Clinical characteristics of tracheobronchial Talaromyces marneffei infection in non-HIV-infected patients in South China.

OBJECTIVES: Tracheobronchial Talaromyces marneffei (T. marneffei) infections among non-HIV-infected patients are rare. To improve understanding, we analysed the clinical features, immune mechanisms, treatment, and prognosis. METHODS: Data on hospitalized patients with tracheobronchial T. marneffei infections from September 2013 to May 2022 were collected. The clinical and imaging features were analysed. RESULTS: Nineteen patients were enrolled, with a median age of 52 years (45-62 years). The most common symptoms were cough, expectoration, fever, weight loss, and anaemia. The total white blood cell and neutrophil counts, erythrocyte sedimentation rate, C-reactive protein, procalcitonin and globulin were increased, and the serum albumin levels were decreased. Chest CT manifestations included patchy shadows, masses, obstructive atelectasis, cavities, pleural effusion, and hilar and mediastinal lymphadenopathy. The fibreoptic bronchoscopy findings included masses, polyps or nodules with mucosal oedema, hypertrophic bulges, lumen stenosis or obstruction, and purulent secretions. T. marneffei infection was confirmed in 10 patients by positive culture, in five by both culture and metagenomic next-generation sequencing (mNGS), in two by mNGS, in one by culture and pathology and in 1 by histopathology. BALF (15/19, 78.9%) had the highest culture positive rate, followed by sputum (3/19), bronchial mucosa (1/1), lung biopsy (1/2); 36.8% of the patients were coinfected with other pathogens. For induction therapy, 7, 6, 2, and 4 patients received voriconazole, amphotericin B, voriconazole combined with amphotericin B, and fluconazole therapy, respectively, and 26.3% received treatment combined with nebulization and/or administration of amphotericin B under fibreoptic bronchoscopy. Four patients were treated for underlying diseases or coinfection, 31.6% were cured, 42.1% improved, and 26.3% died. CONCLUSIONS: T. marneffei infection is common in the tracheobronchial airway tissue or secretions, and bronchoscopy has important diagnostic and treatment value. Antifungal therapy, including systemic therapy, involves triazoles and amphotericin administration, and aerosol inhalation and administration of amphotericin B under bronchoscopy are important.

T. marneffei infection involving the tracheobronchial region in airway tissue or secretions is high, and bronchoscopy has important value in diagnosing and treating these patientsThe use of triazoles and amphotericin and the aerosol inhalation and instillation of amphotericin B under bronchoscopy are essential to antifungal therapy.

RNA Sequencing and Related Differential Gene Expression Analysis in a Mouse Model of Emphysema Induced by Tobacco Smoke Combined with Elastin Peptides.

Objective: To establish a model of emphysema induced by tobacco smoke combined with elastin peptides (EP), explore the biochemical metabolic processes and signal transduction pathways related to emphysema occurrence and development at the transcriptional level, and identify new targets and signaling pathways for emphysema prevention and treatment. Methods: Mice were randomly divided into the air pseudoexposure group (NORMAL group) and the tobacco smoke + EP group (EP group). The differentially expressed genes (DEGs) in lung tissue between the two groups were identified by RNA-seq, and functional annotation and Gene Ontology (GO)/ Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed. The differential expression of the selected genes were verified using qRT‒PCR and immunohistochemistry (IHC). Results: EP group mice showed emphysema-like changes. The expression levels of 1159 genes in the EP group differed significantly (529 up-regulated and 630 down-regulated) from those in the NORMAL group. GO enrichment analysis showed that the DEGs were significantly enriched in the terms immune system, adaptive immune response, and phosphorylation, while KEGG pathway enrichment analysis showed that the DEGs were enriched mainly in the pathways cytokine‒cytokine receptor interaction, T-cell receptor signaling pathway, MAPK signaling pathway, Rap1 signaling pathway, endocytosis, chemokine signaling pathway, Th17 cell differentiation, and Th1 and Th2 cell differentiation. The differential expression of the selected DEGs were verified by qRT‒PCR and IHC, and the expression trends of these genes were consistent with those identified by RNA-seq. Conclusion: Emphysema may be related to the inflammatory response, immune response, immune regulation, oxidative stress injury, and other biological processes. The Bmp4-Smad-Hoxa5/Acvr2a signaling pathway may be involved in COPD/ emphysema occurrence and development.

