Effect of X-ray irradiation combined with PD-1 inhibitor treatment on lung tissue injury in mice.

PURPOSE: To determine the effect of X-ray irradiation combined with PD-1 immune checkpoint inhibitor administration on lung tissue injury in a mouse model and its potential mechanism. METHODS: In all, 20 C57BL/6J mice were randomly divided into four groups with five mice in each group: control group, PD-1 inhibitor group, irradiation group, and irradiation combined with PD-1 inhibitor group. Hematoxylin-eosin staining of the lung tissue was performed 30 days after the end of irradiation to evaluate the morphological and pathological changes in the tissue. Masson staining and analysis of hydroxyproline were used to evaluate the degree of pulmonary fibrosis. The levels of transforming growth factor-ß1 (TGF-ß1) and tumor necrosis factor α(TNF-α) were evaluated by Enzyme-Linked immunosorbent assay (ELISA). CD3+, CD4+, and CD8+ T lymphocytes in the lung tissue were detected by immunohistochemistry. The expression levels of TGF-ß1, Smad3, cGAS, and STING in the lung tissue were evaluated by Western blotting. RESULTS: The lung injury scores and pulmonary fibrosis indices in the irradiation group were higher than those in the control group. Meanwhile, lung pneumonia score, pulmonary fibrosis index, percentage of CD4 cells and expression of TGF-ß1, p-Smad3, and STING in the lung tissue of mice in irradiation combined with PD-1 inhibitor group were higher than those in the other three groups. CONCLUSION: Lung injury and pulmonary fibrosis were induced by whole chest X-ray irradiation in mice, and PD-1 inhibitor could aggravate lung injury and pulmonary fibrosis in mice. Thus, radiotherapy combined with PD-1 inhibitors may affect the immune inflammatory microenvironment in the lung tissues of mice by activating TGF-ß1/Samd3 and cGAS/STING signaling pathways, thus aggravating lung tissue damage induced by radiation.

A New perspective: How Pathogens Manipulate Phagocytosis?

The immune system is a complicated, closely regulated mechanism that evolved to keep people healthy from infectious pathogens. Phagocytosis is important for both innate and acquired immunity, which is a critical process for microbial pathogens and apoptotic cells to be consumed and eliminated. However, several pathogens have evolved different strategies to escape detection and killing by phagocytosis. Recently, with the increase in infectious diseases and antibiotic resistance, it is significant for people to have a deep understanding of immune evasion, which may become an opportunity to explore new treatments and vaccination. Additionally, researchers mostly study immune evasion of a single pathogen but rarely summarize pathogens from the perspective of immune mechanisms. Here, we present the current understanding of phagocytosis and give a brief discussion of how pathogens control phagocytosis at different stages.

Genome-Wide Identification and Characterization of PRR Gene Family and their Diurnal Rhythmic Expression Profile in Maize.

As essential components of the circadian clock, the pseudo-response regulator (PRR) gene family plays critical roles in plant photoperiod pathway. In this study, we performed a genome-wide identification and a systematic analysis of the PRR gene family in maize. Nine ZmPRRs were identified, and the gene structure, conserved motif, evolution relationship, and expression pattern of ZmPRRs were analyzed comprehensively. Phylogenetic analysis indicated that the nine ZmPRR genes were divided into three groups, except for ZmPRR73, two of which were highly homologous to each of the AtPRR or OsPRR quintet members. Promoter cis-element analysis of ZmPRRs demonstrated that they might be involved in multiple signaling transduction pathways, such as light response, biological or abiotic stress response, and hormone response. qRT-PCR analysis revealed that the levels of ZmPRRs transcripts varied considerably and exhibited a diurnal rhythmic oscillation expression pattern in the given 24-h period under both SD and LD conditions, which indicated that the level of transcription of ZmPRRs expression is subjected to a circadian rhythm and modulated by light and the circadian clock. The present study will provide an insight into further exploring the biological function and regulatory mechanism of ZmPRR genes in circadian rhythm and response to photoperiod in maize.

Identification of MYH6 as the potential gene for human ischaemic cardiomyopathy.

