Metformin is a potential therapeutic for COVID-19/LUAD by regulating glucose metabolism.

Lung adenocarcinoma (LUAD) is the most common and aggressive subtype of lung cancer, and coronavirus disease 2019 (COVID-19) has become a serious public health threat worldwide. Patients with LUAD and COVID-19 have a poor prognosis. Therefore, finding medications that can be used to treat COVID-19/LUAD patients is essential. Bioinformatics analysis was used to identify 20 possible metformin target genes for the treatment of COVID-19/LUAD. PTEN and mTOR may serve as hub target genes of metformin. Metformin may be able to cure COVID-19/LUAD comorbidity through energy metabolism, oxidoreductase NADH activity, FoxO signalling pathway, AMPK signalling system, and mTOR signalling pathway, among other pathways, according to the results of bioinformatic research. Metformin has ability to inhibit the proliferation of A549 cells, according to the results of colony formation and proliferation assays. In A549 cells, metformin increased glucose uptake and lactate generation, while decreasing ATP synthesis and the NAD+/NADH ratio. In summary, PTEN and mTOR may be potential targets of metformin for the treatment of COVID-19/LUAD. The mechanism by which metformin inhibits lung adenocarcinoma cell proliferation may be related to glucose metabolism regulated by PI3K/AKT signalling and mTOR signalling pathways. Our study provides a new theoretical basis for the treatment of COVID-19/LUAD.

Down-regulation of interleukin-2 predicts poor prognosis and associated with immune escape in lung adenocarcinoma.

Background and Objective: Lung adenocarcinoma (LUAD) is the most common subtype of lung cancer and has a poor prognosis. Interleukin-2 (IL2) is a cytokine that stimulates lymphocyte proliferation. However, its role in LUAD remains unclear. Methods: The UALCAN, human protein atlas (HPA), and tumor immune estimation resource (TIMER) databases were used to investigate IL2 expression in samples from patients with LUAD. The HPA, PrognoScan, and Kaplan-Meier plotter databases were used to examine the prognostic value of IL2 in LUAD. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses were performed to analyze IL2-interacting genes identified through the GeneMANIA database. TIMER was used to analyze the correlation of IL2 expression with immune cell infiltration and immune checkpoint expression levels in LUAD. Results: Bioinformatic analysis using the TIMER, The University of Alabama at Birmingham Cancer data analysis Portal (UALCAN), and HPA public databases showed that IL2 expression was lower in patients with LUAD than in the normal control group. Moreover, patients with low IL2 expression exhibited poor overall survival. Furthermore, IL2 expression was significantly positively correlated with various immune cells, including B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells, in patients with LUAD. Additionally, IL2 expression was markedly positively associated with the above-mentioned immune cells. Furthermore, IL2 expression was positively correlated with PD-1, PD-L1, and CTLA-4 expression. Conclusion: Our results indicate that down-regulation of IL2 predicts poor prognosis and is associated with immune escape in LUAD, and IL2 could serve as a potential novel prognostic biomarker of LUAD.

SARS-CoV-2 antibody response in SARS survivors with and without the COVID-19 vaccine.

OBJECTIVES: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to spread worldwide. However, it remains unknown whether individuals with prior SARS-CoV-1 infection are protected from SARS-CoV-2 infection. This study assessed protective antibody levels in SARS survivors with and without the COVID-19 vaccine. METHODS: We recruited 17 SARS survivors infected with SARS-CoV-1 in 2003, including 8 not vaccinated with the COVID-19 vaccine and 9 vaccinated with two doses of inactivated whole-virion COVID-19 vaccine (Sinopharm). In addition, 105 healthy adult volunteers without SARS-CoV-1 and SARS-CoV-2 infections were used as controls. The relative concentrations of three protective antibodies including anti-SARS-CoV-2 spike IgG (nCoV S-IgG), anti-SARS-CoV-2 spike receptor-binding domain IgG (nCoV RBD-IgG), and anti-SARS-CoV-2 neutralizing antibodies (nCoV NAbs) were measured to evaluate humoral immunity. RESULTS: We found that the positive rates of these antibodies in unvaccinated SARS survivors were 37.5%, 37.5%, and 62.5%, respectively. In contrast, the corresponding positive rates were all 0% in controls before vaccination. In controls, the levels of protective antibodies reached a peak ca. 28 days after the second dose of vaccine and then started to decline. Surprisingly, the levels of these antibodies were maintained at very high levels even 166 days after the second dose of vaccine in SARS survivors. CONCLUSION: Our study suggests that there are protective antibodies cross-reacting with SARS-CoV-2 in recovered SARS patients and that SARS survivors can generate a much stronger antibody response induced by the COVID-19 vaccine than can controls. These initial findings show the feasibility of developing novel pan-sarbecovirus vaccines.