N7-methylguanosine methylation-related regulator genes as biological markers in predicting prognosis for melanoma.

The aim of this study is to find those N7-methylguanosine (m7G) methylation-related regulator genes (m7GMRRGs) which were associated with melanoma prognosis and use them to develop a prognostic prediction model. Clinical information was retrieved online from The Cancer Gene Atlas (TCGA) and the Gene Expression Omnibus (GEO). R software was used to extract m7GMRRGs by differential expression analysis. To create a prognostic risk model, univariate and multivariate Cox regression analyses were employed for the evaluation of the prognostic significance of m7G methylation modifiers. Internal validation using cohort from TCGA (training set) and external validation using cohort from GEO (validation set) of the model were carried out. The model's predictive performance was confirmed by using the Kaplan-Meier, univariate, and multivariate Cox regression, and receiver operating characteristic curve (ROC) by constructing column line plots incorporating clinical factor characteristics. Immune infiltration analyses were performed to assess the immune function of m7GMRRGs. Drug sensitivity analysis was conducted to study chemotherapeutic drug treatment cues. Prognostic models using four m7GMRRGs (EIF4E3, LARP1, NCBP3, and IFIT5) showed good prognostic power in training and validation sets. The area under the curve (AUC) at 1, 3, and 5 years for GEO-melanoma were 0.689, 0.704, and 0.726, respectively. The prediction model could distinctly classify patients with melanoma into different risk subgroups (P < 0.001 for TCGA-melanoma and P < 0.05 for GEO-melanoma). Clinical characteristics were taken into account in Cox regression and AUC analysis, which highlighted that the risk score served as an independent risk factor determining the prognosis of patients with melanoma. Immuno-infiltration analysis showed that m7GMRRGs could potentially regulate CD8+ T cells as well as regulatory T cells (Treg cells). Results of our study indicate a association between m7GMRRGs and melanoma prognosis, and the prognostic prediction model using m7GMRRGs may predict the prognosis of patients with melanoma well. Nevertheless, these results may provide a clue for potential better options of melanoma treatment but need further validation in futural studies.

Tumor targetable and pH-sensitive polymer nanoparticles for simultaneously improve the Type 2 Diabetes Mellitus and malignant breast cancer.

In the recent study, we have developed novel tumor targetable and pH-sensitive PLGA nanoparticles co-loaded with camptothecin (CPT) and metformin (Metf) to simultaneously improve the Type 2 Diabetes Mellitus (T2DM) and malignant breast cancer. To improve the drug loading efficiency, the hydrophobic CPT was conjugated with PLGA polymer by the pH-sensitive hydrazone bonds (hyd). Then, the Metf was physically loaded into the hydrophobicity inner core of CPT-conjugated PLGA nanocomplex to form the dual drugs-loaded nanoparticles (NP/CPT-Metf). Furthermore, on the surface of NP/CPT-Metf was modified with tumor-homing CGKRK peptides to obtain the tumor targetable and pH-sensitive polymer nanoparticles (CNP/CPT-Metf). It was demonstrated that the developed CNP/CPT-Metf displayed sufficient sensitivity to the weak acidic tumor microenvironment. Besides, excellent ability of CNP/CPT-Metf to mediate accumulation of drugs in cells and tumor tissues finally in turn resulted in a signal enhanced anti-tumor effect. Furthermore, it was demonstrated as well that CNP/CPT-Metf was able of significantly alleviating the type 2 diabetes mellitus in diabetic mice. In summary, the developed multifunctional polymer nanoparticles might represent a promising strategy for simultaneously improve the T2DM and treat malignant breast cancer.

FAM46C as a Potential Marker for Pan-Cancer Prognosis and Predicting Immunotherapeutic Efficacy.

