Background When severe, COVID-19 shares many clinical features with bacterial sepsis. Yet, secondary bacterial infection is uncommon. However, as epithelium is injured and barrier function is lost, bacterial products entering the circulation might contribute to the pathophysiology of COVID-19. Methods We studied 19 adults, severely ill patients with COVID-19 infection, who were admitted to King Chulalongkorn Memorial Hospital, Bangkok, Thailand, between 13th March and 17th April 2020. Blood samples on days 1, 3, and 7 of enrollment were analyzed for endotoxin activity assay (EAA), (1 → 3)-β-d-glucan (BG), and 16S rRNA gene sequencing to determine the circulating bacteriome. Results Of the 19 patients, 13 were in intensive care and 10 patients received mechanical ventilation. We found 8 patients with high EAA (≥ 0.6) and about half of the patients had high serum BG levels which tended to be higher in later in the illness. Although only 1 patient had a positive blood culture, 18 of 19 patients were positive for 16S rRNA gene amplification. Proteobacteria was the most abundant phylum. The diversity of bacterial genera was decreased overtime. Conclusions Bacterial DNA and toxins were discovered in virtually all severely ill COVID-19 pneumonia patients. This raises a previously unrecognized concern for significant contribution of bacterial products in the pathogenesis of this disease.
Background: When severe, COVID-19 shares many clinical features with bacterial sepsis. Yet, secondary bacterial infection is uncommon. However, as epithelium are injured and barrier function is lost, bacterial products entering the circulation might contribute to the pathophysiology of COVID-19. Methods: We studied 19 adults, severely ill patients with COVID-19 infection, who were admitted to King Chulalongkorn Memorial Hospital, Bangkok, Thailand, between 13th March and 17th April 2020. Blood samples on day 1, 3, and 7 of enrollment were analyzed for endotoxin activity assay (EAA), Beta-D-Glucan (BG), and 16S rRNA gene sequencing to determine the circulating bacteriome. Findings: Of the 19 patients, 14 were in intensive care and 10 patients received mechanical ventilation. We found 8 patients with high EAA (≥ 0.6) and about half of the patients had high serum BG levels which tended to be higher in later in the illness. Although only 1 patient had a positive blood culture, 18 of 19 patients were positive for 16S rRNA gene amplification. Proteobacteria was the most abundant phylum. The diversity of bacterial genera was decreased overtime. Interpretation: Bacterial DNA and toxins were discovered in virtual all severely ill COVID-19 pneumonia patients. This raises a previously unrecognized concern for significant contribution of bacterial products in the pathogenesis of this disease.
Despite the development of predictive biomarkers to shape treatment paradigms and outcomes, de novo EGFR TKI resistance advanced non-small cell lung cancer (NSCLC) remains an issue of concern. We explored clinical factors in 332 advanced NSCLC who received EGFR TKI and molecular characteristics through 65 whole exome sequencing of various EGFR TKI responses including; de novo (progression within 3 months), intermediate response (IRs) and long-term response (LTRs) (durability > 2 years). Uncommon EGFR mutation subtypes were significantly variable enriched in de novo resistance. The remaining sensitizing EGFR mutation subtypes (exon 19 del and L858R) accounted for 75% of de novo resistance. Genomic landscape analysis was conducted, focusing in 10 frequent oncogenic signaling pathways with functional contributions; cell cycle, Hippo, Myc, Notch, Nrf2, PI-3-Kinase/Akt, RTK-RAS, TGF-β, p53 and β-catenin/Wnt signaling. Cell cycle pathway was the only significant alteration pathway among groups with the FDR p-value of 6 × 10–4. We found only significant q-values of < 0.05 in 7 gene alterations; CDK6, CCNE1, CDK4, CCND3, MET, FGFR4 and HRAS which enrich in de novo resistance [range 36–73%] compared to IRs/LTRs [range 4–22%]. Amplification of CDK4/6 was significant in de novo resistance, contrary to IRs and LTRs (91%, 27.9% and 0%, respectively). The presence of co-occurrence CDK4/6 amplification correlated with poor disease outcome with HR of progression-free survival of 3.63 [95% CI 1.80–7.31, p-value < 0.001]. The presence of CDK4/6 amplification in pretreatment specimen serves as a predictive biomarker for de novo resistance in sensitizing EGFR mutation.
Background/Aim: Individualized proper chemotherapy using in vitro drug sensitivity testing has been proposed as a novel therapeutic modality and shown to have better efficacy than empiric chemotherapy. However, issues around establishing a patient-derived cell culture or xenograft, the timing of the testing obtained, and the validity of testing represent major limitations to translating the use of such a technique to clinical practice. Patients and Methods: In this study, we assessed the feasibility of an in vitro drug sensitivity technique for testing malignant pleural effusion from advancedstage non-small cell lung cancer. Results: Our technique was able to produce a turnaround time for in vitro drug sensitivity testing of less than 1 week, with a success rate of more than 90% of cases. Correlated with the individual clinical outcome, using the area under the dose response curve (AUC) could define the level of in vitro drug sensitivity as: responsive (AUC>0.25), intermediate response ( 0 .1≤AUC≤0.25), or resistance (AUC<0.1). Conclusion: Data obtained from this method of drug testing were correlated with the clinical outcome. The present drug sensitivity evaluation may benefit the development of individual precision chemotherapy.The response rate from standard platinum-doublet chemotherapy for advanced non-small cell lung cancer (NSCLC) ranges from 25-30% with a 1-year survival rate of up to 30% (1, 2). With the advancement of molecular biomarkers and targeted therapy, the survival of advanced lung cancer patients with sensitizing mutation who receive matched targeted therapy can increase up to 30-36 months (3). It is potentially noteworthy that defining optimized therapeutic agents for individual patients could be beneficial in terms of treatment efficiency, economical concerns, and avoidance of unnecessary toxicity (4, 5). The in vitro drug sensitivity concept has been explored with both patient-derived xenografts (PDXs) and as a primary cell culture model. It was claimed that the PDX model is expensive and has a low engraftment rate, and may not give results back in a timely manner to instruct therapeutic decisions. Further, it might not represent the real clinical response due to the lack of interaction between human stromal cells and the immune system (6). Patient-derived organoids (PDOs) is a model providing another option for drug sensitivity testing but work is still in progress in this area. Among the several in vitro drug sensitivity assays that have been developed, the methyl thiazol-diphenyl-tetrazolium bromide (MTT) assay, based on the measurement of mitochondrial enzyme activity, is the most widely used technique due to its simplicity, sensitivity, and reliability (7). This technique could 6981
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.