Paclitaxel combined with trastuzumab chemotherapy-related posterior reversible encephalopathy syndrome: A case report and literature review.

Posterior reversible encephalopathy syndrome (PRES) in breast carcinoma is a rare disease in clinical practice that is often misdiagnosed and ignored. This study reported a case of a patient admitted to our hospital and discussed the clinical, imaging, and pathogenesis properties of the disease. We retrospectively analyzed the clinical data of this patient and reviewed the relevant literature. Imaging was used to diagnose PRES based on clinical findings, and clinical symptoms improved after discontinuation of the relevant drugs.

Integrin α5ß1 contributes to cell fusion and inflammation mediated by SARS-CoV-2 spike via RGD-independent interaction.

The Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus infects host cells by engaging its spike (S) protein with human ACE2 receptor. Recent studies suggest the involvement of integrins in SARS-CoV-2 infection through interaction with the S protein, but the underlying mechanism is not well understood. This study investigated the role of integrin α5ß1, which recognizes the Arg-Gly-Asp (RGD) motif in its physiological ligands, in S-mediated virus entry and cell-cell fusion. Our results showed that α5ß1 does not directly contribute to S-mediated cell entry, but it enhances S-mediated cell-cell fusion in collaboration with ACE2. This effect cannot be inhibited by the putative α5ß1 inhibitor ATN-161 or the high-affinity RGD-mimetic inhibitor MK-0429 but requires the participation of α5 cytoplasmic tail (CT). We detected a direct interaction between α5ß1 and the S protein, but this interaction does not rely on the RGD-containing receptor binding domain of the S1 subunit of the S protein. Instead, it involves the S2 subunit of the S protein and α5ß1 homo-oligomerization. Furthermore, we found that the S protein induces inflammatory responses in human endothelial cells, characterized by NF-κB activation, gasdermin D cleavage, and increased secretion of proinflammatory cytokines IL-6 and IL-1ß. These effects can be attenuated by the loss of α5 expression or inhibition of the α5 CT binding protein phosphodiesterase-4D (PDE4D), suggesting the involvement of α5 CT and PDE4D pathway. These findings provide molecular insights into the pathogenesis of SARS-CoV-2 mediated by a nonclassical RGD-independent ligand-binding and signaling function of integrin α5ß1 and suggest potential targets for antiviral treatment.

Discovery of a potent and long-acting Xenopus GLP-1-based GLP-1/glucagon/Y2 receptor triple agonist.

The combination of incretin-based therapies and PYY analogue has shown great potential for the treatment of type 2 diabetes (T2DM) and obesity. In this study we developed the first example of a unimolecular triple agonist peptide to simultaneously target GLP-1, glucagon and Y2 receptors, aiming for superior weight loss and better glycemic control. The strategy for constructing such a unimolecular triple agonist peptide is the conjugation of the GLP-1R/GCGR dual-agonistic moiety and PYY moiety via maleimide-thiol specific reaction. A novel triple agonist peptide, 3b, was identified via stepwise structure optimization, long-acting modification and in vitro receptor screens. Peptide 3b exhibited potent and balanced GCGR and GLP-1R activities as well as potent and highly selective Y2R activity. Peptide 3b potently reduced food intake without triggering nausea associated behavior in kaolin consumption and conditioned taste aversion assays. In diet induced obesity (DIO) mice, a lower dose of 3b achieved significantly better effects on lipid metabolism, body weight, and glycemic control than higher dose of GLP-1R mono-agonist, GLP-1R/GCGR dual agonist and GLP-1R/Y2R dual agonist counterparts. Collectively, these data support the therapeutic potential of our GLP-1R/GCGR/Y2R triple agonist 3b as a novel anti-obesity and anti-diabetic agent. Targeting GLP-1R, GCGR and Y2R with unimolecular triple agonist peptide offers a route to develop new obesity and T2DM treatments.

Coagulopathy in COVID-19 and anticoagulation clinical trials.