Background: FAM46C is a common mutated gene in tumours. A comprehensive understanding of the relationship between FAM46C expression and pan-cancer can guide clinical prognosis and broaden the immunotherapeutic targets. Methods: Data from The Cancer Genome Atlas and Genotype-Tissue Expression (GTEx) databases were obtained, and gene expression of different tumour types and stages was analysed. Immunohistochemical analysis was performed to detect differences in the FAM46C protein levels in normal and cancerous tissues. The genetic variation of FAM46C was characterised using cBioPortal. The clinical prognostic value of FAM46C and the impact of FAM46C expression levels on the prognosis of patients with different types of cancer were assessed based on Kaplan-Meier and Cox regression analyses. Gene set enrichment analysis (GSEA) was used to analyse the pathways associated with FAM46C. Correlations between FAM46C expression levels and immune infiltration were assessed using the TIMER2 database and CIBERSORT algorithm, and correlations between FAM46C expression and the ESTIMATE, immune and stromal scores were analysed using the ESTIMATE algorithm. In addition, we also analysed the correlation between FAM46C expression and immune activation, suppression genes and immune chemokines. Results: The expression level of FAM46C was correlated with the prognosis of most tumours, and low expression levels often suggested a poor prognosis. FAM46C was positively correlated with the abundance of CD4+ T cells, CD8+ T cells and plasma B lymphocytes in the tumour microenvironment. FAM46C exhibited a strong correlation with immunomodulatory pathways, immunomodulatory factors and immune markers. In addition, high FAM46C expression correlated with tumour mutational burden in acute myeloid leukaemia and microsatellite instability in endometrial cancer. Conclusion: Our study suggests that FAM46C can be a potential prognostic marker for pan-cancer, is closely associated with immune regulation and may be an immune checkpoint to guide future clinical immunotherapy.

Clinical analysis of hypereosinophilic syndrome first presenting with asthma-like symptoms.

INTRODUCTION: Clinical manifestations of hypereosinophilic syndrome (HES) are diverse. This study aimed to summarise these clinical characteristics with asthma-like onset as the first symptom, and compare these characteristics and treatment strategies between idiopathic and parasitic HES. MATERIALS AND METHODS: We retrospectively analysed 36 HES patients with asthma-like symptoms as the first episode, between January 2013 and October 2019. Data of patients with HES of an unknown cause (idiopathic HES) and parasitic infection (parasite HES) were analysed. RESULTS: The idiopathic and parasite HES groups included 16 and 20 patients, respectively, with more males in the parasite HES group (p < .05). Wheezing and dry rales was the most common symptom and signs, with no significant differences in symptoms and signs between the groups. The most often misdiagnosed disease was bronchial asthma. The peripheral blood eosinophil count was significantly increased compared with normal counts in both groups (p > .05). Abnormal pulmonary function is mainly manifested as obstructive ventilatory disorder and mixed ventilatory disorder. Chest computed tomography showed extensive ground-glass exudation, patches, consolidation, nodules, and pleural effusion. Histopathological examination showed eosinophilic infiltration without vasculitis or granuloma. Glucocorticoids had a significant therapeutic effect, and the parasite HES group required combined deworming drugs. The duration of corticosteroids therapy in the idiopathic HES group was significantly longer than that in the parasite HES group (p < .05). The overall prognosis was good, and 81.25% of the patients were clinically cured in the parasite HES group; however, relapse occurred easily in the idiopathic HES group. CONCLUSIONS: Asthma-like symptoms, obstructive ventilatory disorder or positive bronchial dilation test, and poor response to inhaled corticosteroids are not necessarily indicative of refractory asthma; HES should be considered. The clinical characteristics of HES of different aetiologies are similar. Systemic corticosteroid therapy is preferred for idiopathic and parasitic infections. Idiopathic HES is treated with prolonged corticosteroids and relapses easily.Key MessagesAsthma-like symptoms, obstructive ventilatory disorder or positive bronchial dilation tests, and poor responses to inhaled corticosteroids are not necessarily indicative of refractory asthma, and hypereosinophilic syndrome should be considered.The clinical characteristics of hypereosinophilic syndrome of different aetiologies are similar, and systemic glucocorticoid therapy is preferred for both idiopathic and parasitic infections.Idiopathic hypereosinophilic syndrome is treated with prolonged corticosteroids and relapses easily.

Tumor microenvironment characterization in triple-negative breast cancer identifies prognostic gene signature.

We aimed to elucidate the landscape of tumor microenvironment (TME) in triple-negative breast cancer (TNBC). Cohorts from Gene Expression Omnibus database (N = 107) and METABRIC (N = 299) were used as the training set and validation set, respectively. TME was evaluated via single-sample gene set enrichment analysis, and unsupervised clustering was used for cluster identification. Consequently, TNBC was classified into two distinct TME clusters (Cluster 1 and Cluster 2) according to predefined immune-related terms. Cluster 1 was characterized by low immune infiltration with poor prognosis; whereas, Cluster 2 was characterized by high immune infiltration with better survival probability. Further, Cluster 1 had larger tumor volumes, while Cluster 2 had smaller tumor volumes. Finally, a TME signature for prognosis stratification in TNBC was developed and validated. In summary, we comprehensively evaluated the TME of TNBC and constructed a TME signature that correlated with prognosis. Our results provide new insights for the immunotherapy of TNBC.

