Matrix mechanics regulate the polarization state of bone marrow-derived neutrophils through the JAK1/STAT3 signaling pathway.

Matrix mechanics regulate essential cell behaviors through mechanotransduction, and as one of its most important elements, substrate stiffness was reported to regulate cell functions such as viability, communication, migration, and differentiation. Neutrophils (Neus) predominate the early inflammatory response and initiate regeneration. The activation of Neus can be regulated by physical cues; however, the functional alterations of Neus by substrate stiffness remain unknown, which is critical in determining the outcomes of engineered tissue mimics. Herein, a three-dimensional (3D) culture system made of hydrogels was developed to explore the effects of varying stiffnesses (1.5, 2.6, and 5.7 kPa) on the states of Neus. Neus showed better cell integrity and viability in the 3D system. Moreover, it was shown that the stiffer matrix tended to induce Neus toward an anti-inflammatory phenotype (N2) with less adhesion molecule expression, less reactive oxygen species (ROS) production, and more anti-inflammatory cytokine secretion. Additionally, the aortic ring assay indicated that Neus cultured in a stiffer matrix significantly increased vascular sprouting. RNA sequencing showed that a stiffer matrix could significantly activate JAK1/STAT3 signaling in Neus and the inhibition of JAK1 ablated the stiffness-dependent increase in the expression of CD182 (an N2 marker). Taken together, these results demonstrate that a stiffer matrix promotes Neus to shift to the N2 phenotype, which was regulated by JAK1/STAT3 pathway. This study lays the groundwork for further research on fabricating engineered tissue mimics, which may provide more treatment options for ischemic diseases and bone defects. STATEMENT OF SIGNIFICANCE.

Down-expression of Foxj1 on airway epithelium with impaired cilia architecture in non-cystic fibrosis bronchiectasis implies disease severity.

INTRODUCTION: The pathogenesis of non-cystic fibrosis bronchiectasis has not been clearly clarified. This study aimed to investigate the expression of ciliary regulating protein forkhead box protein j1 (Foxj1) on airway epithelium in non-cystic fibrosis bronchiectasis and its association with airway cilia structure disorder and disease severity. METHODS: Lung tissue sections excised from 47 patients with non-cystic fibrosis bronchiectasis were included between January 2018 and June 2021. Specimens from 26 subjects who underwent a lobectomy due to lung nodule were chosen as controls. Clinical information was collected, and pathologic analysis was performed to assess the epithelial structure and expression of ciliary regulating Foxj1. RESULTS: Of the 47 patients with non-cystic fibrosis bronchiectasis, 25 were considered as mild, 12 were moderate whereas the remaining 10 cases were severe according to the bronchiectasis severity index score evaluation. Epithelial hyperplasia, hyperplasia of goblet cells and inflammatory cell infiltration were observed in non-cystic fibrosis bronchiectasis, compared with control subjects. Cilia length in non-cystic fibrosis bronchiectasis patients were shorter than that in the control group, (5.34 ± 0.89) µm versus (7.34 ± 0.71) µm, respectively (P = 0.002). The expression of Foxj1 was (2.69 ± 1.09) × 106 in non-cystic fibrosis bronchiectasis, compared with (6.67 ± 1.15) × 106 in the control group (P = 0.001). Moreover, patients with lower expression of Foxj1 showed shorter airway cilia and worse in disease severity. CONCLUSION: Foxj1 declined in the airway epithelium of patients with non-cystic fibrosis bronchiectasis, positively correlated to cilia length and might imply worse disease severity.

Chemical Constituents of the Deep-Sea-Derived Penicillium citreonigrum MCCC 3A00169 and Their Antiproliferative Effects.

Six new citreoviridins (citreoviridins J-O, 1-6) and twenty-two known compounds (7-28) were isolated from the deep-sea-derived Penicillium citreonigrum MCCC 3A00169. The structures of the new compounds were determined by spectroscopic methods, including the HRESIMS, NMR, ECD calculations, and dimolybdenum tetraacetate-induced CD (ICD) experiments. Citreoviridins J-O (1-6) are diastereomers of 6,7-epoxycitreoviridin with different chiral centers at C-2-C-7. Pyrenocine A (7), terrein (14), and citreoviridin (20) significantly induced apoptosis for HeLa cells with IC50 values of 5.4 µM, 11.3 µM, and 0.7 µM, respectively. To be specific, pyrenocine A could induce S phase arrest, while terrein and citreoviridin could obviously induce G0-G1 phase arrest. Citreoviridin could inhibit mTOR activity in HeLa cells.

