Blockade of a novel MAP4K4-LATS2-SASH1-YAP1 cascade inhibits tumorigenesis and metastasis in luminal breast cancer.

Novel components in the noncanonical Hippo pathway that mediate the growth, metastasis, and drug resistance of breast cancer (BC) cells need to be identified. Here, we showed that expression of SAM and SH3 domain-containing protein 1 (SASH1) is negatively correlated with expression of mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) in a subpopulation of patients with luminal-subtype BC. Downregulated SASH1 and upregulated MAP4K4 synergistically regulated the proliferation, migration, and invasion of luminal-subtype BC cells. The expression of LATS2, SASH1, and YAP1 and the phosphorylation of YAP1 were negatively regulated by MAP4K4, and LATS2 then phosphorylated SASH1 to form a novel MAP4K4-LATS2-SASH1-YAP1 cascade. Dephosphorylation of Yes1 associated transcriptional regulator (YAP1), YAP1/TAZ nuclear translocation, and downstream transcriptional regulation of YAP1 were promoted by the combined effects of ectopic MAP4K4 expression and SASH1 silencing. Targeted inhibition of MAP4K4 blocked proliferation, cell migration, and ER signaling both in vitro and in vivo. Our findings reveal a novel MAP4K4-LATS2-SASH1-YAP1 phosphorylation cascade, a noncanonical Hippo pathway that mediates ER signaling, tumorigenesis, and metastasis in breast cancer. Targeted intervention with this noncanonical Hippo pathway may constitute a novel alternative therapeutic approach for endocrine-resistant BC.

Downregulated expression of plakophilin-2 gene in patients with colon adenocarcinoma predicts an unfavorable prognosis and immune infiltrate.

BACKGROUND: Plakophilin 2 gene (PKP2) has been revealed to be differentially expressed in various cancer types and is correlated with prognosis. However, the role of PKP2 in colon adenocarcinoma remains indistinct. METHODS: Differences in transcriptional expression of PKP2 between colon adenocarcinoma tissues and normal adjacent tissues were acquired from the publicly available dataset-the Cancer Genome Atlas. A receiver operating curve (ROC) was constructed to differentiate colon adenocarcinoma tissues from adjacent normal tissues. The Kaplan-Meier plot method was performed to evaluate the effect of PKP2 on survival. The correlation between mRNA expression of PKP2 and immune infiltrating was determined by the Tumor Immune Estimation Resource and Tumor-Immune System Interaction databases. RESULTS: The expression of PKP2 in colon adenocarcinoma tissues was significantly downregulated compared with corresponding adjacent normal tissues. Decreased PKP2 mRNA expression was associated with lymph node metastases and advanced pathological stage. The ROC curve analysis indicated that with a cutoff value of 6.034, the sensitivity and specificity for PKP2 differentiating the colon adenocarcinoma tissues from the adjacent normal tissues were 90.2 and 66.5% respectively. Kaplan-Meier plot survival analysis revealed that colon adenocarcinoma patients with low-PKP2 had a worse prognosis than those with high-PKP2 (68.2 vs. 101.4 months, p = 0.028). Correlation analysis showed that mRNA expression of PKP2 was correlative with immune infiltrates. CONCLUSIONS: Downregulated PKP2 is significantly correlated with unfavorable immune infiltrating and survival in colon adenocarcinoma. This research indicates that PKP2 can be selected as a novel biomarker of potential immunotherapy targets and unfavorable prognosis in colon adenocarcinoma.

[18 F] -FAPI-42 PET/CT assessment of Progressive right ventricle fibrosis under pressure overload.