Severe acute respiratory disease coronavirus 2 (SARS-COV-2) first emerged in Wuhan, China, in December 2019 and has caused a global pandemic of a scale unprecedented in the modern era. People infected with SARS-CoV-2 can be asymptomatic, moderate symptomatic or develop severe COVID-19. Other than the typical acute respiratory distress syndrome (ARDS), patients with moderate or severe COVID-19 also develop a distinctive systemic coagulopathy, known as COVID-19-associated coagulopathy (CAC), which is different from sepsis-related forms of disseminated intravascular coagulation (DIC). Endotheliopathy or endotheliitis are other unique features of CAC. The endothelial cell perturbation can further increase the risk of thrombotic events in COVID-19 patients. In this review, we will summarize the current knowledge on COVID-19 coagulopathy and the possible mechanisms for the condition. We also discuss the results of clinical trials testing methods for mitigating thrombosis events in COVID-19 patients.

[Influence regulation of inflammatory immune response by interleukin-17 lipopolysaccharide-induced acute lung injury in mice].

OBJECTIVE: To explore the immunomodulatory effects of interleukin-17 (IL-17) on acute lung injury (ALI) induced by lipopolysaccharide (LPS). METHODS: Thirty-six SPF-class C57BL/6 mice were divided into normal saline control group (NS group) and LPS-induced ALI model group (LPS group, LPS 5 mg/kg intratracheal drip) according to random number table method, with 18 mice in each group. Six mice were sacrificed at 2, 6 and 24 hours after model reproduction, and peripheral blood, lung and spleen tissues were harvested. After staining with hematoxylin-eosin (HE), the pathological changes of lung tissue were observed under microscope and the infiltration level of lymphocytes, neutrophils and macrophages in the alveolar wall and tracheal wall were detected. Immunohistochemistry was used to detect the protein expression of IL-17 in alveolar wall and tracheal wall, and the correlation between IL-17 expression and lymphocytes, neutrophils and macrophages infiltration in alveolar wall and tracheal wall were analyzed. The level of IL-17 in lung tissue homogenate was determined by enzyme linked immunosorbent assay (ELISA). Flow cytometry was used to detect the proportion of CD4+IL-17+ helper T cells (Th17 cells) in CD4+ T cells in peripheral blood, lung tissue and spleen tissue. RESULTS: (1) Microscopy showed that the lung tissue structure of NS group was basically normal at each time after model reproduction, and there was no obvious inflammatory cell infiltration, while the lung tissue edema and inflammatory reaction were gradually aggravated in the LPS group, and the lung injury score was significantly higher than that in NS group at each time (2 hours: 4.47±1.42 vs. 1.10±0.55, 6 hours: 7.93±2.14 vs. 1.23±0.50, 24 hours: 12.67±2.67 vs. 1.20±0.61, all P < 0.01). (2) Immunohistochemistry showed that the protein expression of IL-17 in alveolar wall and tracheal wall of LPS group increased gradually with time, while that in NS group was negative or weak positive. Quantitative analysis showed that the immunohistochemical staining score of IL-17 protein in alveolar wall and tracheal wall of LPS group were higher than those of NS group (alveolar wall: 2.70±1.40 vs. 0.90±0.37 at 2 hours, 5.10±1.76 vs. 1.17±0.59 at 6 hours, 9.67±1.32 vs. 1.10±0.45 at 24 hours; tracheal wall: 2.87±0.89 vs. 0.90±0.39 at 2 hours, 4.97±1.48 vs. 1.10±0.41 at 6 hours, 8.67±1.54 vs. 1.03±0.29 at 24 hours; all P < 0.05). (3) Correlation analysis showed that the protein expression of IL-17 in alveolar wall and tracheal wall were positively correlated with the degree of lymphocyte, neutrophil and macrophage infiltration (alveolar wall: r value was 0.632, 0.550, 0.466; tracheal wall: r value was 0.695, 0.662, 0.575, respectively; all P < 0.01). (4) IL-17 content (µg/L) in lung tissue homogenate was significantly higher than that in NS group at each time after model reproduction (2 hours: 1.37±0.14 vs. 1.01±0.18, 6 hours: 1.65±0.19 vs. 1.11±0.18, 24 hours: 1.92±0.36 vs. 1.17±0.24, all P < 0.01). (5) The proportion of Th17 cells in the peripheral blood, lung tissue and spleen tissue of the LPS group were higher than those of the NS group at each time after model reproduction [peripheral blood: (2.62±0.62)% vs. (1.42±0.40)% at 2 hours, (3.74±0.43)% vs. (1.27±0.32)% at 6 hours, (4.44±0.65)% vs. (1.59±0.45)% at 24 hours; lung tissue: (2.32±0.44)% vs. (1.50±0.25)% at 2 hours, (3.66±0.36)% vs. (1.33±0.24)% at 6 hours, (4.60±0.54)% vs. (1.60±0.27)% at 24 hours; spleen tissue: (1.49±0.36)% vs. (0.69±0.21)% at 2 hours, (2.58±0.55)% vs. (0.59±0.18)% at 6 hours, (3.76±0.57)% vs. (0.65±0.26)% at 24 hours; all P < 0.01]. CONCLUSIONS: IL-17 is involved in the inflammatory immune regulation of ALI mice.