Long Term Characteristics of Clinical Distribution and Resistance Trends of Carbapenem-Resistant and Extended-Spectrum ß-Lactamase Klebsiella pneumoniae Infections: 2014-2022.

Purpose: Through long-term and large sample size statistical analysis, we revealed the pattern of Klebsiella pneumoniae (KP) infection and drug resistance and provided epidemiological data for the treatment and prevention and control of multidrug-resistant bacterial infection in our hospital. Patients and Methods: Strains were identified using the BD PhoenixTM100 system, minimal inhibitory concentration of antibiotics were determined by the broth method, and data were statistically analyzed using WHONET 5.6 and SPSS27.0. Results: The isolation rate of KP from Enterobacteriaceae (26.2%, 4547/17358) in our hospital showed an increasing annual trend, ranking second only to Escherichia coli. Carbapenem-resistant KP (CRKP) accounted for the highest proportion of carbapenem-resistant Enterobacteriaceae (72.2%, 431/597), showing an upward trend. Infected patients had a male-to-female ratio of approximately 2:1 and were mainly >60 years of age (66.2%), with intensive care units being the most commonly distributed department. Sputum was the most common specimen type (74.0%). Compared with spring and summer, autumn and winter were the main epidemic seasons for KP and extended-spectrum ß-lactamase KP (ESBL-KP). The resistance rate of KP to common antibiotics was low, but all showed an increasing trend each year. ESBL-KP was >90% resistant to piperacillin, amoxicillin/clavulanic acid, and cefotaxime and less resistant to other common antibiotics, but showed an increasing trend in resistance to most antibiotics. CRKP resistance to common antibiotics was high, with resistance rates >90%, excluding amikacin (64.1%), gentamicin (87.4%), cotrimoxazole (44.3%), chloramphenicol (13.6%), and tetracycline (30.5%). Conclusion: KP in our hospital mainly caused pulmonary infection in older men, which occurred frequently in autumn and winter, and the isolation and drug resistance rates showed an increasing trend. Age over 70 years, admission to intensive care unit, and urinary tract infection were found to be the risk factors for CRKP and ESBL-KP-resistance.

Antibodies against neutrophil extracellular traps (NETs) potentiate clinical performance of anti-double-stranded DNA antibodies in systemic lupus erythematosus.

Autoantibodies against NETs (ANETA) are present in SLE patients. We aimed to determine the clinical relevance of ANETA in SLE. Serum from 129 SLE patients, 161 patients with various rheumatoid diseases (DC), and 53 healthy controls (HC) were tested by a home-made ANETA ELISA platform. ANETA showed a sensitivity of 35.7% and a specificity of 92.5%, respectively, in the diagnosis of SLE. The combination of ANETA with anti-dsDNA antibody increased the diagnostic sensitivity from 49.6% to 62.8% for SLE. The presence of ANETA potentiates the clinical utility of anti-dsDNA antibodies in identifying a subset of SLE patients with higher disease activity and hematological abnormalities. The binding of ANETA to NETs did not inhibit the immunostimulatory effect of NETs. Our findings suggested that ANETA have potential as clinically relevant biomarkers that potentiate the clinical performance of anti-dsDNA antibodies in the diagnosis, risk stratification and subtyping of patients with SLE.

In vitro susceptibility profiles of Candida parapsilosis species complex subtypes from deep infections to nine antifungal drugs.