Combined Neutrophil-to-Lymphocyte Ratio and CURB-65 Score as an Accurate Predictor of Mortality for Community-Acquired Pneumonia in the Elderly.

PURPOSE: Community-acquired pneumonia (CAP) is common among the elderly; it typically has a poor prognosis and high mortality. This study evaluated the factors predicting CAP-related in-hospital mortality in the elderly to identify a simpler and more accurate predictor. PATIENTS AND METHODS: This was a single-center, retrospective study. The data used in this study was collected from all older patients (≥65) with CAP admitted to our hospital between January 2012 and April 2020. RESULTS: A total of 2028 older patients with CAP were included; 121 (5.97%) died in hospital. Of the patients in the study, 1267 (62.5%) were men and 261 (12.9%) had a history of malignant tumors. After performing univariate and multivariate Cox regression analyses, sex, history of malignant tumor, CURB-65 score, neutrophil-to-lymphocyte ratio (NLR), hemoglobin level, and NLR*CURB-65 levels were associated with CAP mortality. By comparing the area under the receiver operating characteristic (ROC) curves of the predicted factors, the NLR*CURB-65 level used to predict CAP mortality in the elderly was 0.755, and was superior to other measurements. All included patients were then dichotomized into two groups based on NLR*CURB-65 level (≤9.06 and >9.06) according to the ROC analysis. Patients with a high NLR*CURB-65 level had higher in-hospital mortality than those with a low NLR*CURB-65 level. The two divided groups showed significant differences in age, sex, smoking history, comorbidity, and laboratory findings. This indicates that NLR*CURB-65 is a predictive index that could reflect the comprehensive condition of older patients with CAP. CONCLUSION: NLR*CURB-65 is a simpler and more accurate predictor of CAP-related in-hospital mortality in the elderly.

Study on the Mechanism of Acori Graminei Rhizoma in the Treatment of Alzheimer's Disease Based on Network Pharmacology and Molecular Docking.

Alzheimer's disease is a common neurodegenerative disease in the elderly. This study explored the curative effect and possible mechanism of Acori graminei rhizoma on Alzheimer's disease. In this paper, 8 active components of Acori graminei rhizoma were collected by consulting literature and using the TCMSP database, and 272 targets were screened using the PubChem and Swiss Target Prediction databases. Introduce it into the software of Cytoscape 3.7.2 and establish the graph of "drug-active ingredient-ingredient target." A total of 276 AD targets were obtained from OMIM, Gene Cards, and DisGeNET databases. Import the intersection targets of drugs and diseases into STRING database for enrichment analysis, and build PPI network in the Cytoscape 3.7.2 software, whose core targets involve APP, AMPK, NOS3, etc. GO analysis and KEGG analysis showed that there were 195 GO items and 30 AD-related pathways, including Alzheimer's disease pathway, serotonin synapse, estrogen signaling pathway, dopaminergic synapse, and PI3K-Akt signaling pathway. Finally, molecular docking was carried out to verify the binding ability between Acori graminei rhizoma and core genes. Our results predict that Acori graminei rhizoma can treat AD mainly by mediating Alzheimer's signal pathway, thus reducing the production of Aß, inhibiting the hyperphosphorylation of tau protein, regulating neurotrophic factors, and regulating the activity of kinase to change the function of the receptor.

Using the internet search data to investigate symptom characteristics of COVID-19: A big data study.