[The relationship between pulmonary arterial and small airway inflammation in smokers with and without chronic obstructive pulmonary disease].

OBJECTIVE: To investigate the relationship between pulmonary arterial and small airway inflammation in smokers with normal lung function and smokers with chronic obstructive pulmonary disease (COPD). METHODS: Patients requiring lung resection for peripheral lung cancer were divided into group A (nonsmokers with normal lung function, n = 10), group B (smokers with normal lung function, n = 13) and group C (smokers with stable COPD, n = 10). Normal pulmonary tissue was obtained more than 5 cm away from cancer lesion. The pathomorphological changes of the pulmonary muscularized arteries (MA) and small airways were observed by HE and Victoria blue-Van Gieson's stains.Lymphocytes infiltrated in the MA and small airways were observed by immunohistochemical methods. The characteristics and the correlations between pulmonary arterial inflammation and small airway inflammation were analyzed. RESULTS: The thickness of MA wall in the three groups was (119 ± 11), (139 ± 25) and (172 ± 28) µm respectively. The total small airway pathology score was (49 ± 10), (101 ± 34) and (163 ± 36) respectively. The score in group B and C was significantly higher than that in group A (P < 0.05), and the thickness of MA wall and total small airway pathology score in group C was significantly higher than that in group B (P < 0.05). The degree of CD(+)(3) T-lymphocytes and CD(+)(8) T-lymphocytes infiltration in the intima, media and adventitia of MA and epithelial layer, lamina propria and adventitia of small airway in group B and C was more significant than that in group A, especially CD(+)(8) T-lymphocytes infiltration in adventitia of MA and small airway (P < 0.05). Expression of CD(+)(4) T-lymphocytes on epithelial layer, lamina propria and adventitia of small airway in group C was higher than that in group A (P < 0.05), but the CD(+)(4)/CD(+)(8) ratio in the whole layer of airway wall declined (P < 0.01). Among three groups, the infiltration of B-lymphocytes in three layers compared each other had no statistical differences (P > 0.05). The infiltration of CD(+)(3)T-lymphocytes and CD(+)(8)T-lymphocytes in the whole layer of MA was positively correlated with the total small airway pathology score respectively (r = 0.431,0.633, P < 0.05), and the degree of CD(+)(3)T-lymphocytes and CD(+)(8)T-lymphocytes infiltration in MA showed positive correlation with that in small airway (r = 0.655,0.725, P < 0.01). The degree of CD(+)(8)T-lymphocytes infiltration in MA and small airway was positively correlated with thickness of MA (r = 0.589,0.556, P < 0.01). CONCLUSIONS: Both in smokers with normal lung function and smokers with stable COPD, CD(+)(8)T-lymphocytes infiltration in the whole layer of pulmonary arteries and small airways is the same kind of inflammation, mainly in the adventitia of pulmonary arteries and small airways. They are a part of pulmonary inflammation in COPD and promote the development of COPD.

Increased expression of CD4+IL-17+ cells in the lung tissue of patients with stable chronic obstructive pulmonary disease (COPD) and smokers.