The present study aimed to explore the potential hub genes and pathways of ischaemic cardiomyopathy (ICM) and to investigate the possible associated mechanisms. Two microarray data sets (GSE5406 and GSE57338) were downloaded from the Gene Expression Omnibus (GEO) database. The limma package was used to analyse the differentially expressed genes (DEGs). Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, Disease Ontology (DO) and Gene Ontology (GO) annotation analyses were performed. A protein-protein interaction (PPI) network was set up using Cytoscape software. Significant modules and hub genes were identified by the Molecular Complex Detection (MCODE) app. Then, further functional validation of hub genes in other microarrays and survival analysis were performed to judge the prognosis. A total of 1065 genes were matched, with an adjusted p < 0.05, and 17 were upregulated and 25 were downregulated with|log2 (fold change)|≥1.2. After removing the lengthy entries, GO identified 12 items, and 8 pathways were enriched at adjusted p < 0.05 (false discovery rate, FDR set at <0.05). Three modules with a score >8 after MCODE analysis and MYH6 were ultimately identified. When validated in GSE23561, MYH6 expression was lower in patients with CAD than in healthy controls (p < 0.05). GSE60993 data suggested that MYH6 expression was also lower in AMI patients (p < 0.05). In the GSE59867 data set, MYH6 expression was lower in CAD patients than in AMI patients and lower in heart failure (HF) patients than in non-HF patients. However, there was no difference at different periods within half a year, and HF was increased when MYH6 expression was low (p < 0.05-0.01). We performed an integrated analysis and validation and found that MYH6 expression was closely related to ICM and HF. However, whether this marker can be used as a predictor in blood samples needs further experimental verification.

Selective photodynamic inactivation of Helicobacter pylori by a cationic benzylidene cyclopentanone photosensitizer - an in vitro and ex vivo study.

The rise in the antibiotic resistance rate of Helicobacter pylori has led to an increasing eradication failure of this carcinogenic bacterial pathogen worldwide. This underlines the need for alternative antibacterial strategies against H. pylori infection. Antimicrobial photodynamic therapy (aPDT) is a promising non-pharmacological antibacterial technology. In this study, the selective killing activities of three benzylidene cyclopentanone (BCP) photosensitizers (Y1, P1 and P3) towards H. pylori over normal human gastric epithelial GES-1 cells were evaluated and the ex vivo photodynamic inactivation effect was preliminarily assessed on twelve H. Pylor-infected mice. Results showed that under the irradiation of 24 J/cm2 532 nm laser, Y1, P1 and P3 at 2.5 µM induced a 3-log10 reduction of H. pylori CFU (99.9% killing). Confocal images showed that P3, unlike Y1 and P1, could not be uptaken by GES-1 cells. P3 at 2.5 to 20 µM showed not significant (p > 0.05) phototoxicity to GES-1 cells, nevertheless, Y1 and P1 under the same concentrations exhibited remarkable phototoxicity to GES-1 cells. In the co-culture of H. pylori and GES-1 cells, P3 at 2.5 µM led to a complete eradication of H. pylori under the irradiation of 24 J/cm2 532 nm laser. While for the GES-1 cells, no significant (p > 0.05) phototoxicity was observed under the same aPDT dosage. The ex vivo experiments showed that P3 mediated aPDT resulted in 82.4% to 100% reduction of H. pylori CFU without damaging the gastric mucosa. To sum up, P3 is a promising anti-H. pylori photosensitizer with the ability to selectively photo-inactivate H. pylori while sparing normal gastric tissues.

Clinical Indications of Recombinant Human Erythropoietin in a Single Center: A 10-Year Retrospective Study.

In the 1980s, recombinant human erythropoietin (rhEPO) began to be used in clinical practice. In this study, the clinical application of rhEPO from single-center in recent ten years was reviewed, and the scope of indications and clinical efficacy were evaluated. The medical records of 35829 in-patients who were treated with rhEPO in the first Medical Center of the Chinese PLA General Hospital from 2009 to 2018 were collected. According to the scope of indications approved by CFDA (China Food and Drug Administration), curative effect and off-label of rhEPO were analyzed. Of the 35829 patients, 19013 (53.1%) were male and 16816 (46.9%) were female, with an average age of (52.1 ± 18.6) years. The usage of rhEPO is increasing year by year. The overall effective rate was 53.1%. The number of patients who met the indications accounted for 67.2%, and the effective rate patients with indications and Off-label were 48.8% and 50.7%. Among the patients with irregular use of rhEPO perioperative imperfect laboratory examination patients accounted for the highest proportion (7.1%). The volume of RBC(s) (red blood cell(s)) transfusion in patients with rhEPO was significantly less than that in patients without rhEPO (p<0.05). The use of rhEPO Off-label is very common and has a certain curative effect. It can be used as evidence support for the update of the scope of indications. In addition, There are still irregular use of rhEPO and transfusion in clinic. The unreasonable use of rhEPO and transfusion should be further standardized to ensure the safety and effectiveness.