BACKGROUND: Right heart failure (RHF) is a complication of pulmonary hypertension (PH) and increases the mortality independently of the underlying disease. However, the process of RHF development and progression is not fully understood. We aimed to develop effective approaches for early diagnosis and precise evaluation of RHF. METHODS: Right ventricle (RV) pressure overload was performed via pulmonary artery banding (PAB) surgery in Sprague-Dawley (SD) rats to induce RHF. Echocardiography, right heart catheterization, histological staining, fibroblast activation protein (FAP) immunofluorescence and 18 F-labelled FAP inhibitor-42 ([18 F] -FAPI-42) positron emission tomography/computed tomography (PET/CT) were performed at day 3, week 1, 2, 4 and 8 after PAB. RNA sequencing was performed to explore molecular alterations between PAB and sham group at week 2 and week 4 after PAB respectively. RESULTS: RV hemodynamic disorders were aggravated, and RV function was declined based on right heart catheterization and echocardiography at week 2, 4 and 8 after PAB. Progressive cardiac hypertrophy, fibrosis and capillary rarefaction could be observed in RV from 2 to 8 weeks after PAB. RNA sequencing indicated 80 upregulated genes and 43 downregulated genes in the RV at both week 2 and week 4 after PAB; Gene Ontology (GO) analysis revealed that fibrosis as the most significant biological process in the RV under pressure overload. Immunofluorescence indicated that FAP was upregulated in the RV from week 2 to week 8 after PAB; and [18 F] -FAPI-42 PET/CT revealed FAPI uptake was significantly higher in RV at week 2 and further increased at week 4 and 8 after PAB. CONCLUSION: RV function is progressively declined with fibrosis as the most prominent molecular change after pressure overload, and [18 F] -FAPI-42 PET/CT is as sensitive and accurate as histopathology in RV fibrosis evaluation.

LACC1: A critical involvement in macrophage immunometabolism.

Laccase domain-containing 1 (LACC1) protein is an enzyme highly expressed in inflammatory macrophages, and studies have shown that it has a key role in diseases such as inflammatory bowel disease, arthritis, and microbial infections. Therefore, in this review, we focus on LACC1-mediated catalysis. In detail, LACC1 converts l-CITrulline (l-CIT) to l-ORNithine (l-ORN) and isocyanic acid in mice and humans and acts as a bridge between proinflammatory nitric oxide synthase (NOS2) and polyamine immunometabolism, thus exerting anti-inflammatory and antibacterial effects. Considering the actions of LACC1, targeting LACC1 may be a potent therapeutic avenue for inflammation-related diseases and microbial infection diseases.

Hydrogen sulfide ameliorates abdominal aorta coarctation-induced myocardial fibrosis by inhibiting pyroptosis through regulating eukaryotic translation initiation factor 2α phosphorylation and activating PI3K/AKT1 pathway.

This study aimed to assess the effects of exogenous hydrogen sulfide (H2S) on abdominal aorta coarctation (AAC) induced myocardial fibrosis (MF) and autophagy in rats. Forty-four Sprague-Dawley rats were randomly divided into control group, AAC group, AAC + H2S group, and H2S control group. After a model of rats with AAC was built surgically, AAC + H2S group and H2S group were injected intraperitoneally with H2S (100 µmol/kg) daily. The rats in the control group and the AAC group were injected with the same amount of PBS. We observed that H2S can improve left ventricular function and the deposition of myocardial collagen fibers, inhibit pyroptosis, down-regulate the expression of P-eif2α in myocardial tissue, and inhibit cell autophagy by activating the phosphatidylinositol 3-kinase (PI3K)/AKT1 signaling pathway (p < 0.05). In addition, angiotensin II (1 µM) H9c2 cardiomyocytes were injured in vitro experiments, and it was also observed that pyroptosis was inhibited after H2S (400 µmol/kg) intervention, the expression of P-eif2α in cardiomyocytes was significantly down-regulated, and the PI3K/AKT1 signaling pathway was activated at the same time. Therefore, increasing the expression of P-eif2α reverses the activation of the PI3K/AKT1 signaling pathway by H2S. In conclusion, these findings suggest that exogenous H2S can ameliorate MF in rats with AAC by inhibiting pyroptosis, and the mechanism may be associated with inhibiting the phosphorylation of eif2α and activating the PI3K/AKT1 signaling pathway to inhibit excessive cell autophagy.

Reconstruction of aortic sinus using patches in patients with acute type A aortic dissection.