Effects of Cinnamaldehyde on the Cell Wall of A. fumigatus and Its Application in Treating Mice with Invasive Pulmonary Aspergillosis.

BACKGROUND: The invasive pulmonary aspergillosis is a kind of high incidence of disease with difficulties in treatment, poor prognosis, and high mortality. OBJECTIVES: The study aimed to reveal the effect of cinnamaldehyde on the fungal cell wall and verify its efficacy on invasive pulmonary aspergillosis on immunosuppressed Institute of Cancer Research mice (ICR mice). METHODS: ICR mice were given cyclophosphamide 200 mg.kg-1. d-1 by intraperitoneal injection for 2 days. On the 4th day, the mice were given 50 µL of Aspergillosis fumigatus spore (107colony form unit CFU/mL) by intranasal injection to establish immunosuppressive animal models with invasive Aspergillosis fumigatus infection. Then the mice in treatment group orally administered cinnamaldehyde for 14 consecutive days, while voriconazole was given to the mice in the positive control group. RESULTS: The clearance rate of pulmonary fungi, cure rate, and reduction of 1,3-ß-D-glucans in treatment group were 80.00%, 80.00%, and 81.00%, respectively while in positive control group they were 67.00%, 60.00%, and 62.00%, respectively. There were significant differences in the results between two groups as mentioned above (P<0.05). Electron microscopy showed that, in treatment group, the cell wall of Aspergillus fumigatus was dissolved and detached and the cell surface was incomplete. There were edema, degeneration, and necrosis in nucleus and organelle, which lead to cellular necrocytosis. The cytomembrane of Aspergillus fumigatus was intact, clear, and complete, whereas the cytomembrane in the positive control group disappeared. The hyphal morphology of Aspergillus fumigatus was deformed, but the cell wall was intact. CONCLUSION: Cinnamaldehyde has a good curative effect in the treatment of invasive pulmonary aspergillus infection in immunodeficient mice. It mainly affects the synthesis of 1,3-ß-D-glucans from the cytoderm of Aspergillus fumigatus but does not affect cell wall. It would potentially be an effective and novel drug for targeted treatment of Aspergillus fumigatus deep infection.

Mechanisms, clinically curative effects, and antifungal activities of cinnamon oil and pogostemon oil complex against three species of Candida.

The anti-fungus mechanisms and curative effects of cinnamon oil and pogostemon oil complexes towards intestinal Candida infections were investigated. We measured the minimal inhibitory concentration (MIC) values of the complexes against Candida using proportionally-diluted test-tube medium, and examined the evolution of the morphology and structures of Candida albicans using scanning electronic microscopy (SEM) and transmission electronic microscopy (TEM). We found that the average MIC values of the complexes against the fungi were 0.064 mg/mL (cinnamon oil), 0.032 mg/mL (pogostemon oil) for Candida albicans, 0.129 mg/ mL (cinnamon oil), 0.064 mg/mL (pogostemon oil) for Candida tropicalis, and 0.129 mg/mL (cinnamon oil), 0.064 mg/mL (pogostemon oil), for Candida krusei. SEM examination over a 24-48 h period showed that the morphology of Candida albicans cells changed significantly. Irregular hollows appeared on the surfaces, inside organelles were destroyed and the cells burst after treatment. TEM examination over a 48 - 72 h period indicated that the cell walls were damaged, organelles were destroyed and most cytoplasms became empty bubbles. Sixty intestinal Candida-infected patients were treated with a capsule containing cinnamon and pogostemon oil. The curative ratio was 71.67% (43/60), and the improvement ratio was 28.33% (17/ 60), giving a total ratio of 100%. Thus, the cinnamon oil and pogostemon oil complexes had strong anti-fungus effects against Candida albicans, Candida tropicalis, and Candida krusei. They impacted the morphology and sub-micro structures of the fungus within 48 - 72 h, and eventually denatured and killed the cells. The complexes have also shown considerable curative effects to intestinal Candida infections.