Melatonin attenuates ER stress and mitochondrial damage in septic cardiomyopathy: A new mechanism involving BAP31 upregulation and MAPK-ERK pathway.

Septic cardiomyopathy is associated with mitochondrial damage and endoplasmic reticulum (ER) dysfunction. However, the upstream mediator of mitochondrial injury and ER stress has not been identified and thus little drug is available to treat septic cardiomyopathy. Here, we explored the role of B-cell receptor-associated protein 31 (BAP31) in septic cardiomyopathy and figure out whether melatonin could attenuate sepsis-mediated myocardial depression via modulating BAP31. Lipopolysaccharide (LPS) was used to establish the septic cardiomyopathy model. Pathway analysis was performed via western blot, quantitative polymerase chain reaction and immunofluorescence. Mitochondrial function and ER stress were detected via enzyme-linked immunosorbent assay, western blot, and immunofluorescence. After exposure to LPS, cardiac function was reduced due to excessive inflammation response and extensive cardiomyocyte death. Mechanistically, melatonin treatment could dose-dependently improve cardiomyocyte viability via preserving mitochondrial function and reducing ER stress. Further, we found that BAP31 transcription was repressed by LPS whereas melatonin could restore BAP31 expression; this effect was dependent on the MAPK-ERK pathway. Inhibition of the ERK pathway and/or knockdown of BAP31 could attenuate the beneficial effects of melatonin on mitochondrial function and ER homeostasis under LPS stress. Altogether, our results indicate that ERK-BAP31 pathway could be used as a critical mediator for mitochondrial function and ER homeostasis in sepsis-related myocardial injury. Melatonin could stabilize BAP31 via the ERK pathway and thus contribute to the preservation of cardiac function in septic cardiomyopathy.

Clinical Features, Outcomes, and Risk Factors of Bloodstream Infections due to Stenotrophomonas maltophilia in a Tertiary-Care Hospital of China: A Retrospective Analysis.

Background. Stenotrophomonas maltophilia bacteremia (SMB) is the most perilous situation as compared to other types of S. maltophilia infection. The present study aimed to investigate the clinical features, distribution, drug resistance, and predictors of survival of SMB in a tertiary-care hospital of China. Methods. SMB that occurred in a tertiary-care hospital in Beijing, China, within 9 years (2010-2018) was investigated in a retrospective study. Demographics, incidence, commodities, drug resistance, mortality, as well as antibiotics administration were summarized according to the electronic medical records. The risk factors for survival were analyzed by Chi-square test, Kaplan-Meier curve and Cox regression. Results. A total of 76 episodes of SMB were analyzed. The overall incidence of SMB fluctuated from 3.4 to 15.4 episodes per 1000 admissions over 9 years. Malignancy was the most common comorbidity. High in vitro sensitivity was observed to minocycline (96.1%), levofloxacin (81.6%), and trimethoprim-sulfamethoxazole (89.5%). Central venous catheter (CVC) (p = 0.004), mechanical ventilation (MV) (p = 0.006), hemodialysis (p = 0.024), and septic shock (p = 0.016) were significantly different between survival and death group. The 30-day mortality was 34.2% within 30 days after confirmation of blood culture. Factors such as hemodialysis (OR 0.287, 95% CI: 0.084-0.977, p = 0.046), T-tube (OR 0.160, 95% CI: 0.029-0.881, p = 0.035), and septic shock (OR 0.234, 95% CI: 0.076-0.719, p = 0.011) were associated with survival. Conclusions. S. maltophilia is the major nosocomial blood stream infectious pathogenic bacteria. Trimethoprim-sulfamethoxazole and minocycline are optimal antibiotics for the treatment of SMB. T-tube, hemodialysis, and septic shock were the risk factors associated with survival of SMB patients.