OBJECTIVES: Acute type A aortic dissection involving the aortic sinus is often combined with varying degrees of aortic regurgitation, while the structure of the aortic valve is often undamaged. The aim of this study was to evaluate the clinical effects of reconstruction of the aortic sinus using patches in patients with acute type A aortic dissection. METHODS: From January 2016 to December 2019, 52 patients with acute type A aortic dissection involving the aortic sinus were treated with aortic sinus reconstruction using pericardial or artificial vascular patches. The clinical and follow-up data were summarized. RESULTS: Bovine pericardial patches were used in 31 cases and artificial vascular patches were used in 21 cases for aortic sinus reconstruction. Cardiopulmonary bypass time was (250.4 ± 65.7) min, aortic cross clamp time was (143.7 ± 42.3) min, and hypothermic circulatory arrest time was (9.6 ± 8.1) min. Three patients died in hospital, with a mortality rate of 5.8%. Fifteen patients (28.8%) had mild postoperative aortic regurgitation. The follow-up duration was 40 ± 12 (range, 21-66) months. Five patients (10.2%) developed moderate to severe aortic regurgitation and 3 (6.1%) died during the follow-up period. CONCLUSIONS: The application of patches for aortic sinus reconstruction is a relatively easy method in aortic valve-sparing root reconstruction for acute type A aortic dissection involving the aortic sinus. The clinical and follow-up results are favorable.

Expression and mechanism of exosome-mediated A FOXM1 related long noncoding RNA in gastric cancer.

BACKGROUND: Forkhead box protein M1 (FOXM1) is an oncogene regulating tumor growth and metastasis. Exosome was suggested to mediate cell communication by delivering active molecules in cancers. However, the existence of FOXM1 in circulating exosomes and the role of exosome FOXM1 in gastric cancer (GC) were not clear. This study aims to investigate the potential role of FOXM1 related long noncoding RNA (FRLnc1) in exosomes in GC. RESULTS: The prepared CD63 immunomagnetic beads (CD63-IMB) had the characteristics of good dispersity and high magnetic response. The isolated exosomes were presented with elliptical membranous particles under a transmission electron microscope (TEM), with the particle size of 89.78 ± 4.8 nm. Western blot (WB) results showed that the exosomes were rich in CD9 and CD81. The Dil-labeled exosomes were distributed around cytoplasm and nucleus of cells by imaging flow cytometry (IFC) analysis. The results of quantitative real-time PCR (qRT-PCR) revealed that the FRLnc1 expressions were up-regulated in GC cells, tumor tissues, and serum of GC patients. An obviously up-regulated FRLnc1 expression was found in serum exosomes of GC patients. Up-regulation of FRLnc1 expression was closely correlated to lymph node metastasis (LNM) and TNM stage with the combination of relevant clinicopathological parameter analysis. The in vitro functional analyses demonstrated that FRLnc1 knockdown by RNA interference suppressed cell proliferation and migration in HGC-27 cells, whereas FRLnc1 overexpression promoted cell proliferation and migration in MKN45 cells. After exosome treatment, the FRLnc1 expression was significantly increased in MKN45 cells, and the MKN45 cells showed increased ability of proliferation and migration. CONCLUSION: GC cells-derived exosomes played roles in promoting the growth and metastasis of GC by transporting FRLnc1, suggesting that FRLnc1 in the exosomes may be a potential biomarker for the diagnosis and treatment of GC. The delivery of FRLnc1 by the exosomes may provide a new way for the treatment of GC. Trial registration 2020-KYSB-094. Registered 23 March 2020-Retrospectively registered.

Monitoring Strain Response of Epoxy Resin during Curing and Cooling Using an Embedded Strain Gauge.

The present work describes the monitoring system of the real-time strain response on the curing process of epoxy resin from the initial point of curing to the end, and the change in strain during temperature changes. A simple mould was designed to embed the strain gauge, thermometer, and quartz standard sample into the epoxy resin, so that the strain and the temperature were simultaneously measured and recorded. A cryogenic-grade epoxy resin was tested and the Differential Scanning Calorimetry (DSC) was used to analyse the curing process. Based on the DSC results, three curing processes were adopted to investigate their influence on strain response as well as residual strain of the epoxy resin. Moreover, impact strength of the epoxy resin with various curing temperatures were tested and the results indicate that the curing plays a crucial role on the mechanical properties. The method will find cryogenic application of epoxy adhesives and epoxy resin based composites to monitor the strain during the curing process as well as the cryogenic service.

Endothelial dysfunction in tristetraprolin-deficient mice is not caused by enhanced tumor necrosis factor-α expression.