OBJECTIVE: Analyzing the symptom characteristics of Coronavirus Disease 2019(COVID-19) to improve control and prevention. METHODS: Using the Baidu Index Platform (http://index.baidu.com) and the website of Chinese Center for Disease Control and Prevention as data resources to obtain the search volume (SV) of keywords for symptoms associated with COVID-19 from January 1 to February 20 in each year from 2017 to 2020 and the epidemic data in Hubei province and the other top 9 impacted provinces in China. Data of 2020 were compared with those of the previous three years. Data of Hubei province were compared with those of the other 9 provinces. The differences and characteristics of the SV of COVID-19-related symptoms, and the correlations between the SV of COVID-19 and the number of newly confirmed/suspected cases were analyzed. The lag effects were discussed. RESULTS: Comparing the SV from January 1, 2020 to February 20, 2020 with those for the same period of the previous three years, Hubei's SV for cough, fever, diarrhea, chest tightness, dyspnea, and other symptoms were significantly increased. The total SV of lower respiratory symptoms was significantly higher than that of upper respiratory symptoms (P＜0.001). The SV of COVID-19 in Hubei province was significantly correlated with the number of newly confirmed/suspected cases (r confirmed = 0.723, r suspected = 0.863, both p < 0.001). The results of the distributed lag model suggested that the patients who searched relevant symptoms on the Internet may begin to see doctors in 2-3 days later and be confirmed in 3-4 days later. CONCLUSION: The total SV of lower respiratory symptoms was higher than that of upper respiratory symptoms, and the SV of diarrhea also increased significantly. It warned us to pay attention to not only the symptoms of the lower respiratory tract but also the gastrointestinal symptoms, especially diarrhea in patients with COVID-19. Internet search behavior had a positive correlation with the number of newly confirmed/suspected cases, suggesting that big data has an important role in the early warning of infectious diseases.

Neutrophil-To-Lymphocyte Ratio Predicted Long-Term Chemotherapy Benefits In Stage IIIB-IV Non-Squamous Non-Small Cell Lung Cancer Patients Without Sensitive Mutations.

PURPOSE: To investigate the predictive capability of clinical parameters for long-term chemotherapy benefits among stage IIIB-IV non-squamous non-small cell lung cancer (NSCLC) patients without sensitive mutations. PATIENTS AND METHODS: We investigated the clinical features of 206 stage IIIB-IV non-squamous NSCLC patients without sensitive mutations and assessed their predictive value for disease control rate (DCR) at 6 and 12 months post-treatment. RESULTS: Seventy-two patients received docetaxel and platinum-based chemotherapy while 134 received pemetrexed and platinum-based chemotherapy. The 6-month and 12-month DCR were 33 (45.8%) and 6 (8.3%) in the docetaxel group and 69 (51.5%) and 19 (14.2%) in the pemetrexed group, respectively. Univariate Cox regression revealed that age, sex, smoking history, adrenal gland metastasis, stage IV disease, neutrophil-to-lymphocyte ratio (NLR), and serum albumin were associated with unfavorable progression-free survival (PFS). Age, stage IV disease, and NLR were identified as independent predictors of PFS using multivariate analysis. NLR was the only parameter that could predict 3-month and 6-month DCRs. NLR and age were able to predict 12-month DCR, with NLR presenting a larger area under the curve. Kaplan-Meier curves demonstrated that patients with NLR > 2.231 displayed significantly reduced long-term disease control. The group with higher NLR had more male patients, lower ALB levels, and serum sodium levels as well as higher platelet counts. CONCLUSION: NLR was an independent predictor of long-term chemotherapy benefits among non-squamous NSCLC patients without sensitive mutations. Patients with lower NLR were optimal candidates for chemotherapy. Patients with high NLR may receive alternative treatments or be included in clinical trials.

Thymic stromal lymphopoietin induced early stage of epithelial-mesenchymal transition in human bronchial epithelial cells through upregulation of transforming growth factor beta 1.