Clinical value of (1,3)-ß-D-glucan, mannan, antimannan IgG and IgM antibodies in diagnosis of invasive candidiasis.

Diagnosis of invasive candidiasis (IC) is still challenging due to absence of specific clinical signs and symptoms. In this study we investigate the clinical value of (1,3)-ß-D-glucan (BDG), mannan (MN), antimannan immunoglobulin G (AM-IgG), and antimannan immunoglobulin M (AM-IgM) assay in diagnosis of IC. During 2016 to 2018 serum samples from 71 patients with IC and 185 patients without IC were collected. Serum samples from 41 patients with bacteremia were also enrolled as additional control. Significant differences in mean serum biomarkers levels between IC and control group were observed. At low cutoff threshold the sensitivity and specificity of BDG (70 pg/ml), MN (50 pg/ml), AM-IgG (80 AU/ml), and AM-IgM (80 AU/ml) assay were 64.8% and 90.8%, 64.8 and 89.2%,74.6% and 87.0%, 57.7% and 60.0%, respectively. Combined use of BDG/MN, BDG/AM-IgG and MN/AM-IgG improved the sensitivity and specificity to 85.9% and 81.1%, 85.9% and 80.0%, 81.7% and 81.6%, respectively. The combination of BDG/MN, BDG/AM-IgG, or MN/AM-IgG may provide an encouraging approach for diagnosis of IC.

In vitro photodynamic inactivation effects of benzylidene cyclopentanone photosensitizers on clinical fluconazole-resistant Candida albicans.

BACKGROUND: The incidence of Candida infections has increased for various reasons, including, the more frequent use of immunosuppresants or broad-spectrum antibiotics. Photodynamic inactivation (PDI) is a promising approach for treating localized Candida infections. METHODS: The PDI efficacies of three benzylidene cyclopentanone-based (BCB) photosensitizers (PSs: P1, P2 and Y1) against three fluconazole-resistant C. albicans (cal-1, cal-2, and cal-3) and one control C. albicans (ATCC 90028), respectively, were evaluated using an established plate dilution method. The binding of PSs to C. albicans was determined by fluorescence spectroscopy. The mechanism of antifungal PDI was investigated using confocal laser scanning microscopy (CLSM) and transmission electron microscopy (TEM). RESULTS: Three BCB PSs all bound rapidly to C. albicans. After incubation with PSs for 30 min and irradiation with a 532 nm laser for 10 min (40 mW cm-2, 24 J cm-2), the fungicidal activity was achieved as 7.5 µM for P1 and P2, and 25 µM for Y1. CLSM confirmed that P1 and Y1 were located in intracellular components, including mitochondria, while P2 bound to the protoplast exterior and failed to enter the cells. TEM revealed the damage of mitochondria ultrastructures after P1- or Y1-mediated PDI, consistenting with the CLSM results. However, most cells became edematous, enlarged or deformation after P2-mediated PDI. CONCLUSIONS: The three BCB PSs all have remarkable PDI effects on C. albicans. The best effect is obtained by P1, which has one cationic charge with a proper lipophilicity. The respective subcellular localization of the three PSs led to different PDI mechanisms.

ATP binding cassette subfamily A member 7 rs3764650 polymorphism and the risk of Alzheimer's disease.

We did a meta-analysis to assess the association between ABCA7 rs3764650 polymorphism and the risk of Alzheimer's Disease (AD). A total of 10 eligible studies with 20511 patients and 40503 controls met the inclusion criteria. ABCA7 rs3764650 polymorphism was significantly associated with AD risk (OR=1.21, 95% CI 1.16-1.26, P<0.00001; I2=5%). In the subgroup analysis by race, statistically significant associations were found in Asians (OR=1.09, 95% CI 1.01-1.18, P =0.03; I2=0%) and in Caucasians (OR=1.25, 95% CI 1.19-1.31, P<0.00001; I2=0%). In conclusion, this meta-analysis suggested that ABCA7 rs3764650 polymorphism is significantly associated with AD risk.

Similarity and divergence of phylogenies, antimicrobial susceptibilities, and virulence factor profiles of Escherichia coli isolates causing recurrent urinary tract infections that persist or result from reinfection.