Cardiovascular events are important co-morbidities in patients with chronic inflammatory diseases like rheumatoid arthritis. Tristetraprolin (TTP) regulates pro-inflammatory processes through mRNA destabilization and therefore TTP-deficient mice (TTP(-/-) mice) develop a chronic inflammation resembling human rheumatoid arthritis. We used this mouse model to evaluate molecular signaling pathways contributing to the enhanced atherosclerotic risk in chronic inflammatory diseases. In the aorta of TTP(-/-) mice we observed elevated mRNA expression of known TTP targets like tumor necrosis factor-α (TNF-α) and macrophage inflammatory protein-1α, as well as of other pro-atherosclerotic mediators, like Calgranulin A, Cathepsin S, and Osteopontin. Independent of cholesterol levels TTP(-/-) mice showed a significant reduction of acetylcholine-induced, nitric oxide-mediated vasorelaxation. The endothelial dysfunction in TTP(-/-) mice was associated with increased levels of reactive oxygen and nitrogen species (RONS), indicating an enhanced nitric oxide inactivation by RONS in the TTP(-/-) animals. The altered RONS generation correlates with increased expression of NADPH oxidase 2 (Nox2) resulting from enhanced Nox2 mRNA stability. Although TNF-α is believed to be a central mediator of inflammation-driven atherosclerosis, genetic inactivation of TNF-α neither improved endothelial function nor normalized Nox2 expression or RONS production in TTP(-/-) animals. Systemic inflammation caused by TTP deficiency leads to endothelial dysfunction. This process is independent of cholesterol and not mediated by TNF-α solely. Thus, other mediators, which need to be identified, contribute to enhanced cardiovascular risk in chronic inflammatory diseases.

Interleukin 17 drives vascular inflammation, endothelial dysfunction, and arterial hypertension in psoriasis-like skin disease.

OBJECTIVE: Interleukin (IL)-17A is regarded as an important cytokine to drive psoriasis, an inflammatory skin disease marked by increased cardiovascular mortality. We aimed to test the hypothesis that overproduction of IL-17A in the skin leading to dermal inflammation may systemically cause vascular dysfunction in psoriasis-like skin disease. APPROACH AND RESULTS: Conditional overexpression of IL-17A in keratinocytes caused severe psoriasis-like skin inflammation in mice (K14-IL-17A(ind/+) mice), associated with increased reactive oxygen species formation and circulating CD11b(+) inflammatory leukocytes in blood, with endothelial dysfunction, increased systolic blood pressure, left ventricular hypertrophy, and reduced survival compared with controls. In K14-IL-17A(ind/+) mice, immunohistochemistry and flow cytometry revealed increased vascular production of the nitric oxide/superoxide reaction product peroxynitrite and infiltration of the vasculature with myeloperoxidase(+)CD11b(+)GR1(+)F4/80(-) cells accompanied by increased expression of the inducible nitric oxide synthase and the nicotinamide dinucleotide phosphate (NADPH) oxidase, nox2. Neutrophil depletion by anti-GR-1 antibody injections reduced oxidative stress in blood and vessels. Neutralization of tumor necrosis factor-α and IL-6 (both downstream of IL-17A) reduced skin lesions, attenuated oxidative stress in heart and blood, and partially improved endothelial dysfunction in K14-IL-17A(ind/+) mice. CONCLUSIONS: Dermal overexpression of IL-17A induces systemic endothelial dysfunction, vascular oxidative stress, arterial hypertension, and increases mortality mainly driven by myeloperoxidase(+)CD11b(+)GR1(+)F4/80(-) inflammatory cells. Depletion of the GR-1(+) immune cells or neutralization of IL-17A downstream cytokines by biologicals attenuates the vascular phenotype in K14-IL-17A(ind/+) mice.

[Effect of hydrogen sulfide on myocardial fibrosis and expression of PKCα and HSP70 in diabetic rats].

OBJECTIVE: To explore the eff ect of hydrogen sulfide (H2S) on protein kinase C α (PKCα) and heat shock protein 70 (HSP70) expression and myocardial fibrosis in diabetic rats. METHODS: Rats were randomly divided into 4 groups: the control group, diabetes group (STZ group), the H2S intervention group (STZ+H2S group) and the normal rats plus H2S group (the H2S group). Diabetic rats were induced by intraperitoneal injections of streptozotocin (STZ). The pathological morphological changes in myocardial fiber was analyzed by HE staining. The expression of PKCα, HSP70 and type III collagen were analyzed by Western blot. RESULTS: Compared with the control group, the expressions of PKCα, HSP70 and type III collagen in diabetic rats were significantly increased (P<0.05), accompanied by the disordered arrangement of myocardial cells, which were dramatically reversed by H2S treatment (P<0.05). CONCLUSION: H2S could reduce myocardial fibrosis in diabetic rats, which is related to the inhibition of PKCα and HSP70 expression.

