Prognostic value of adjuvant external beam radiotherapy for papillary thyroid cancer based on competitive risk model and propensity score matching.

This study aimed to assess the impact of adjuvant external beam radiotherapy (EBRT) on the survival of patients with locally invasive papillary thyroid carcinoma. This retrospective study used data from the Surveillance, Epidemiology, and End Results database for the diagnosis of papillary thyroid carcinoma, using Cox models to screen for adverse prognostic factors. The prognostic value of using adjuvant external beam radiotherapy in papillary thyroid carcinoma was further evaluated, based on the competing risk model and propensity score matching. Based on the competitive risk model, the sub-distribution hazard ratio (SHR) of the multivariate analysis of patients receiving EBRT alone versus those receiving radioiodine-131 alone was 9.301 (95% CI 5.99-14.44) (P < 0.001), and the SHR of the univariate analysis was 1.97 (95% CI 1.03-3.78) (P = 0.042). In the propensity score-matched Kaplan-Meier analysis, patients who received EBRT still had worse OS (6-year OS, 59.62% vs 74.6%; P < 0.001) and DSS (6-year DSS, 66.6% vs 78.2%; P < 0.001) than patients who did not receive EBRT. Patients who received EBRT had a higher cumulative risk of death due to thyroid cancer after PSM (P < 0.001). Adjuvant EBRT was not associated with survival benefit in the initial management of locally invasive papillary thyroid cancer.

Immunoprotective Analysis of the NFA49590 Protein from Nocardia farcinica IFM 10152 Demonstrates Its Potential as a Vaccine Candidate.

Nocardia is emerging as a serious and easily neglected pathogen in clinical practice with multidrug resistance that extends the treatment period for months or even years. This has led to the investigation of a vaccine approach to prevent Nocardia infections. However, studies on the protective proteins of Nocardia have not yet been carried out. In the present work, over 500 proteins in the supernatant of N. farcinica IFM10152 were identified by LC−MS/MS. In silico analysis of these proteins with a high content (score > 2000) predicted that NFA49590 was one of the conserved proteins in N. farcinica strains with potential antigenicity. After the rNFA49590 protein was cloned and expressed in E. coli (DE3) and purified using a Ni-NTA column, its good antigenicity was confirmed with sera from mice immunized with different Nocardia species by Western blot. Then we confirmed its ability to activate innate immunity by examining the phosphorylation status of ERK1/2, JNK, p38, and p65 and the cytokine levels of IL-6, TNF-α, and IL-10. Finally, we evaluated its immunoprotective effect in BALB/c mice, and we found that mice immunized with rNFA49590 protein exhibited high antibody titers, enhanced bacterial clearance ability, and generated robust protective effects from the N. farcinica challenge. These results offer strong support for the use of NFA49590 protein as a vaccine candidate and open the possibilities for the exploration of a large array of immunoprotective proteins.

Molecular, cellular and neurological consequences of infection by the neglected human pathogen Nocardia.

BACKGROUND: Nocardia is a facultative intracellular pathogen that infects the lungs and brains of immunocompromised patients with consequences that can be fatal. The incidence of such infections is rising, immunocompetent individuals are also being infected, and there is a need to learn more about this neglected bacterial pathogen and the interaction with its human host. RESULTS: We have applied dual RNA-seq to assess the global transcriptome changes that occur simultaneously in Nocardia farcinica (N. farcinica) and infected human epithelial alveolar host cells, and have tested a series of mutants in this in vitro system to identify candidate determinants of virulence. Using a mouse model, we revealed the profiles of inflammation-related factors in the lung after intranasal infection and confirmed that nbtB and nbtS are key virulence genes for Nocardia infection in vivo. Regarding the host response to infection, we found that the expression of many histones was dysregulated during the infection of lung cells, indicating that epigenetic modification might play a crucial role in the host during Nocardia infection. In our mouse model, Nocardia infection led to neurological symptoms and we found that 15 of 22 Nocardia clinical strains tested could cause obvious PD-like symptoms. Further experiments indicated that Nocardia infection could activate microglia and drive M1 microglial polarization, promote iNOS and CXCL-10 production, and cause neuroinflammation in the substantia nigra, all of which may be involved in causing PD-like symptoms. Importantly, the deletion of nbtS in N. farcinica completely attenuated the neurological symptoms. CONCLUSIONS: Our data contribute to an in-depth understanding of the characteristics of both the host and Nocardia during infection and provide valuable clues for future studies of this neglected human pathogen, especially those addressing the underlying causes of infection-related neurological symptoms.

Whole genome sequencing reveals the genomic diversity, taxonomic classification, and evolutionary relationships of the genus Nocardia.

Nocardia is a complex and diverse genus of aerobic actinomycetes that cause complex clinical presentations, which are difficult to diagnose due to being misunderstood. To date, the genetic diversity, evolution, and taxonomic structure of the genus Nocardia are still unclear. In this study, we investigated the pan-genome of 86 Nocardia type strains to clarify their genetic diversity. Our study revealed an open pan-genome for Nocardia containing 265,836 gene families, with about 99.7% of the pan-genome being variable. Horizontal gene transfer appears to have been an important evolutionary driver of genetic diversity shaping the Nocardia genome and may have caused historical taxonomic confusion from other taxa (primarily Rhodococcus, Skermania, Aldersonia, and Mycobacterium). Based on single-copy gene families, we established a high-accuracy phylogenomic approach for Nocardia using 229 genome sequences. Furthermore, we found 28 potentially new species and reclassified 16 strains. Finally, by comparing the topology between a phylogenomic tree and 384 phylogenetic trees (from 384 single-copy genes from the core genome), we identified a novel locus for inferring the phylogeny of this genus. The dapb1 gene, which encodes dipeptidyl aminopeptidase BI, was far superior to commonly used markers for Nocardia and yielded a topology almost identical to that of genome-based phylogeny. In conclusion, the present study provides insights into the genetic diversity, contributes a robust framework for the taxonomic classification, and elucidates the evolutionary relationships of Nocardia. This framework should facilitate the development of rapid tests for the species identification of highly variable species and has given new insight into the behavior of this genus.

Microbiological profile of distinct virulence of Nocardia cyriacigeorgica strains in vivo and in vitro.

There are significant differences between different Nocardia species regarding geographical distribution, biochemical features, phenotypic characterization, and drug sensitivity. In this study, we explored the differences in virulence and pathogenic mechanisms of two Nocardia cyriacigeorgica strains. We examined the difference in virulence between N. cyriacigeorgica ATCC14759 and N. cyriacigeorgica GUH-2 by measuring cytotoxicity, animal survival after infection, the ability of host cell invasion, and viability in host cells. Western blotting was used to compare the differences in activation of MAPKs, including p38, ERK, and JNK, the NF-κB signaling pathway, and the PI3K/Akt signaling pathway in A549 and RAW264.7 cells. We measured the difference in stimulatory effects on production of the cytokines IL-6, IL-10, and TNF-α by ELISA. We found that N. cyriacigeorgica ATCC14759 causes higher cytotoxicity in cultured cells and higher lethality in mice, and exhibits superior invasion ability and viability in host cells compared with N. cyriacigeorgica GUH-2. Moreover, these two strains show marked differences in activation of the expression of cytokines and signaling pathways. N. cyriacigeorgica ATCC14759 is more virulent than N. cyriacigeorgica GUH-2. Furthermore, there is a significant difference in pathogenesis between the two strains. Our results provide a theoretical basis for the prevention and treatment of Nocardia infection.