Purpose: Epithelial-mesenchymal transition (EMT) involved in asthmatic airway remodeling. Thymic stromal lymphopoietin (TSLP), an epithelial-derived cytokine, was a key component in airway immunological response in asthma. But the role of TSLP in the EMT process was unknown. We aimed to access whether TSLP could induce EMT in airway epithelia and its potential mechanism. Materials and Methods: Human bronchial epithelial (HBE) cells were incubated with TSLP or transforming growth factor beta 1 (TGF-ß1) or both. SB431542 was used to block TGF-ß1 signal while TSLP siRNA was used to performed TSLP knockdown. Changes in E-cadherin, vimentin, collagen I and fibronectin level were measured by real-time PCR, western blot and immunofluorescence staining. Expressions of TGF-ß after TSLP administration were measured by real-time PCR, western blot and ELISA. Results: TSLP induced changes of EMT relevant markers alone and promoted TGF-ß1-induced EMT in HBEs. Intracellular and extracellular expression of TGF-ß1 were upregulated by TSLP. SB431542 blocked changes of EMT relevant markers induced by TSLP. Knockdown of TSLP not only reduced TSLP and TGF-ß1 expression but also inhibited changes of EMT relevant markers induced by TGF-ß1 in HBEs. Conclusions: TSLP could induce early stage of EMT in airway epithelial cells through upregulation of TGF-ß1. This effect may act as a targeting point for suppression of asthma.

Aberrant epithelial remodeling with impairment of cilia architecture in non-cystic fibrosis bronchiectasis.

BACKGROUND: Aberrant epithelial remodeling and/or abnormalities in mucociliary apparatus in airway epithelium contribute to infection and inflammation. It is uncertain if these changes occur in both large and small airways in non-cystic fibrosis bronchiectasis (non-CF bronchiectasis). In this study, we aim to investigate the histopathology and inflammatory profile in the epithelium of bronchi and bronchioles in bronchiectasis. METHODS: Excised lung tissue sections from 52 patients with non-CF bronchiectasis were stained with specific cellular markers and analyzed by immunohistochemistry and immunofluorescence to assess the epithelial structures, including ciliated cells and goblet cells morphology. Inflammatory cell counts and ciliary proteins expression levels of centrosomal protein 110 (CP110) and dynein heavy chain 5, axonemal (DNAH5) were assessed. RESULTS: Epithelial hyperplasia is found in both bronchi and bronchioles in all specimens, including hyperplasia and/or hypertrophy of goblet cells. The median cilia length is longer in hyperplastic epithelium [bronchi: 8.16 (7.03-9.14) µm, P<0.0001; bronchioles: 7.46 (6.41-8.48) µm, P<0.0001] as compared to non-hyperplastic epithelium (bronchi: 5.60 µm; bronchioles: 4.89 µm). Hyperplastic epithelium is associated with overexpression of CP110 and decreased intensity of DNAH5 expression in both bronchial and bronchiolar epithelium. Though infiltration of neutrophils is predominant (63.0% in bronchi and 76.7% in bronchioles), eosinophilic infiltration is also present in the mucosa of bronchi (30.8%) and bronchioles (54.8%). CONCLUSIONS: Aberrant epithelial remodeling with impaired mucociliary architecture is present in both large and small airways in patients with refractory non-CF bronchiectasis. Future studies should evaluate the interplay between these individual components in driving chronic inflammation and lung damage in patients.

Secondary acute promyelocytic leukemia following chemotherapy for gastric cancer: a case report.

Therapy-related acute myeloid leukemia (t-AML) refers to a heterogeneous group of myeloid neoplasms that develop in patients following extensive exposure to either cytotoxic agents or radiation. The development of t-AML has been reported following treatment of cancers ranging from hematological malignancies to solid tumors; however, to our knowledge, t-AML has never been reported following treatment of gastric cancer. In this study, we report the development of t-acute promyelocytic leukemia in a cT4N1M0 gastric cancer patient after an approximate 44 mo latency period following treatment with 4 cycles of oxaliplatin (OXP) (85 mg/m(2) on day 1) plus capecitabine (1250 mg/m(2) orally twice daily on days 1-14) in combination with recombinant human granulocyte-colony stimulating factor treatment. Karyotype analysis of the patient revealed 46,XY,t(15;17)(q22;q21)[15]/46,idem,-9,+add(9)(p22)[2]/46,XY[3], which, according to previous studies, includes some "favorable" genetic abnormalities. The patient was then treated with all-trans retinoic acid (ATRA, 25 mg/m(2)/d) plus arsenic trioxide (ATO, 10 mg/d) and attained complete remission. Our case illuminated the role of certain cytotoxic agents in the induction of t-AML following gastric cancer treatment. We recommend instituting a mandatory additional evaluation for patients undergoing these therapies in the future.