Self-Stacked 3D Anisotropic BNNS Network Guided by Para-Aramid Nanofibers for Highly Thermal Conductive Dielectric Nanocomposites.

The enhancement of the heat-dissipation property of polymer-based composites is of great practical interest in modern electronics. Recently, the construction of a three-dimensional (3D) thermal pathway network structure for composites has become an attractive way. However, for most reported high thermal conductive composites, excellent properties are achieved at a high filler loading and the building of a 3D network structure usually requires complex steps, which greatly restrict the large-scale preparation and application of high thermal conductive polymer-based materials. Herein, utilizing the framework-forming characteristic of polymerization-induced para-aramid nanofibers (PANF) and the high thermal conductivity of hexagonal boron nitride nanosheets (BNNS), a 3D-laminated PANF-supported BNNS aerogel was successfully prepared via a simple vacuum-assisted self-stacking method, which could be used as a thermal conductive skeleton for epoxy resin (EP). The obtained PANF-BNNS/EP nanocomposite exhibits a high thermal conductivity of 3.66 W m-1 K-1 at only 13.2 vol % BNNS loading. The effectiveness of the heat conduction path was proved by finite element analysis. The PANF-BNNS/EP nanocomposite shows outstanding practical thermal management capability, excellent thermal stability, low dielectric constant, and dielectric loss, making it a reliable material for electronic packaging applications. This work also offers a potential and promotable strategy for the easy manufacture of 3D anisotropic high-efficiency thermal conductive network structures.

Improving enteral nutrition tolerance and protein intake maybe beneficial to intensive care unit patients.

Enteral nutrition (EN) is important for critically ill patients. This study investigated the current situation of EN treatment in SHANGHAI intensive care units (ICUs). We hypothesized that improving EN practice in SHANGHAI may benefit the prognosis of ICU patients. Clinical information on EN use was collected using clinic information forms in 2019. The collected data included the patient's general clinical information, EN prescription status, EN tolerance status, and clinical outcomes. The observation time points were days 1, 3, and 7 after starting EN. A total of 491 patients were included. The proportion of EN intolerance (defined as < 20 kcal/kg/day) decreased, with rates of intolerance of 100%, 82.07%, 70.61%, and 52.23% at 1, 3, 7, and 14 days, respectively. Age, mNutric score, and protein intake < 0.5 g/kg/day on day 7 were risk factors for 28-day mortality.The EN tolerance on day 7 and protein intake > 0.5 g/kg/day on day 3 or day 7 might affect the 28-day mortality. Risk factors with EN tolerance on day 7 by logistic regression showed that the AGI grade on day 1 was a major factor against EN tolerance. The proportion of EN tolerance in SHANGHAI ICU patients was low. Achieving tolerance on day 7 after the start of EN is a protective factor for 28-day survival. Improving EN tolerance and protein intake maybe beneficial for ICU patients.

miR-4461 inhibits the progression of Gallbladder carcinoma via regulating EGFR/AKT signaling.

Increasing evidence has demonstrated that microRNAs (miRNAs) participated in the tumorigenesis, progression and recurrence of various malignancies including Gallbladder carcinoma (GBC). miR-4461 was reported to work as a tumor suppressor gene in renal cell carcinoma. However, the role of miR-4461 in GBC remains unknown. Herein, we show that miR-4461 is downregulated in gallbladder cancer stem cells (CSCs). Forced miR-4461 expression attenuates the self-renewal, tumorigenicity of gallbladder CSCs, and inhibits proliferation and metastasis of GBC cells. Conversely, miR-4461 knockdown promotes the self-renewal of gallbladder CSCs, and facilities proliferation and metastasis of GBC cells. Mechanistically, miR-4461 inhibits GBC progression via downregulating EGFR/AKT pathway. Special EGFR siRNA or AKT overexpression virus abolishes the discrepancy of self-renewal, tumorigenesis, growth, and metastasis between miR-4461 overexpression GBC cells and their control cells. In conclusion, miR-4461 suppresses GBC cells self-renewal, tumorigenicity, proliferation, and metastasis by inactivating EGFR/AKT signaling, and may therefore prove to be a potential therapeutic target for GBC patients.

