Pan-omics-based characterization and prediction of highly multidrug-adapted strains from an outbreak fungal species complex.

Strains from the Cryptococcus gattii species complex (CGSC) have caused the Pacific Northwest cryptococcosis outbreak, the largest cluster of life-threatening fungal infections in otherwise healthy human hosts known to date. In this study, we utilized a pan-phenome-based method to assess the fitness outcomes of CGSC strains under 31 stress conditions, providing a comprehensive overview of 2,821 phenotype-strain associations within this pathogenic clade. Phenotypic clustering analysis revealed a strong correlation between distinct types of stress phenotypes in a subset of CGSC strains, suggesting that shared determinants coordinate their adaptations to various stresses. Notably, a specific group of strains, including the outbreak isolates, exhibited a remarkable ability to adapt to all three of the most commonly used antifungal drugs for treating cryptococcosis (amphotericin B, 5-fluorocytosine, and fluconazole). By integrating pan-genomic and pan-transcriptomic analyses, we identified previously unrecognized genes that play crucial roles in conferring multidrug resistance in an outbreak strain with high multidrug adaptation. From these genes, we identified biomarkers that enable the accurate prediction of highly multidrug-adapted CGSC strains, achieving maximum accuracy and area under the curve (AUC) of 0.79 and 0.86, respectively, using machine learning algorithms. Overall, we developed a pan-omic approach to identify cryptococcal multidrug resistance determinants and predict highly multidrug-adapted CGSC strains that may pose significant clinical concern.

The pathways and the mechanisms by which Cryptococcus enters the brain.

Generally, Cryptococcus initially infects the respiratory tract, but can spread, eventually crossing the blood-brain barrier (BBB) and causing meningitis or meningoencephalitis. Specifically, Cryptococcus invades the vascular endothelial cells of the BBB, from which it enters the brain. The main mechanisms through which Cryptococcus crosses the BBB are transcellular traversal, the paracellular pathway, and via Trojan horse. In this paper, the mechanisms by which Cryptococcus crosses the BBB were explained in detail. In addition to pathways of entry to the brain, this paper presents a discussion on some rare cryptococcal infections and provides some insights for future research directions.

Tertiary Lymphoid Structure in Tumor Microenvironment and Immunotherapy of Lung Cancer.

Immune checkpoint inhibitors have opened an era of lung cancer therapy. However, a notable disparity exists in the efficacy of immunotherapy among individual patients. The tertiary lymphoid structure (TLS) is an ectopic lymphocyte aggregation that appears under pathological conditions and is the primary site of action for anti-tumor immunity. It is commonly reported that the presence of TLS within the tumor microenvironment (TME) relates to a favorable clinical prognosis and an excellent response to immunotherapy in lung cancer patients. A thorough understanding of TLS and its dynamic changes in TME has become an attractive focus for optimizing immunotherapy strategies for lung cancer. In this review, we comprehensively generalize the composition, formation, mechanism, detection methods of TLS, and summarize the role of TLS in lung cancer immunotherapy. Finally, induction of TLS is also discussed, which may provide more effective therapeutic strategies for lung cancer therapy.

Tertiary lymphoid structures as potential biomarkers for cancer prediction and prognosis.

Tertiary lymphoid structures (TLSs) are ectopic lymphocyte aggregates formed in non-lymphoid tissues, including cancers, and are loci for the generation of in situ anti-tumor immune responses, which play a crucial role in cancer control. The state of TLS presence in cancer and its composition can significantly impact the treatment response and prognosis of patients. TLSs have the potential to serve as predictive and prognostic biomarkers for cancer. However, the mechanisms underlying TLS formation in cancer and how the essential components of TLSs affect cancer are not fully understood. In this review, we summarized TLS formation in cancer, the value of the TLS in different states of existence, and its key constituents for cancer prediction and prognosis. Finally, we discussed the impact of cancer treatment on TLSs.

Cardiovascular toxicity in antitumor therapy: biological and therapeutic insights.

The evolution of antitumor therapies has significantly improved cancer prognosis but has concurrently resulted in cardiovascular toxicities. Understanding the biological mechanisms behind these toxicities is crucial for effective management. Immunotherapy-related cardiovascular toxicities are primarily mediated by immune cells and secreted cytokines. Chemotherapy may cause cardiovascular damage through autophagy disruption and mitochondrial dysfunction. Targeted therapies can induce toxicity through endothelin-1 (ET-1) production and cardiac signaling disruption. Radiotherapy may lead to cardiomyopathy and myocardial fibrosis by affecting endothelial cells, triggering inflammatory responses and accelerating atherosclerosis. This review provides insights into these mechanisms and strategies, aiming to enhance the clinical prevention and treatment of cardiovascular toxicities.

Mature tertiary lymphoid structures: important contributors to anti-tumor immune efficacy.

Tertiary lymphoid structures (TLS) represent the ectopic aggregations of immune cells arising during chronic inflammation or tumor progression. In cancer, TLS are often associated with beneficial clinical outcomes in patients undergoing immunotherapy, underscoring their prognostic and predictive significance. Mature TLS, characterized by germinal centers and areas of T-cell and B-cell aggregation, are considered primary locations for activating and maintaining both humoral and cellular anti-tumor immune effects. Despite their recognized importance, the mechanisms driving the formation of mature TLS in cancer and their influence on the immune response within tumors remain insufficiently understood. Therefore, this review aims to comprehensively explore the structural composition, development mechanisms, maturity impact factors, immunological function, and innovative therapeutic strategies of mature TLS within the tumor microenvironment. The research summarized herein offers novel insights and considerations for therapeutic approaches to promote TLS generation and maturation in patients with cancer, representing a promising avenue for future cancer therapies.