Xiaotan Sanjie decoction attenuates tumor angiogenesis by manipulating Notch-1-regulated proliferation of gastric cancer stem-like cells.

AIM: To determine the underlying mechanisms of action and influence of Xiaotan Sanjie (XTSJ) decoction on gastric cancer stem-like cells (GCSCs). METHODS: The gastric cancer cell line MKN-45 line was selected and sorted by FACS using the cancer stem cell marker CD44; the stemness of these cells was checked in our previous study. In an in vitro study, the expression of Notch-1, Hes1, Vascular endothelial growth factor (VEGF), and Ki-67 in both CD44-positive gastric cancer stem-like cells (GCSCs) and CD44-negative cells was measured by Western blot. The effect of XTSJ serum on cell viability and on the above markers was measured by MTT assay and Western blot, respectively. In an in vivo study, the ability to induce angiogenesis and maintenance of GCSCs in CD44-positive-MKN-45- and CD44-negative-engrafted mice were detected by immunohistochemical staining using markers for CD34 and CD44, respectively. The role of XTSJ decoction in regulating the expression of Notch-1, Hes1, VEGF and Ki-67 was measured by Western blot and real-time polymerase chain reaction. RESULTS: CD44(+) GCSCs showed more cell proliferation and VEGF secretion than CD44-negative cells in vitro, which were accompanied by the high expression of Notch-1 and Hes1 and positively associated with tumor growth (GCSCs vs CD44-negative cells, 2.72 ± 0.25 vs 1.46 ± 0.16, P < 0.05) and microvessel density (MVD) (GCSCs vs CD44-negative cells, 8.15 ± 0.42 vs 3.83 ± 0.49, P < 0.001) in vivo. XTSJ decoction inhibited the viability of both cell types in a dose-dependent manner in vitro. Specifically, a significant difference in the medium- (82.87% ± 6.53%) and high-dose XTSJ groups (77.43% ± 7.34%) was detected at 24 h in the CD44(+) GCSCs group compared with the saline group (95.42% ± 5.76%) and the low-dose XTSJ group (90.74% ± 6.57%) (P < 0.05). However, the efficacy of XTSJ decoction was reduced in the CD44(-) groups; significant differences were only detected in the high-dose XTSJ group at 48 h (78.57% ± 6.94%) and 72 h (72.12% ± 7.68%) when compared with the other CD44- groups (P < 0.05). Notably, these differences were highly consistent with the Notch-1, Hes1, VEGF and Ki-67 expression in these cells. Similarly, in vivo, XTSJ decoction inhibited tumor growth in a dose-dependent manner. A significant difference was observed in the medium- (1.76 ± 0.15) and high-dose XTSJ (1.33 ± 0.081) groups compared with the GCSCs control group (2.72 ± 0.25) and the low-dose XTSJ group (2.51 ± 0.25) (P < 0.05). We also detected a remarkable decrease of MVD in the medium- (7.10 ± 0.60) and high-dose XTSJ (5.99 ± 0.47) groups compared with the GCSC control group (8.15 ± 0.42) and the low-dose XTSJ group (8.14 ± 0.46) (P < 0.05). Additionally, CD44 expression was decreased in these groups [medium- (4.43 ± 0.45) and high-dose XTSJ groups (3.56 ± 0.31) vs the GCSC control (5.96 ± 0.46) and low dose XTSJ groups (5.91 ± 0.38)] (P < 0.05). The significant differences in Notch-1, Hes1, VEGF and Ki-67 expression highly mirrored the results of XTSJ decoction in inhibiting tumor growth, MVD and CD44 expression. CONCLUSION: Notch-1 may play an important role in regulating the proliferation of GCSCs; XTSJ decoction could attenuate tumor angiogenesis, at least partially, by inhibiting Notch-1.

Inhibitory effects of lipoteichoic acid from Staphylococcus aureus on platelet function and platelet-monocyte aggregation.

