferritin, and fibrinogen levels are suggested for detecting infection by this virus. Overall, COVID-19-associated coagulopathy should be managed like other patients with critical conditions, and supportive care and thromboembolic prophylaxis should be used for severe patients.

Inflammatory Markers Related to Innate and Adaptive Immunity in Atherosclerosis: Implications for Disease Prediction and Prospective Therapeutics.

Several lines of evidence have linked a dysregulated inflammatory setting to the pathogenesis of atherosclerosis, which is a form of chronic vascular inflammation. Various inflammatory biomarkers have been associated with inflammation and are recognized as potential tools to monitor the progression of atherosclerosis. A well-studied inflammatory marker in the context of cardiovascular diseases is C-reactive protein (CRP) or, more accurately, highly sensitive-CRP (hs-CRP), which has been established as an inflammatory biomarker for atherosclerotic events. In addition, a growing body of investigations has attempted to disclose the potential of inflammatory cytokines, enzymes, and genetic polymorphisms related to innate and adaptive immunity as biomarkers for predicting the development of atherosclerosis. In this review article, we clarify both traditional and novel inflammatory biomarkers related to components of the innate and adaptive immune system that may mirror the progression or phases of atherosclerotic inflammation/lesions. Furthermore, the contribution of the inflammatory biomarkers in developing potential therapeutics against atherosclerotic treatment will be discussed.

Phase 2 study of accelerated hypofractionated thoracic radiation therapy and concurrent chemotherapy in patients with limited-stage small-cell lung cancer.

PURPOSE: To prospectively investigate the efficacy and toxicity of accelerated hypofractionated thoracic radiation therapy (HypoTRT) combined with concurrent chemotherapy in the treatment of limited-stage small-cell lung cancer (LS-SCLC), with the hypothesis that both high radiation dose and short radiation time are important in this setting. METHODS AND MATERIALS: Patients with previously untreated LS-SCLC, Eastern Cooperative Oncology Group performance status of 0 to 2, and adequate organ function were eligible. HypoTRT of 55 Gy at 2.5 Gy per fraction over 30 days was given on the first day of the second or third cycle of chemotherapy. An etoposide/cisplatin regimen was given to 4 to 6 cycles. Patients who had a good response to initial treatment were offered prophylactic cranial irradiation. The primary endpoint was the 2-year progression-free survival rate. RESULTS: Fifty-nine patients were enrolled from July 2007 through February 2012 (median age, 58 years; 86% male). The 2-year progression-free survival rate was 49.0% (95% confidence interval [CI] 35.3%-62.7%). Median survival time was 28.5 months (95% CI 9.0-48.0 months); the 2-year overall survival rate was 58.2% (95% CI 44.5%-71.9%). The 2-year local control rate was 76.4% (95% CI 63.7%-89.1%). The severe hematologic toxicities (grade 3 or 4) were leukopenia (32%), neutropenia (25%), and thrombocytopenia (15%). Acute esophagitis and pneumonitis of grade ≥3 occurred in 25% and 10% of the patients, respectively. Thirty-eight patients (64%) received prophylactic cranial irradiation. CONCLUSION: Our study showed that HypoTRT of 55 Gy at 2.5 Gy per fraction daily concurrently with etoposide/cisplatin chemotherapy has favorable survival and acceptable toxicity. This radiation schedule deserves further investigation in LS-SCLC.

Overexpression of periostin predicts poor prognosis in non-small cell lung cancer.

The periostin protein, encoded by the POSTN gene, is a component of the extracellular matrix, which is expressed by fibroblasts and has been observed in a variety of human malignancies. The present study aimed to detect the expression of periostin in the tissues of non-small cell lung cancer (NSCLC) patients and benign lung tumors, and to correlate the results with the clinicopathological data of the subjects, in order to evaluate periostin as a potential prognostic marker. In total, 49 NSCLC patients and 6 benign lung tumors were included in this study. The protein level of periostin was detected in paired normal/paratumor/cancer tissues by a western blot analysis and the mRNA level in paired normal/cancer tissues was detected by quantitative polymerase chain reaction (qPCR). The results were then correlated with established biological and prognostic factors. Immunohistochemistry was used to confirm the location of periostin in the NSCLC tissues. Uni- and multivariate analyses were performed using Cox's proportional hazards regression model. The protein level of periostin was elevated in the cancer tissue of the NSCLC patients compared with the normal (P=0.017) and paratumor (P=0.000) tissues. The expression level in the male patients was much higher than in the female patients at the protein (P=0.001) and mRNA (P=0.010) levels. The mRNA level in the non-adenocarcinoma (non-ADC) patients was much higher than in the adenocarcinoma (ADC) patients (P=0.029). Periostin was demonstrated higher expression at the protein level in the pseudotumors and tuberculosis patients than in the adjacent (P=0.016) and surrounding tissues (P=0.001). Immunostaining indicated that high levels of periostin were present in the mesenchymal areas, but not in the cancer cells themselves. The patients with tumors exhibiting high-level periostin expression showed a significantly shorter survival time (P=0.036, log-rank test). The 3-year survival rate was 81.5% for patients with low-level periostin expression (periostin-L; n=27) and 45.4% for patients with high-level periostin expression (periostin-H; n=22). Similarly, pathological node (pN) status was a significant prognostic marker in the univariate Cox survival analysis. Notably, periostin-H expression was also identified as an independent prognostic factor by the multivariate analysis (P=0.011). These results showed that the overexpression of periostin predicts a poor prognosis, therefore it may be regarded as a novel molecule in the progression and development of NSCLC. The results provide an additional target for the adjuvant treatment of NSCLC.