A bibliometric analysis of the application of artificial intelligence to advance individualized diagnosis and treatment of critical illness.

Background: Artificial intelligence (AI) has been extensively applied in the individualized diagnosis and treatment of critical illness, and numerous studies have been published on this topic. Therefore, a bibliometric analysis of these publications should be performed to provide a direction of hot topics and future research trends. Methods: A bibliometric analysis was performed on the research articles to identify the hot topics and any unsolved issues regarding the use of AI in individualized diagnosis and treatment of critical illness. Articles published from January 2011 to December 2021 were retrieved from the Web of Science (WOS) core collection database for bibliometric analysis, and a cross-sectional analysis of the relevant studies that had been registered at ClinicalTrials.gov was also conducted. Results: The number of articles published showed an annually increasing trend, with a worldwide geographic distribution over the past decade. Ultimately, 427 research articles were included in the bibliometric analysis. The relevant articles were divided into four separate clusters that focused on AI application aspects, prediction model establishment, coronavirus disease 2019 (COVID-19) treatment and outcome assessments, respectively. "Machine learning" was the most frequent keyword (147 occurrences, 165 links, and 395 total link strengths) followed by "risk", "models", and "mortality". With 205 articles, the United States of America (USA) had interacted the most with other countries (20 links, and 94 total link strength), while the domestic research institutes in China had infrequently collaborated with others. Approximately 130 trials focusing on the application of AI in the intensive care unit (ICU) and emergency department (ED) had been registered at ClinicalTrial.gov, and most of them (n=71, 54.6%) were interventional. The main research objectives of these trials were to provide decision making assistance and establish prediction models. However, only 3.8% (5 trials) of them had reached exact conclusions which favored the application of AI. Conclusions: The application of AI has raised great interest in critical illness and has mainly been focused on decision making assistance and prediction model establishment. Cooperation between agencies engaged in AI research needs to be strengthened. An increasing number of trials have been registered at ClinicalTrial.gov, and the results of them are promising. Keywords: Bibliometric analysis; artificial intelligence (AI); individualized diagnosis; critical care medicine; emergency department (ED).

[Comparative analysis of clinical features between severe coronavirus disease 2019 and severe community acquired pneumonia].