OBJECTIVE: Lipoteichoic acid (LTA) from Staphylococcus aureus has been demonstrated to inhibit agonist-stimulated platelet aggregation. However, its effects on platelet inflammatory mediator release and platelet-monocyte aggregation are still unclear. In the present study, LTA is examined for its anti-inflammatory properties and effects on platelet-monocyte aggregation. METHODS: Blood samples were obtained from 5 healthy volunteers who had taken no medicine in the previous 2 weeks. Washed platelets were prepared and incubated with LTA (0.5-2.0 µg/mL), then platelet aggregation, P-selectin expression, and soluble CD40L (sCD40L) release were measured by light transmission aggregometry, flow cytometry and enzyme-linked immunoassays, respectively. Platelet-monocyte aggregate formation in whole blood was measured by flow cytometry. Thrombin was used as a stimulant. RESULTS: LTA dose-dependently decreased platelet aggregation from 89.32 ± 10.24% to 36.28 ± 9.01% (P < 0.05), sCD40L release from 3.28 ± 0.76 to 1.13 ± 0.45 ng/mL (P < 0.05) and surface P-selectin expression from 82.01 ± 11.20 to 22.78 ± 6.42% (P < 0.05). In human whole blood, 1.0 µg/mL LTA inhibited platelet-monocyte aggregation from 78.19 ± 10.94 to 38.24 + 8.74% (P < 0.05). CONCLUSIONS: These results indicate that LTA from S. aureus can inhibit platelet-dependent inflammatory mediator release and platelet-monocyte aggregation. These findings suggest that LTA-mediated functional alteration of platelets may contribute to immune evasion of S. aureus.

[Transposed ovarian function conservation in cervical cancer patients with radiotherapy].

OBJECTIVE: To evaluate the transposed ovarian function and complications in cervical cancer patients with postoperative pelvic radiotherapy. METHODS: Sixty-two women with stage I-IIa cervical cancer were treated with radical hysterectomy and pelvic lymphadenectomy and transposition of both ovaries to paracolic gutters from 1997 to 2003 at the Cancer Hospital of Fudan University. Menopausal symptoms, levels of follicle-stimulating hormone (FSH) and E2 were evaluated to assess ovarian function. RESULTS: Of 31 patients with stage IIa or poorly differentiated tumor or tumor > or = 2 cm in diameter, preoperative vaginal radiation was employed to deliver a dose of 15 Gy at point A. Postoperative pelvic radiation was performed in 15 patients. Totally 20% (6/30) of patients undergoing ovaries transposition without any radiation experienced ovarian failure within a mean of 15.7 months. In 35% (6/17) of patients with preoperative vaginal radiation, ovarian failure occurred within a mean of 12.0 months. When patients receiving postoperative pelvic radiation and ovaries transposition were considered together, 64% (9/14) experienced ovarian failure within a mean of 9.2 months (P < 0.05). Only 2 (3%) patients had cysts in transposed ovaries not requiring further surgery. There was no metastasis of the ovaries. CONCLUSIONS: Lateral ovarian transposition is safe to patients with early stage cervical cancer. Both pre- and post-operative radiation significantly damages the ovarian function. Even ovaries transposition procedure also reduces the effectiveness.

An engineered multidomain bactericidal peptide as a model for targeted antibiotics against specific bacteria.

We constructed a peptide consisting of a staphylococcal AgrD1 pheromone fused to the channel-forming domain of colicin Ia and named it pheromonicin. This fusion peptide had bactericidal effects against methicillin-sensitive and methicillin-resistant Staphylococcus aureus (MSSA and MRSA, respectively), but not against Staphylococcus epidermidis or Streptococcus pneumoniae. Growth rates, vital staining and colony forming unit (CFU) counts showed that pheromonicin did not merely suppress growth but killed S. aureus cells. The specificity of pheromonicin was shown by the absence of bactericidal effects against an accessory gene regulator (agr) locus knockout of S. aureus, and a dose-dependent inhibition of the bactericidal effects of pheromonicin by competition with corresponding free AgrD pheromone. In vivo, all pheromonicin-treated mice survived administration of MRSA that was lethal to controls. No toxicity was detectable in human liver or renal cells in culture, or in livers, kidneys or spleens of pheromonicin-treated mice. The results suggest that these types of chimeric peptides may be of value as antibiotics against specific bacterial infections.