Introduction. The Candida parapsilosis complex can be divided into C. parapsilosis sensu stricto, C. orthopsilosis, and C. metapsilosis subtypes. It is uncommon for drug sensitivity tests to type them.Gap Statement. In routine susceptibility reports, drug susceptibility of C. parapsilosis complex subtypes is lacking.Aim. The aim of this study is to investigate the antifungal susceptibility and clinical distribution characteristics of the C. parapsilosis complex subtypes causing deep infection in patients.Methodology. Non-repetitive strains of C. parapsilosis complex isolated from deep infection from 2017 to 2019 were collected. Species-level identification was performed using a matrix-assisted laser desorption/ionization time-of-flight mass spectrometer and confirmed using ITS gene sequencing, when necessary. Antifungal susceptibility testing was performed using the Sensititre YeastOne system method.Results. A total of 244 cases were included in the study, including 176 males (72.13 %, 60.69±13.43 years) and 68 females (27.87 %, 60.21±10.59 years). The primary diseases were cancer (43.44 %), cardiovascular disease (25.00 %), digestive system diseases, (18.44 %), infection (6.97 %), and nephropathy (6.15 %). Strains were isolated from the bloodstream (63.11 %), central venous catheters (15.16 %), pus (6.56 %), ascites (5.74 %), sterile body fluid (5.33 %), and bronchoalveolar lavage fluid (BALF, 4.09 %). Of the 244 C. parapsilosis complex strains, 179 (73.26 %) were identified as C. parapsilosis sensu stricto, 62 (25.41 %) were C. orthopsilosis, and three (1.23 %) were C. metapsilosis. Only one C. parapsilosis sensu stricto strain was resistant to anidulafungin, micafungin, caspofungin, and voriconazole, and it was non-wild-type (NWT) to amphotericin B. Furthermore, six C. parapsilosis sensu stricto strains were resistant to fluconazole, and one was dose-dependent susceptible. Five C. parapsilosis sensu stricto strains were NWT to posaconazole. Only one C. orthopsilosis strain was NWT for anidulafungin, micafungin, caspofungin, fluconazole, voriconazole, amphotericin B, and posaconazole, while the rest of the strains were wild-type.Conclusion. C. parapsilosis sensu stricto was the main clinical isolate from the C. parapsilosis complex in our hospital. Most strains were isolated from the bloodstream. The susceptibility rate to commonly used antifungal drugs was more than 96 %. Furthermore, most of the infected patients were elderly male cancer patients.

Prevalence of Carbapenem-Resistant Klebsiella pneumoniae Infection in a Northern Province in China: Clinical Characteristics, Drug Resistance, and Geographic Distribution.

PURPOSE: In this study, we analyzed the clinical distribution and drug resistance of carbapenem-resistant Klebsiella pneumoniae (CRKP) strains, the minimum inhibitory concentrations (MIC), MIC50 and MIC90, and geographical distribution in Hebei Province, China. We aimed to provide epidemiological research data, formulate appropriate combined treatment schemes, reasonably select antibiotics, and standardize nosocomial infection control schemes. PATIENTS AND METHODS: A total of 6328 strains of CRKP were collected from 2017 to 2019. The MIC was determined for the drug sensitivity test, and the experimental data were statistically analyzed using WHONET5.6. RESULTS: The detection rate of CRKP increased annually from 13.4% in 2017 to 14.5% in 2018, and 14.6% in 2019. The ratio of males to females was approximately 2:1; 53.6% were elderly, 39% were adults, 4.8% were minors, and 2.5% were newborns. The specimens collected were mainly sputum (70.9%). The resistance rate of CRKP to carbapenems and other ß-lactam antibiotics was found to be increasing, with resistance rates generally greater than 90%. The resistance rate to aminoglycoside antibiotics decreased yearly to approximately 50%, and the resistance rate to quinolones remained unchanged at approximately 80%. From 2017 to 2019, the resistance rate of CRKP in Hebei Province to various antibiotics was high, and the resistance rate to ß-lactam antibiotics increased each year. CONCLUSION: The situation of CRKP resistance is severe in Hebei Province, China. The resistance rate to most antibiotics is very high and shows an upward trend. Among them, the resistance rate to polymyxin is low; however, few resistant strains do exist. MIC50 and MIC90 are higher than their MICs. It mainly causes lung infection in elderly men. This study is helpful to improve the diagnosis, treatment, and prevention of CRKP infection in our province.

Serum Human Epididymis Protein 4 as a Novel Biomarker in Identifying Patients With Interstitial Lung Disease in Rheumatoid Arthritis.

Objective: Human epididymis protein 4 (HE4) have been implicated in the pulmonary involvements. We aimed to investigate the clinical utility of HE4 in clinical stratification in patients with rheumatoid arthritis (RA). Methods: This study included a discovery cohort comprising 70 RA patients and 64 healthy controls (HCs), and a validation cohort comprising 98 RA patients and 75 HCs. Human epididymis protein 4 were determined by electrochemical luminescence analyzer. Results: The levels of HE4 were significantly elevated in patients with RA compared to HCs. The positive rates of HE4 in patients with RA and HCs were 50.0% and 0, respectively, in the discovery cohort and 53.1 and 1.3%, respectively, in the validation cohort. When RA patients were subgrouped according to HE4 status, HE4-positive group displayed higher prevalence of interstitial lung disease (ILD) compared to HE4-negative group (28.6 vs. 11.4% in discovery cohort and 57.7 vs. 8.7% in the validation cohort). A positive correlation between the levels of HE4 with the degree of lung impairment was identified. Receiver operating curve (ROC) analysis revealed an optimal cut-off value of 104.3 pmol/L in HE4 for distinguishing RA-ILD from RA-non ILD with the areas under the curve (AUC) of 0.790. Multivariate logistic regression analysis illustrated that high levels of HE4 independently identified patients with RA-ILD (OR, 9.080, p < 0.001). Conclusion: Our findings showed a novel role of HE4 in RA risk stratification, suggest that introducing HE4 to the current RA test panel may serve as an indicator in identifying RA patients for further RA-ILD workups, such as high-resolution computed tomography (HRCT).