OBJECTIVE: To compare and analyze the clinical features of patients with severe coronavirus disease 2019 (sCOVID-19) and severe community acquired pneumonia (sCAP) who meet the diagnostic criteria for severe pneumonia of the Infectious Diseases Society of America/American Thoracic Society (IDSA/ATS). METHODS: A retrospective comparative analysis of the clinical records of 116 patients with sCOVID-19 admitted to the department of critical care medicine of Wuhan Third Hospital from January 1, 2020 to March 31, 2020 and 135 patients with sCAP admitted to the department of critical care medicine of Shanghai First People's Hospital from January 1, 2010 to December 31, 2017 was conducted. The basic information, diagnosis and comorbidities, laboratory data, etiology and imaging results, treatment, prognosis and outcome of the patients were collected. The differences in clinical data between sCOVID-19 and sCAP patients were compared, and the risk factors of death were analyzed. RESULTS: The 28-day mortality of sCOVID-19 and sCAP patients were 50.9% (59/116) and 37.0% (50/135), respectively. The proportion of arterial partial pressure of oxygen/fraction of inspired oxygen (PaO2/FiO2) ≤ 250 mmHg (1 mmHg ≈ 0.133 kPa) in sCOVID-19 patients was significantly higher than that of sCAP [62.1% (72/116) vs. 34.8% (47/135), P < 0.01]. The possible reason was that the proportion of multiple lung lobe infiltration in sCOVID-19 was significantly higher than that caused by sCAP [94.0% (109/116) vs. 40.0% (54/135), P < 0.01], but the proportion of sCOVID-19 patients requiring mechanical ventilation was significantly lower than that of sCAP [45.7% (53/116) vs. 60.0% (81/135), P < 0.05]. Further analysis of clinical indicators related to patient death found that for sCOVID-19 patients PaO2/FiO2, white blood cell count (WBC), neutrophils (NEU), neutrophil percentage (NEU%), neutrophil/lymphocyte ratio (NLR), total bilirubin (TBil), blood urea nitrogen (BUN), albumin (ALB), Ca2+, prothrombin time (PT), D-dimer, C-reactive protein (CRP) and other indicators were significantly different between the death group and the survival group, in addition, the proportion of receiving mechanical ventilation, gamma globulin, steroid hormones and fluid resuscitation in death group were higher than survival group. Logistic regression analysis showed that the need for mechanical ventilation, NLR > 10, TBil > 10 µmol/L, lactate dehydrogenase (LDH) > 250 U/L were risk factors for death at 28 days. For sCAP patients, there were significant differences in age, BUN, ALB, blood glucose (GLU), Ca2+ and D-dimer between the death group and the survival group, but there was no significant difference in treatment. Logistic regression analysis showed that BUN > 7.14 mmol/L and ALB < 30 g/L were risk factors for 28-day death of sCAP patients. CONCLUSIONS: The sCOVID-19 patients in this cohort have worse oxygen condition and symptoms than sCAP patients, which may be due to the high proportion of lesions involving the lungs. The indicators of the difference between the death group and the survival group were similar in sCOVID-19 and sCAP patients. It is suggested that the two diseases have similar effects on renal function, nutritional status and coagulation function. But there were still differences in risk factors affecting survival. It may be that sCOVID-19 has a greater impact on lung oxygenation function, inflammatory cascade response, and liver function, while sCAP has a greater impact on renal function and nutritional status.

A novel algorithm for diagnosis of invasive pulmonary aspergillosis based on pentraxin 3 gene polymorphisms and its adjusted value among autoimmune diseases patients.

BACKGROUND: Invasive pulmonary aspergillosis (IPA) is a rapidly progressive and fatal disease for those with autoimmune diseases. The performance of existing diagnostic tools is unsatisfactory, and a novel algorithm based on pentraxin 3 (PTX3) gene polymorphisms with adjusted PTX3 and galactomannan (GM) values is urgently needed. METHODS: Levels of PTX3 and GM were measured in the bronchoalveolar lavage fluid (BALF) and blood samples of patients who had autoimmune diseases with IPA between June 2017 and June 2021. Urea dilution was applied internally to correct the real BALF PTX3 and GM values. Three single-nucleotide polymorphisms (SNPs; rs1840680, rs2305619, and rs3816527) in the PTX3 gene were detected by polymerase chain reaction direct sequencing, and their associations with IPA were evaluated. Receiver operating characteristic (ROC) curves based on different variables were generated to determine the best algorithm for IPA diagnosis. RESULTS: This study enrolled 50 patients with IPA and 100 without IPA in the control groups (comprising 50 patients with Aspergillus airway colonization and 50 patients with bacterial pneumonia). The levels of adjusted BALF PTX3 and GM were higher in the IPA group than in the control groups (P<0.05, respectively). For diagnosing IPA, the best adjusted cutoff value for PTX in BALF was 14.5 ng/mL and the best adjusted cutoff value for GM in BALF was 2.5 optical density index (ODI). The SNP rs1840680 AA homozygote was associated with a higher risk of IPA [odds ratio (OR) 18.86, 95% confidence interval (CI): 7.96-44.69; P<0.01], while no genotypic distribution differences were observed for the other 2 SNPs (rs2305619 and rs3816527). Six algorithms were established based on PTX3 gene polymorphisms. The algorithm consisting of PTX3 gene polymorphisms with adjusted BALF PTX3 and BALF GM values demonstrated the best diagnostic performance (sensitivity 90.03%; specificity 97.09%; area under the curve 0.94). CONCLUSIONS: It was revealed that our new algorithm based on PTX3 gene polymorphisms combined with adjusted BALF GM and BALF PTX3 values performed well in diagnosing IPA.

COVID-19 associated EBV reactivation and effects of ganciclovir treatment.