CD4(+)IL-17(+) cells have an important role in controlling immune and inflammatory reactions. The authors of the present study hypothesize that these cells may be involved in the pathogenesis of chronic obstructive pulmonary disease (COPD). To characterize the frequency of CD4(+)IL-17(+) cells in the lung alveolar walls, small airways and muscular pulmonary arteries of nonsmokers, smokers with normal lung function and COPD patients, CD4(+)IL-17(+) cell number was assessed using double immunofluorescence staining, and IL-17 and IL-21 expression were measured using real-time quantitative PCR in the peripheral lung tissues of 10 nonsmokers, 10 smokers with normal lung function and 10 smokers with stable COPD. In the lung alveolar walls, the number of CD4(+)IL-17(+) cells was increased in COPD patients compared with nonsmokers and in normal smokers compared with nonsmokers. In the small airways, the CD4(+)IL-17(+) cell numbers were higher in COPD patients than in normal smokers and nonsmokers. A positive correlation was observed between CD4(+)IL-17(+) cell expression and pathological changes in the lung tissue. In the small airways, the number of CD4(+)IL-17(+) cells was positively correlated with airflow limitations. The IL-17 mRNA levels in lung tissues were increased in COPD patients and normal smokers compared with nonsmokers. Increased CD4(+)IL-17(+) cell number in lung tissue is involved in chronic inflammation of the lungs and parallels lung injury aggravation in COPD patients and in smokers without airway limitations. These findings contribute to a better understanding of CD4(+) cell-related pathogenesis in COPD.

The expression of Foxp3 and ROR gamma t in lung tissues from normal smokers and chronic obstructive pulmonary disease patients.

Foxp3- and ROR gamma t-expressing cells are involved in acquired immune responses. The change in Foxp3 and ROR gamma t expression in lung tissue and their role in emphysema has not been studied for COPD patients and normal smokers. In the present study, Foxp3 and ROR gamma t were assessed using real-time quantitative polymerase chain reaction and western blotting, and the expression and distribution of Foxp3, IL-17, IL-23R and CCR6 were measured by immunohistochemistry in peripheral lung tissue (10 smokers with COPD, 10 smokers and 10 nonsmokers with normal lung function). Foxp3 expression was lower and ROR gamma t expression was higher in COPD patients when compared with smokers and nonsmokers (all P values were less than 0.001). The ratios of Foxp3/ROR gamma t mRNA and protein were positively correlated to FEV1%pred and negatively correlated to the mean alveoli area. Foxp3(+) cell numbers were decreased, while the number of IL-17(+) cells, IL-23R(+) cells and CCR6(+) cells were increased in the lung alveolar walls of COPD patients compared with normal smokers and nonsmokers (all P values were less than 0.001). The IL-17(+) cell numbers were positively correlated to both CCR6(+) and IL-23R(+) cells. Our data show a decreased Foxp3 expression and an increased ROR gamma t expression in COPD patients and normal smokers that parallels the aggravation of the disease. The IL-17(+)-cell-related cytokines receptors CCR6 and IL-23R had an association with the mechanism of IL-17(+) cell number increasing, which will provide a new immuno-therapeutic target for COPD.

[The clinical characteristics of intra-acinar pulmonary artery inflammation and its effect on clinical parameters in smokers with normal lung function and patients with chronic obstructive pulmonary disease].