Clinical Distribution Characteristics of 1439 Carbapenem-Resistant Escherichia coli Strains in China: Drug Resistance, Geographical Distribution, Antibiotic MIC50/90.

PURPOSE: To explore the clinical distribution characteristics and antimicrobial susceptibilities of carbapenem-resistant Escherichia coli (CR-ECO) in Hebei Province, China, from 2017 to 2019, and provide data on the treatment of this bacterial infection and the prevention of its spread. MATERIALS AND METHODS: A total of 1439 CR-ECO strains were collected from 2017 to 2019 in Hebei Province, China. Drug sensitivity tests were performed using the minimum inhibitory concentration (MIC) method, and the data were analyzed statistically using WHONET5.6 software. RESULTS: A total of 54,377 strains of Escherichia coli were isolated in Hebei Province from 2017 to 2019, of which 1439 strains were CR-ECO (2.65%). The highest proportion (33.78%) of strains was isolated from urine, and the detection rate showed a slow downward trend over the past 3 years. CR-ECO was mainly detected in densely populated and economically developed areas. Of all the patients, 54.2% were from the medical ward; the ratio of male to female patients with CR-ECO infections was 1.35:1; elderly patients and adults accounted for 59.6% and 30.8%, respectively, whereas minors and newborns accounted for 4.9% and 4.7%, respectively. For CR-ECO, the drug resistance rates to ß-lactams were all higher than 80% and there was an annual increasing trend, while the drug resistance rates to quinolones remained nearly unchanged. The rate of resistance to aminoglycosides was relatively low, especially to amikacin (approximately 22%). The MIC50 of other antibacterial drugs, except amikacin, was equal to or higher than the break point of drug resistance. CONCLUSION: From 2017 to 2019, the isolation rate of CR-ECO in Hebei Province, China, remained stable; however, the drug resistance rate showed an upward trend, primarily in cases of urinary tract infections in older men; the resistance rate to amikacin was the lowest.

Elevated Serum Human Epididymis Protein 4 Is Associated With Disease Activity and Systemic Involvements in Primary Sjögren's Syndrome.

Background: We aimed to investigate the clinical utility of human epididymis protein 4, a tumor biomarker being widely utilized in clinical practice in the diagnosis of ovarian cancer, in primary Sjögren's Syndrome (pSS). Methods: A total of 109 pSS patients and 113 healthy controls (HCs) were included in the study. HE4 were determined by Roche Cobas E601 electrochemical luminescence analyzer. Clinical and laboratory findings were reviewed, and the relationships between HE4 and clinical parameters were determined by Spearman's correlation test. The European league against rheumatism Sjögren's syndrome disease activity index (ESSDAI) was utilized to evaluate disease activity. Findings: The levels of HE4 were significantly elevated in patients with pSS compared to HCs (103.65 pmol/L vs. 46.52 pmol/L, p<0.001). The levels of HE4 were positively correlated with ESSDAI scores (r=0.462, p<0.001). Significant positive correlations between the levels of HE4 with pulmonary involvements (r=0.442, p<0.001) and renal involvements (r=0.320, p=0.001) were observed. Receiver operating curve (ROC) analysis revealed an optimal cut-off value of 104.90 pmol/L and 128.05 pmol/L for distinguishing patients with pulmonary and renal involvements, with the areas under the ROC curve (AUCs) of 0.778 (95%CI 0.685-0.870, p<0.001) and 0.768 (95%CI 0.646-0.891, p=0.001), respectively. Among patients with pulmonary involvement, the levels of HE4 were positively correlated with the semiquantitative HRCT grade (r=0.417, p=0.016), and negatively correlated with the percentage of forced vital capacity (FVC) (r= -0.460, p=0.047) and diffusing capacity of the lung for carbon monoxide (DLco) (r= -0.623, p=0.004). For patients with renal involvement, HE4 was positively correlated with creatinine (r=0.588, p=0.021) and negatively correlated with estimated glomerular filtration rate (r= -0.599, p=0.030). Conclusions: Our findings demonstrated a novel role of HE4 in clinical stratification of pSS, suggesting that introducing HE4 to the current pSS test panel may provide additional diagnostic value, particularly in evaluating disease activity and pulmonary/renal involvements.