Search

ObjectivePneumonia is a common clinical condition primarily treated with antibiotics and organ support. Exploring the pathogenesis to identify therapeutic targets may aid in the adjunct treatment of pneumonia and improve survival rates.MethodsTranscriptomic data from peripheral blood of 183 pneumonia patients were analyzed using Gene Set Variation Analysis (GSVA) and univariate Cox regression analysis to identify signaling pathways associated with pneumonia mortality. A pneumonia mouse model was established via airway injection of Klebsiella pneumoniae, and pathway-specific blockers were administered via tail vein infusion to assess whether the identified signaling pathways impact the mortality in pneumonia.ResultsThe combination of GSVA and Cox analysis revealed 17 signaling pathways significantly associated with 28-day mortality in pneumonia patients (P < 0.05). Notably, the RIG-I-like receptor signaling pathway exhibited the highest hazard ratio of 2.501 with a 95% confidence interval of [1.223–5.114]. Infusion of RIG012 via the tail vein effectively inhibited the RIG-I-like receptor signaling pathway, significantly ameliorated lung injury in pneumonia mice, reduced pulmonary inflammatory responses, and showed a trend toward improved survival rates.ConclusionRIG012 may represent a novel adjunctive therapeutic agent for pneumonia.

Abstract Background Uncontrolled inflammation caused by macrophages and monocytes plays a crucial role in worsening acute respiratory distress syndrome (ARDS). Previous studies have highlighted the importance of IFIH1 in regulating macrophage polarisation in ARDS triggered by pneumonia. However, the mechanisms by which IFIH1 is activated in ARDS remain unclear. Methods In this study, we utilised multiomics sequencing and molecular interaction experiments to explore the molecular mechanisms underlying IFIH1 activation in ARDS. Through the use of conditional gene knockout mice and primary cells, we demonstrated the significant role of these mechanisms in the development of ARDS. Additionally, we validated the associations between these mechanisms and ARDS by quantitative PCR analysis of CD14+ cells obtained from the peripheral blood of 140 ARDS patients. Results Our investigation revealed that lipopolysaccharide, a critical component derived from Gram‐negative bacteria, activated IFIH1 by upregulating a novel transcript known as IFIH1‐binding RNA1 (IBR1) in monocytes and macrophages. Specifically, as an endogenous double‐stranded RNA, IBR1 bind to the helicase domain of IFIH1 because of its unique double‐stranded structure. Deletion of IBR1 significantly reduced the activation of IFIH1, M1 polarisation of macrophages, and inflammatory lung injury in ARDS. Moreover, IBR1 directly induced M1 polarisation of macrophages and ARDS, whereas deletion of IFIH1 inhibited IBR1‐induced macrophage M1 polarisation and inflammatory lung injury. Importantly, we observed a notable increase in IBR1 expression in ARDS patients with pneumonia caused by Gram‐negative bacteria. Furthermore, we demonstrated that the delivery of IFIH1 mutants through exosomes effectively counteracted IBR1, thereby reducing pulmonary inflammation and alleviating lung injury. Conclusions This study revealed a novel mechanism involving IBR1, an endogenous double‐stranded RNA (dsRNA) that binds to IFIH1, shedding light on the complex process of macrophage polarisation in ARDS. The administration of IFIH1 variants has the potential to eliminate pulmonary dsRNA and alleviate inflammatory lung injury in ARDS. Highlights In monocytes and macrophages, the endogenous double‐stranded RNA, IFIH1‐binding RNA 1 (IBR1), binds to the helicase domain of IFIH1 because of its unique double‐stranded structure. IBR1 plays a significant role in macrophage polarisation and the development of acute respiratory distress syndrome (ARDS) induced by Gram‐negative bacteria or lipopolysaccharide (LPS). Administration of IFIH1 variants has potential for eliminating pulmonary IBR1 and reducing inflammatory lung injury in ARDS patients.