In order to obtain a better molecular understanding of recurrent urinary tract infection (RUTI), we collected 75 cases with repeatedly occurring uncomplicated UTI. The genetic relationships among uropathogenic Escherichia coli (UPEC) isolates were analyzed by pulsed-field gel electrophoresis. While 39 (52%) of the RUTI cases were defined as "persistence" of the same strain as the primary infecting strain, 36 (48%) were characterized by "reinfection" with a new strain that is different from the primary strain. We then examined the antimicrobial susceptibilities and phylogenetic backgrounds of 39 persistence and 86 reinfection UPEC isolates, and screened 44 virulence factor (VF) genes. We found that isolates had significant differences in the following: placement in phylogenetic group B2 (41% versus 21%; P = 0.0193) and the presence of adhesin genes iha (49% versus 28%; P = 0.0233) and papG allele I' (51% versus 24%; P = 0.003), iron uptake genes fyuA (85% versus 58%; P = 0.0037), irp-2 (87% versus 65%; P = 0.0109), and iutA (87% versus 58%; P = 0.0014), and an aggregate VF score (median, 11 versus 9; P = 0.0030). In addition, 41% of persistence strains harbored three adhesin genes simultaneously, whereas 22% of reinfection isolates did (P = 0.0289). Moreover, 59% versus 29% (P = 0.0014) of persistence and reinfection isolates contained seven types of iron uptake genes. Taken together, the antimicrobial susceptibilities of UPEC isolates had little effect on the RUTI. Compared with reinfection strains, persistence UPEC isolates exhibited higher VF scores and carried more VF genes than may be involved in the development and progression of RUTI.

Nosocomial bloodstream infection in patients caused by Staphylococcus aureus: drug susceptibility, outcome, and risk factors for hospital mortality.

BACKGROUND: Previous studies have different viewpoints about the clinical impact of methicillin resistance on mortality of hospital-acquired bloodstream infection (BSI) patients with Staphylococcus aureus (S. aureus). The objective of this study was to investigate the mortality of hospital-acquired BSI with S. aureus in a military hospital and analyze the risk factors for the hospital mortality. METHODS: A retrospective cohort study was performed in patients admitted to the biggest military tertiary teaching hospital in China between January 2006 and May 2011. All included patients had clinically significant nosocomial BSI with S. aureus. Multivariate Logistic regression analysis was used to identify the risk factors for hospital mortality of patients with S. aureus BSI. RESULTS: One hundred and eighteen patients of more than one year old were identified as clinically and microbiologically confirmed nosocomial bacteraemia due to S. aureus, and 75 out of 118 patients were infected with methicillin-resistant S. aureus (MRSA). The overall mortality of nosocomial S. aureus BSI was 28.0%. Methicillin resistance in S. aureus bacteremia was associated with significant increase in the length of hospitalization and high proportion of inappropriate empirical antibiotic treatment. After Logistic regression analysis, the severity of clinical manifestations (APACHE II score) (odds ratio (OR) 1.22, 95% confidence interval (CI) 1.12 - 1.34) and inadequacy of empirical antimicrobial therapy (OR 0.25, 95%CI 0.09 - 0.69) remained as risk factors for hospital mortality. CONCLUSIONS: Nosocomial S. aureus BSI was associated with high in-hospital mortality. Methicillin resistance in S. aureus has no significant impact on the outcome of patients with staphylococcal bacteremia. Proper empirical antimicrobial therapy is very important to the prognosis.

Prevalence of ß-lactamases and 16S rRNA methylase genes amongst clinical Klebsiella pneumoniae isolates carrying plasmid-mediated quinolone resistance determinants.