OBJECTIVE: To study the pathological characteristics of intra-acinar pulmonary artery inflammation and its correlation with smoking index and disease progression in smokers with normal lung function and smokers with chronic obstructive pulmonary disease (COPD). METHODS: Patients requiring lung resection for peripheral lung cancer were divided into group A (nonsmokers with normal lung function, n = 10), group B (smokers with normal lung function, n = 13), and group C (smokers with stable COPD, n = 10). The lung tissue far away from tumor were resected to compare the pathological changes of intra-acinar pulmonary arteries and infiltration level of inflammatory cell in pulmonary non-muscularized arteries (NMA), pulmonary partially muscularized arteries (PMA) and muscularized arteries (MA) among the three groups. The correlation analysis was made among infiltration level, smoking index, percentage of predicted value of forced expiratory volume in one second (FEV(1)%Pred), six-minute-walk distance (6MWD) and BODE index. RESULTS: (1) Both group B and group C showed the intima and media thickness of MA was significantly higher, the lumen area of MA was narrower and the proportion of MA was higher, and collagenous fiber of MA adventitial proliferated and area increased in group C (P < 0.05 or P < 0.01). (2) In group B and group C, the percentage of the intra-acinar pulmonary arteries that contained leukocytes, T lymphocytes, CD(8)(+)T lymphocytes and the number of these positive cells infiltrating the intra-acinar pulmonary arteries were increased, especially an increased number of CD(8)(+)T lymphocytes infiltrating in the arterial adventitia as compared with group A, moreover there were significant difference between group C and group B (P < 0.05 or P < 0.01). In group B and group C, the degree of these positive cells infiltrating NMA, PMA and MA presented a decreasing sequence (P < 0.05 or P < 0.01). Among the intima, media and adventitia of MA, the infiltration of these positive cells was the highest in the adventitia. Among group A, group B and group C, infiltration degree of CD(4)(+)T lymphocyte, B lymphocyte, macrophage and neutrophil demonstrated no significant difference, also among NMA, PMA and MA (P > 0.05). (3) The number of leukocytes, T lymphocytes, CD(8)(+)T lymphocytes infiltrating MA showed a positive correlation with the thickness of MA (r = 0.563, 0.627, 0.589, P < 0.01, respectively) and smoking index (r = 0.551, 0.665, 0.600, P < 0.01, respectively), moreover the degree of these cells infiltrating MA demonstrated negative correlation with FEV(1)%Pred (r = -0.763, -0.703, -0.767, P < 0.01, respectively). Also infiltrating degree of T lymphocytes and CD(8)(+)T lymphocytes was positively correlated with BODE (r = 0.390, 0.476, P < 0.05, respectively). Furthermore the infiltrating degree of CD(8)(+)T lymphocytes had negative correlation with 6MWD (r = -0.356, P < 0.05). CONCLUSIONS: (1) Pulmonary arterial inflammation appears in smokers with normal lung function and smokers with COPD patients. It involves in all types of intra-acinar pulmonary arteries especially NMA and infiltrates whole layer of MA with a characteristic of CD(8)(+)T lymphocytes infiltrating in the adventitia of intra-acinar pulmonary arteries. (2) Pulmonary inflammation is closely correlated to cigarette smoking and clinical parameters such as BODE index, FEV(1)% pred and 6MWD. It is one of the key factors affecting the progression of COPD.

[Interleukin-17 expression and significance in normal lung function smokers and chronic obstructive pulmonary disease patients].

OBJECTIVE: To study the effect of interleukin 17 (IL-17) with mechanism of pulmonary inflammatory in smokers with normal lung function and chronic obstructive pulmonary disease (COPD) patients. METHODS: The peripheral lung cancer patients in need of a surgical therapy were divided into normal lung function and non-smoking group (NS group, n = 10), normal lung function and smoking group (S group, n = 13) and smoking with stable COPD group (COPD group, n = 10). The fresh normal lung tissue was harvested from the surgical specimens with a margin of 5 cm away from resection foci. Then the lung tissue levels of IL-17 were detected with enzyme-linked immunosorbent assay. The average alveolar area, the total small airway pathology score and the pulmonary muscular artery (MA) wall thickness were measured by HE and Victoria blue-Van Gieson's stains. The IL-17+ cells and CD4+, CD8+ lymphocytes in alveolar walls, small airways and lung MA were analyzed by immunohistochemistry. The investigators also explored the relationships between IL-17 level, pathological morphology of pulmonary parenchyma, small airway, pulmonary artery reconstruction and pulmonary functions. RESULTS: The IL-17 levels in lung tissue of NS, S and COPD groups were 6.1 (3.7 - 12.4), 9.7 (3.5 - 69.7) and 22.7 (7.0 - 114.4) pg/mg respectively. The S and COPD groups were significantly higher than the NS group (P < 0.05, P < 0.01). The S group was significantly higher than the NS group (P < 0.05). The average alveolar area were (50 708 +/- 14 125), (106 517 +/- 13 851) and (152 344 +/- 43 783) microm(2), the total small airway pathology score (49 +/- 10), (101 +/- 34) and (163 +/- 36), and the MA wall thickness (119 +/- 11), (139 +/- 25) and (172 +/- 28) microm respectively. The S and COPD groups were significantly higher than the NS group (P < 0.05, P < 0.01). And the COPD group was significantly higher than the S group (P < 0.05, P < 0.01). IL-17 was predominantly expressed in lung infiltration of inflammatory cells. IL-17 of alveolar walls, small airway wall and MA wall in the S and COPD groups were significantly higher than the NS group. And the COPD group was significantly higher than NS group (P < 0.05). IL-17+ cells were positively correlated with the average alveolar area in pulmonary parenchyma (r = 0.561, P < 0.01), the pulmonary artery wall thickness in MA (r = 0.682, P < 0.01) and the pathological score in small airways (r = 0.425, P < 0.05). IL-17+ cells of pulmonary parenchyma, small airways and MA were positively correlated with CD4+ and CD8+ lymphocytes in lung (P < 0.05, P < 0.01). The levels of IL-17 in lung homogenate tissue showed a negative correlation with the FEV(1) percentage of predicted value (r = -0.471, P < 0.01). CONCLUSIONS: IL-17 is up-regulated in lung tissues of normal lung function smokers and COPD patients. And it has a close correlation with CD4+ and CD8+ lymphocytes in lung, lung parenchyma destruction, pulmonary inflammation, pulmonary artery reconstruction and airflow limitation. All of these suggest that IL-17 plays an important pro-inflammatory role in COPD.