Abstract Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a common life‐threatening syndrome with no effective pharmacotherapy. Sepsis‐related ARDS is the main type of ARDS and is more fatal than other types. Extracellular vesicles (EVs) are considered novel mediators in the development of inflammatory diseases. Our previous research suggested that endothelial cell‐derived EVs (EC‐EVs) play a crucial role in ALI/ARDS development, but the mechanism remains largely unknown. Here, we demonstrated that the number of circulating EC‐EVs was increased in sepsis, exacerbating lung injury by targeting monocytes and reprogramming them towards proinflammatory macrophages. Bioinformatics analysis and further mechanistic studies revealed that vascular cell adhesion molecule 1 (VCAM1), overexpressed on EC‐EVs during sepsis, activated the NF‐κB pathway by interacting with integrin subunit alpha 4 (ITGA4) on the monocyte surface, rather than the tissue resident macrophage surface, thereby regulating monocyte differentiation. This effect could be attenuated by decreasing VCAM1 levels in EC‐EVs or blocking ITGA4 on monocytes. Furthermore, the number of VCAM1+ EC‐EVs was significantly increased in patients with sepsis‐related ARDS. These findings not only shed light on a previously unidentified mechanism underling sepsis‐related ALI/ARDS, but also provide potential novel targets and strategies for its precise treatment.

Abstract Background To evaluate the diagnostic performance of multiparametric transrectal ultrasound (TRUS) and to design diagnostic scoring systems based on four modes of TRUS to predict peripheral zone prostate cancer (PCa) and clinically significant prostate cancer (csPCa). Methods A development cohort involved 124 nodules from 116 patients, and a validation cohort involved 72 nodules from 67 patients. Predictors for PCa and csPCa were extracted to construct PCa and csPCa models based on regression analysis of the development cohort. An external validation was performed to assess the performance of models using area under the curve (AUC). Then, PCa and csPCa diagnostic scoring systems were established to predict PCa and csPCa. The diagnostic accuracy was compared between PCa and csPCa scores and PI-RADS V2, using receiver operating characteristics (ROC) and decision curve analysis (DCA). Results Regression models were established as follows: PCa = − 8.284 + 4.674 × Margin + 1.707 × Adler grade + 3.072 × Enhancement patterns + 2.544 × SR; csPCa = − 7.201 + 2.680 × Margin + 2.583 × Enhancement patterns + 2.194 × SR. The PCa score ranged from 0 to 6 points, and the csPCa score ranged from 0 to 3 points. A PCa score of 5 or higher and a csPCa score of 3 had the greatest diagnostic performance. In the validation cohort, the AUC for the PCa score and PI-RADS V2 in diagnosing PCa were 0.879 (95% confidence interval [CI] 0.790–0.967) and 0.873 (95%CI 0.778–0.969). For the diagnosis of csPCa, the AUC for the csPCa score and PI-RADS V2 were 0.806 (95%CI 0.700–0.912) and 0.829 (95%CI 0.727–0.931). Conclusions The multiparametric TRUS diagnostic scoring systems permitted better identifications of peripheral zone PCa and csPCa, and their performances were comparable to that of PI-RADS V2.

Abstract Background Combining targeted biopsy (TB) with systematic biopsy (SB) is currently recommended as the first-line biopsy method by the European Association of Urology (EAU) guidelines in patients diagnosed with prostate cancer (PCa) with an abnormal magnetic resonance imaging (MRI). The combined SB and TB indeed detected an additional number of patients with clinically significant prostate cancer (csPCa); however, it did so at the expense of a concomitant increase in biopsy cores. Our study aimed to evaluate if ipsilateral SB (ipsi-SB) + TB or contralateral SB (contra-SB) + TB could achieve almost equal csPCa detection rates as SB + TB using fewer cores based on a different csPCa definition. Methods Patients with at least one positive prostate lesion were prospectively diagnosed by MRI. The combination of TB and SB was conducted in all patients. We compared the csPCa detection rates of the following four hypothetical biopsy sampling schemes with those of SB + TB: SB, TB, ipsi-SB + TB, and contra-SB + TB. Results The study enrolled 279 men. The median core of SB, TB, ipsi-SB + TB, and contra-SB + TB was 10, 2, 7 and 7, respectively (P