[Effect of heparin upon inflammatory reaction of endotoxin-induced acute lung injury in rat].

OBJECTIVE: To investigate the effects of heparin upon inflammatory reaction and associated mechanism of endotoxin-induced acute lung injury (ALI) in rat. METHODS: Thirty-six male Sprague-Dawley rats were randomly divided into three equal groups namely: ALI group, heparin treatment group and normal control group. The ALI rats were induced by injecting endotoxin intravenously and sacrificed at 4 h after model establishment. The lung histology was scored by a modification of Smith technique. The albumin permeability of pulmonary microvascular (P(alb)) was measured by single nuclide tracer technique. Tumor necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6) and von Willebrand factor (vWF) levels of serum were determined using commercial enzyme-linked immunosorbent assay kits. The expressions of lung tissue extacellular signal-regulated kinases (ERK)-1/2, P38 mitogen-activated protein kinase (MAPK) and c-jun N-terminal kinases (JNK) were determined by Western blotting. RESULTS: The Smith lung injury score in heparin treatment group and ALI group were (5.00 +/- 1.26) and (8.00 +/- 1.09) respectively. The values were significantly higher than that of normal control group (0.67 +/- 0.52, both P < 0.01). However, the Smith lung injury score in heparin treatment group was significantly lower than that of ALI group (P < 0.01). The P(alb), TNF-alpha, IL-6 and vWF of heparin treatment group were (0.28 +/- 0.04), (1.92 +/- 0.35) microg/L, (1.22 +/- 0.13) ng/ml and (24.9 +/- 4.0) U/L respectively. The values were significantly higher than those of normal control group [0.20 +/- 0.02, (0.51 +/- 0.09) microg/L, (0.23 +/- 0.05) ng/ml and (14.0 +/- 3.0) U/L respectively, all P < 0.01] but significantly lower than those of ALI group [(0.38 +/- 0.04), (2.77 +/- 0.37) microg/L, (1.62 +/- 0.13) ng/ml and (31.8 +/- 7.5) U/L respectively, all P < 0.01]. The lung tissue levels of phospho-ERK1/2 and phospho-P38 MAPK expressions of heparin treatment group were markedly higher than those of normal control group, whereas markedly lower than those of ALI group. There was no marked difference of phospho-JNK expression in all three groups. CONCLUSION: Heparin markedly inhibits the expressions of phospho-ERK1/2 and phospho-P38 MAPK, down-regulates the inflammatory reaction, attenuates the endothelial permeability of pulmonary vasculature and significantly improves endotoxin-induced lung injury in rats.

Antithrombin-III without concomitant heparin improves endotoxin-induced acute lung injury rats by inhibiting the activation of mitogen-activated protein kinase.

BACKGROUND: Antithrombin-III (AT-III), the major inhibitor of thrombin in plasma, also has anti-inflammation property and might have positive effect on sepsis. The present study aimed to investigate the effects of AT-III on inflammatory reaction and pulmonary protection in endotoxin-induced acute lung injury (ALI) rat. METHODS: Sixty male Sprague-Dawley rats were randomly assigned equally to normal control group, ALI group, AT-III treatment group, AT-III + heparin treatment group, and heparin treatment group. The pulmonary vascular permeability index (PVPI) was measured by single nuclide tracer technique. The activity of AT-III in plasma was determined by the method of synthetic chromogenic substrata. Tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) levels in serum were determined by enzyme-linked immunosorbent assay. The expressions of lung tissue mitogen-activated protein kinases (ERK1/2, P38 and JNK MAPK) were determined by Western blotting. RESULTS: Rats had significantly improved lung histopathology in the AT-III treatment group and heparin treatment group compared with the ALI group. The PVPI of the ALI group was 0.38 + or - 0.04, significantly higher than that of the normal control group (0.20 + or - 0.02, P < 0.01), AT-III treatment group (0.30 + or - 0.04, P < 0.01) and heparin treatment group (0.28 + or - 0.04, P < 0.01) respectively. There were no significant differences of PVPI in the ALI group and AT-III + heparin treatment group. The activity of AT-III in plasma in the ALI group was (76 + or - 8)%, significantly lower than that of the normal control group ((96 + or - 11)%, P < 0.05) and AT-III treatment group ((105 + or - 17)%, P < 0.05) respectively. The serum levels of TNF-alpha and IL-6 of the ALI group were (2.770 + or - 0.373) microg/L and (1.615 + or - 0.128) ng/ml respectively, significantly higher than those of the normal control group ((0.506 + or - 0.093) microg/L and (0.233 + or - 0.047) ng/ml respectively, all P < 0.01), AT-III treatment group ((1.774 + or - 0.218) microg/L and (1.140 + or - 0145) ng/ml respectively, all P < 0.01) and heparin treatment group ((1.924 + or - 0.349) microg/L and (1.223 + or - 0.127) ng/ml respectively, all P < 0.01). The lung tissue levels of phospho-ERK1/2 and phospho-P38 MAPK expressions were markedly higher in the ALI group than in the normal control group, AT-III treatment group and heparin treatment group respectively. CONCLUSIONS: AT-III without concomitant heparin inhibited the activation of ERK1/2 and P38 MAPK, down-regulated the levels of downstream cytokines TNF-alpha and IL-6, relieved endothelial permeability, and improved the ALI in endotoxin-induced rats. It might be helpful to administrate AT-III alone, not with concomitant heparin, to those patients with ALI and sepsis.