[The changes and significance of interleukin-16 and CXC chemokine receptor 3 expression in pulmonary artery of smokers with chronic obstructive pulmonary disease].

OBJECTIVE: To study the pathological characteristics of interleukin-16 (IL-16) and CXC chemokine receptor 3(CXCR3) in pulmonary artery of smokers with normal lung function and smokers with chronic obstructive pulmonary disease (COPD). METHODS: We examined surgical specimens from three groups of subjects undergoing lung resection for localized pulmonary lesions: group NS (nonsmokers with normal lung function, n = 10); group S (smokers with normal lung function, n = 13); group COPD (smokers with stable COPD, n = 10). The clinical datas including blood gas analysis, pulmonary function, BMI, smoking index, BODE index, six-minute-walk distance (6MWD), Medical Research Council dyspnea scale (MRC), St. George Respiratory Questionnaire (SGRQ) were recorded in all subjects before the operation. We applied technique of hematoxylin-eosin staining to observe pathomorphological changes of the pulmonary arteries. The concentration of IL-16 in lung tissues were measured by ELISA. Muscularized arteries were examined with immunohistochemical methods to identify T-lymphocytes (CD(3)), CD(4) T-lymphocytes, CD(8) T-lymphocytes, IL-16, CXCR3. The correlation of IL-16 and CXCR3 in muscularized arteries in smokers with stable COPD were analysed. RESULTS: (1) The group COPD showed the highest concentration of IL-16 in lung tissue (P < 0.01). The concentration of IL-16 in group S was higher than group NS (P < 0.05). (2) Both in group S and group COPD, the percentage of the muscularized arteries that contained CXCR3 and IL-16 were increased as compared with group NS (P < 0.01). Moreover there were statistical significance have been observed between group COPD and group S (P < 0.01). (3) The intensity of IL-16 infiltrating the muscularized arteries in group COPD showed a positive correlation with CD(3)(+)T-lymphocytes, CD(8)(+)T-lymphocytes, CXCR3 (r = 0.639, 0.803, 0.696; P < 0.05 or P < 0.01), smoking index, BODE index (r = 0.737, 0.704; P < 0.05). There was inverse relationship between the content of IL-16 in the muscularized arteries in group COPD and forced expiratory volume in one second% predicted (FEV(1)% Pred) and 6MWD (r = -0.803, -0.787; P < 0.01). We also found the intensity of CXCR3 infiltrating the muscularized arteries in group COPD showed a positive correlation with CD(3)(+) T-lymphocytes, CD(8)(+)T-lymphocytes (r = 0.650, 0.767; P < 0.05), smoking index, BODE index (r = 0.650, 0.767; P < 0.05). There was inverse relationship between the content of CXCR3 in the muscularized arteries in group COPD and FEV(1)% Pred and 6MWD (r = -0.778, -0.774; P < 0.01). CONCLUSIONS: (1) Both in group S and group COPD, IL-16 and CXCR3 were mainly expressed in lymphocytes which were correlated with CD(8)(+)T-lymphocytes infiltrating the muscularized arteries. There were some suggestion that IL-16 probably recruited CD(8)(+)T-lymphocytes into muscularized arteries by enhancing the expression of CXCR3. (2) The intensity of IL-16 and CXCR3 were correlated with the index of clinical and pulmonary function that suggested pulmonary arterial inflammation might be one of the key factors associated with the progression of COPD, and inhibiting the pulmonary artery inflammation played an important role in prevention and cure of COPD.