Abstract Purpose Therapeutic hypothermia management remains controversial in patients with traumatic brain injury. We conducted a meta-analysis to evaluate the risks and benefits of therapeutic hypothermia management in patients with traumatic brain injury. Methods We searched the Web of Science, PubMed, Embase, Cochrane (Central) and Clinical Trials databases from inception to January 17, 2019. Eligible studies were randomised controlled trials that investigated therapeutic hypothermia management versus normothermia management in patients with traumatic brain injury. We collected the individual data of the patients from each included study. Meta-analyses were performed for 6-month mortality, unfavourable functional outcome and pneumonia morbidity. The risk of bias was evaluated using the Cochrane Risk of Bias tool. Results Twenty-three trials involving a total of 2796 patients were included. The randomised controlled trials with a high quality show significantly more mortality in the therapeutic hypothermia group [risk ratio (RR) 1.26, 95% confidence interval (CI) 1.04 to 1.53, p = 0.02]. Lower mortality in the therapeutic hypothermia group occurred when therapeutic hypothermia was received within 24 h (RR 0.83, 95% CI 0.71 to 0.96, p = 0.01), when hypothermia was received for treatment (RR 0.66, 95% CI 0.49 to 0.88, p = 0.006) or when hypothermia was combined with post-craniectomy measures (RR 0.69, 95% CI 0.48 to 1.00, p = 0.05). The risk of unfavourable functional outcome following therapeutic hypothermia management appeared to be significantly reduced (RR 0.78, 95% CI 0.67 to 0.91, p = 0.001). The meta-analysis suggested that there was a significant increase in the risk of pneumonia with therapeutic hypothermia management (RR 1.48, 95% CI 1.11 to 1.97, p = 0.007). Conclusions Our meta-analysis demonstrated that therapeutic hypothermia did not reduce but might increase the mortality rate of patients with traumatic brain injury in some high-quality studies. However, traumatic brain injury patients with elevated intracranial hypertension could benefit from hypothermia in therapeutic management instead of prophylaxis when initiated within 24 h.

Global climate change leads to simultaneous changes in multiple environmental drivers in the marine realm. Although physiological characterization of coccolithophores have been studied under climate change, there is limited knowledge on the biochemical responses of this biogeochemically important phytoplankton group to changing multiple environmental drivers. Here we investigate the interactive effects of reduced phosphorus availability (4 to 0.4 μmol L-1), elevated pCO2 concentrations (426 to 946 μatm) and increasing light intensity (40 to 300 μmol photons m-2 s-1) on elemental content and macromolecules of the cosmopolitan coccolithophore Emiliania huxleyi. Reduced phosphorus availability reduces particulate organic nitrogen and protein contents under low light intensity, but not under high light intensity. Reduced phosphorus availability and ocean acidification act synergistically to increase particulate organic carbon (POC) and carbohydrate contents under high light intensity but not under low light intensity. Reduced phosphorus availability, ocean acidification and increasing light intensity act synergistically to increase the allocation of POC to carbohydrates. Under future ocean acidification and increasing light intensity, enhanced carbon fixation could increase carbon storage in the phosphorus-limited regions of the oceans where E. huxleyi dominates the phytoplankton assemblages. In each light intensity, elemental carbon to phosphorus (C : P) and nitrogen to phosphorus (N : P) ratios decrease with increasing growth rate. These results suggest that coccolithophores could reallocate chemical elements and energy to synthesize macromolecules efficiently, which allows them to regulate its elemental content and growth rate to acclimate to changing environmental conditions. [ABSTRACT FROM AUTHOR]