BACKGROUND: Systemic reactivation of Epstein-Barr virus (EBV) may occur in novel coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). However, the clinical consequences of EBV reactivation remain uncertain. METHODS: In this retrospective study, we screened 1314 patients with confirmed COVID-19 who died or were discharged between January 1, 2020 and March 12, 2020, in Wuhan Infectious Disease Hospital, Wuhan, China. Patients who had complete data for EBV serology and cytomegalovirus (CMV) serology were eligible. Serum levels of viral capsid antigen (VCA)-immunoglobulin G (IgG), Epstein-Barr nuclear antigen-IgG, VCA-IgM, early antigen (EA)-IgG, CMV-IgG, and CMV-IgM were compared between survivors and nonsurvivors. Dynamic changes of laboratory tests and outcomes were compared in patients with and without ganciclovir treatment. We used 1:1 matching based on age, gender, and illness severity to balance baseline characteristics. RESULTS: EBV reactivation was present in 55 of 217 patients. EBV reactivation was associated with age (57.91 [13.19] vs. 50.28 [12.66] years, p < .001), female gender (31 [56%] vs. 60 [37%], p = .02). Patients with EBV reactivation have statistically nonsignificant higher mortality rate (12 [22%] vs. 18 [11%], p = .08). EA-IgG levels were significantly higher in nonsurvivors than in survivors (median difference: -0.00005, 95% confidence interval, CI [-3.10, 0.00], p = .05). As compared to patients with COVID-19 who did not receive ganciclovir therapy, ganciclovir-treated patients had improved survival rate (0.98, 95% CI [0.95, 1.00] vs. 0.88, 95% CI [0.81, 0.95], p = .01). Hemoglobin (p < .001) and prealbumin (p = .02) levels were significantly higher in ganciclovir-treated patients. CONCLUSION: A high proportion of COVID-19 patients had EBV reactivation that may be associated with an increased risk of death. Whether treatment with ganciclovir may decrease the mortality of COVID-19 patients complicated with EBV reactivation warrants to be addressed in a placebo-controlled randomized trial in the future.

[Expert statement on the construction criteria of critical care department in municipal and district designated hospitals under the pandemic prevention and control].

The global coronavirus disease 2019 epidemic is still in a pandemic state. Aging population with underlying diseases is prone to become severe, and have a higher mortality. The treatment capacity of the critical care department directly determines the treatment success rate of critical illness. At present, there is still a certain gap between domestic and foreign countries in intensive care unit (ICU), which is not only in the allocation of medical staff, but also in the beds and settings. The current medical model cannot fully meet the needs of development. The experience and lessons of many major public health emergencies suggested that "dual track of peace and war" approach in discipline construction of critical care is the best medical model. Following the concept of "combination of peace and war", strengthening the discipline construction of critical care department in municipal and district designated hospitals, allocating reasonable standard ICU, step-down ICU and combat readiness ICU, establishing rapid response team, and strengthening regular training and scientific management may be the key measures to deal with the epidemic.

A circGLIS3/miR-644a/PTBP1 positive feedback loop promotes the malignant biological progressions of non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is a severe cancer which critically threatens human health in the world. Circular RNAs (circRNAs) are non-coding RNAs that involve in cancer progression. We want to explore the roles of circRNAs in NSCLC in this study. In current study, circGLIS3 was found to be highly expressed in NSCLC tissues and cell lines and high circGLIS3 level was correlated to malignant characteristics and poor prognosis of NSCLC. Functional experiments suggested that circGLIS3 promoted proliferation, migration and invasion and arrested apoptosis of NSCLC cells in vitro. CircGLIS3 also participated in the in vivo process by accelerate NSCLC tumor growth and metastasis. Mechanistically, circGLIS3 could sponging multiple anti-cancer miRNAs including miR-526b, miR-198, miR-498 and miR-664a. Here, we for the first time confirmed that miR-644a was downregulated and functioned as a tumor suppression gene in NSCLC. In addition, we found PTBP1 as a novel target of miR-644a and circGLIS3 could raise the expression of PTBP1 via miR-644a. And PTBP1 could bind to the flanking introns of circGLIS3 and thereby promoting looping of circGLIS3. In conclusion, CircGLIS3 functions as an oncogene via sponging multiple tumor-suppressive miRNAs in NSCLC. A circGLIS3/miR-644a/PTBP1 positive feedback loop exists in the tumorigenesis and development of NSCLC.