A dual-targeting antifungal is effective against multidrug-resistant human fungal pathogens.

Drug-resistant fungal infections pose a significant threat to human health. Dual-targeting compounds, which have multiple targets on a single pathogen, offer an effective approach to combat drug-resistant pathogens, although ensuring potent activity and high selectivity remains a challenge. Here we propose a dual-targeting strategy for designing antifungal compounds. We incorporate DNA-binding naphthalene groups as the hydrophobic moieties into the host defence peptide-mimicking poly(2-oxazoline)s. This resulted in a compound, (Gly0.8Nap0.2)20, which targets both the fungal membrane and DNA. This compound kills clinical strains of multidrug-resistant fungi including Candida spp., Cryptococcus neoformans, Cryptococcus gattii and Aspergillus fumigatus. (Gly0.8Nap0.2)20 shows superior performance compared with amphotericin B by showing not only potent antifungal activities but also high antifungal selectivity. The compound also does not induce antimicrobial resistance. Moreover, (Gly0.8Nap0.2)20 exhibits promising in vivo therapeutic activities against drug-resistant Candida albicans in mouse models of skin abrasion, corneal infection and systemic infection. This study shows that dual-targeting antifungal compounds may be effective in combating drug-resistant fungal pathogens and mitigating fungal resistance.

Comparative study of imaging and pathology of primary mucinous adenocarcinoma with different imaging manifestations.

BACKGROUND: Pulmonary mucinous adenocarcinoma is a special type of lung cancer. Its imaging manifestations are diverse, which brings challenges to clinical diagnosis. However, its formation mechanism is unclear. OBJECTIVE: The objective of this study is to analyse the relevant mechanisms of the formation of pulmonary mucinous adenocarcinoma by observing its different imaging and pathological manifestations. DATA AND METHODS: Retrospective analysis was conducted on imaging manifestations and pathological data of 103 patients with pulmonary mucinous adenocarcinoma confirmed intraoperatively or pathologically. RESULTS: Forty-three patients had pulmonary mucinous adenocarcinoma with a solitary nodule/mass, 41 patients with localized pneumonia and 19 patients with diffuse pneumonia. Their CT manifestations included 'falling snowflake sign', ground-glass opacity close to the heart, vacuous signs/honeycombing and withered tree branches. Under the microscope, all the three types of pulmonary mucinous adenocarcinoma had visibly formed mucus lakes but were made of tumour cells with totally different shapes, which included the goblet-like shape (tall column-like shape) and quasi-circular shape. Tall column-shaped tumour cells were negative or weakly positive for thyroid transcription factor-1 (TTF-1) and strongly positive for ALK mutation, whereas quasi-circular tumour cells were positive for TTF-1 and less positive for ALK mutation. CONCLUSION: The different imaging manifestations of mucinous adenocarcinoma are possibly due to the different amounts or viscosity of mucus produced, and the mechanisms of its formation may include (1) tumour cells in different shapes have different abilities to produce mucus; (2) tumours in different stages produce different amounts or viscosity of mucus; and (3) the TTF-1 and ALK genes affect the production of mucus.

The radiological characteristics, tertiary lymphoid structures, and survival status associated with EGFR mutation in patients with subsolid nodules like stage I-II LUAD.

BACKGROUND: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) recommended for the patients with subsolid nodule in early lung cancer stage is not routinely. The clinical value and impact in patients with EGFR mutation on survival outcomes is further needed to be elucidated to decide whether the application of EGFR-TKIs was appropriate in early lung adenocarcinoma (LUAD) stage appearing as subsolid nodules. MATERIALS AND METHODS: The inclusion of patients exhibiting clinical staging of IA-IIB subsolid nodules. Clinical information, computed tomography (CT) features before surgical resection and pathological characteristics including tertiary lymphoid structures of the tumors were recorded for further exploration of correlation with EGFR mutation and prognosis. RESULTS: Finally, 325 patients were enrolled into this study, with an average age of 56.8 ± 9.8 years. There are 173 patients (53.2%) harboring EGFR mutation. Logistic regression model analysis showed that female (OR = 1.944, p = 0.015), mix ground glass nodule (OR = 2.071, p = 0.003, bubble-like lucency (OR = 1.991, p = 0.003) were significant risk factors of EGFR mutations. Additionally, EGFR mutations were negatively correlated with TLS presence and density. Prognosis analysis showed that the presence of TLS was associated with better recurrence-free survival (RFS)(p = 0.03) while EGFR mutations were associated with worse RFS(p = 0.01). The RFS in patients with TLS was considerably excel those without TLS within EGFR wild type group(p = 0.018). Multivariate analyses confirmed that EGFR mutation was an independent prognostic predictor for RFS (HR = 3.205, p = 0.037). CONCLUSIONS: In early-phase LUADs, subsolid nodules with EGFR mutation had specific clinical and radiological signatures. EGFR mutation was associated with worse survival outcomes and negatively correlated with TLS, which might weaken the positive impact of TLS on prognosis. Highly attention should be paid to the use of EGFR-TKI for further treatment as agents in early LUAD patients who carrying EGFR mutation.