To characterise the prevalence of ß-lactamases and 16S rRNA methylase genes amongst clinical Klebsiella pneumoniae isolates carrying plasmid-mediated quinolone resistance (PMQR) determinants in China, 59 non-duplicate K. pneumoniae isolates harbouring at least one PMQR gene were screened for common ß-lactamases and 16S rRNA methylases genes. The genetic relatedness of the isolates was analysed by pulsed-field gel electrophoresis (PFGE). Most of PMQR gene-positive isolates carried no substitutions within the quinolone resistance-determining regions (QRDRs) or single point mutation in GyrA or ParC. Over one-half (52.5%) of the isolates exhibited decreased susceptibility to ciprofloxacin [minimum inhibitory concentration (MIC)=0.5-2 µg/mL] or low-level resistance to ciprofloxacin (MIC=4-8 µg/mL). qnr, aac(6')-Ib-cr and qepA were positive in 52 (88.1%), 16 (27.1%) and 3 (5.1%) isolates, respectively. The identified genes for ß-lactamases were distributed as follows: bla(TEM), 50.8%; bla(SHV), 91.5%; bla(CTX-M), 55.9%; bla(DHA), 59.3%; and bla(OXA-1), 22.1%. armA and rmtB were detected in 16.9% and 3.4% of isolates, respectively. All qnrB were detected in DHA-producing K. pneumoniae. Approximately 81.3%, 68.8% and 43.8% of aac(6')-Ib-cr carrying isolates produced OXA-1, DHA and ArmA, respectively. In conclusion, owing to few QRDR substitutions, most of the PMQR gene-carrying K. pneumoniae isolates exhibited low-level resistance to fluoroquinolones. qnr appears to be the predominant PMQR gene and it presented a significant correlation with bla(SHV), bla(CTX-M) and bla(DHA), whereas aac(6')-Ib-cr exhibited a close relationship with bla(OXA-1), bla(DHA) and armA. qepA was rarely detected in this study.

[Clinical results of stent revascularization as treatment for renal artery stenosis during 6 months of follow-up].

OBJECTIVES: To evaluate the safety and midterm efficacy of stent revascularization as treatment for renal artery stenosis. METHODS: Percutaneous transluminal renal angioplasty with stent (PTRA) was performed because of poorly controlled hypertension or preservation of renal function in 150 consecutive patients with severe renal artery stenosis, caused by atheroma (96 patients), arteritis (44 patients) and fibromuscular dysplasia (10 patients). All of them subsequently underwent 6-month clinical follow-up to observe the effect of the procedure on renal function, blood pressure control, number of antihypertensive medications. RESULT: Angiographic success was obtained in 148 (98.7%) of 150 patients after PTRA. At 6 months, both systolic and diastolic blood pressures significantly decreased (from 169.6 to 142.7 mm Hg and from 97.3 to 83.3 mm Hg, respectively; P < 0.001), and less antihypertensive medication was taken (from 2.7 to 1.9). The blood pressure became normal without taking any antihypertensive medications in 48 of 150 patients (32.0%), and the blood pressure control was more facile in 78 patients (52.0%), however, there were no improvement in 22 patients (16.0%). Creatinine level decreased in 34 patients (22.7%), remained stable in 112 patients (74.6%), and increased in 4 (2.7%). There was no statistical significance. No deaths occurred during 6-months follow-up. CONCLUSIONS: Renal artery stent revascularization had a beneficial effect on blood pressure control and a nondeleterious effect on renal function during 6-months follow-up. The long-term efficacy should be investigated. The procedure is safe in usual.

[Preliminary results of stenting revascularization as treatment for renal artery stenosis].

OBJECTIVES: To evaluate the safety and short-term efficacy of stent revascularization as treatment for renal artery stenosis. METHODS: Percutaneous transluminal renal angioplasty with stent (PTRAS) was performed on 30 consecutive patients with severe renal artery stenosis for poorly controlled hypertension or preservation of renal function. They subsequently underwent 3-month clinical follow-up for the effect of the procedure on renal function, blood pressure control and the number of antihypertensive medications used. RESULTS: Angiographic success was obtained in 29 (96.7%) of the 30 patients after PTRAS. 3 months after the procedure systolic and diastolic blood pressures significantly decreased (from 173.5 to 135.8 mm Hg and from 95.8 to 75.6 mm Hg, respectively; P < 0.001) and less antihypertensive medications were taken (from 2.5 to 1.5). Blood pressure in 5 (16.7%) of the 30 patients became normal without taking any antihypertensive medication and blood pressure control was more facile in 22 (73.3%) of the patients. However, there was no improvement in 3 (10.0%) of the patients. Creatinine slightly decreased in 2 (6.7%) of the 30 patients and remained stable in 28 (93.3%) of the 30 patients. There was no statistical significance in this respect. CONCLUSIONS: Renal artery stent revascularization has a short-term beneficial effect on blood pressure control and a nondeleterious effect on renal function. The long-term efficacy should be investigated. The procedure is safe in usual.