Progress in the application of nanoparticles for the treatment of fungal infections: A review.

The burden of fungal infections on human health is increasing worldwide. Aspergillus, Candida, and Cryptococcus are the top three human pathogenic fungi that are responsible for over 90% of infection-related deaths. Moreover, effective antifungal therapeutics are lacking, primarily due to host toxicity, pathogen resistance, and immunodeficiency. In recent years, nanomaterials have proved not only to be more efficient antifungal therapeutic agents but also to overcome resistance against fungal medication. This review will examine the limitations of standard antifungal therapy as well as focus on the development of nanomaterials.

Phaeohyphomycosis caused by Corynespora cassiicola, a plant pathogen worldwide.

Although rare, trans-kingdom infection features an interesting infection biology concept, in which highly versatile pathogenic attributes allow successful infections in evolutionarily highly divergent species. Corynespora cassiicola is a phytopathogenic fungus and occasionally causes human infections. Herein, we report a phaeohyphomycosis case caused by C. cassiicola. Given that sporadic reports may contribute to a lack of awareness of the transmission route, clinical manifestations, and diagnostic and clinical management, we systematically reviewed the cases reported thus far. Nine patients were identified and included in the pooled analysis, 88.9% (8/9) of whom were reported after 2010. All patients were from Asian, African, and Latin American countries, among whom 77.8% (7/9) were farmers or lived in areas with active agriculture. Exposed body parts were the major affected infection area, and clinical manifestations were mainly non-specific inflammatory reactions. Although biochemical and morphological examinations confirmed the presence of fungal infection, molecular analysis was used for the final diagnosis, with 77.8% (7/9) being identified by internal transcribed spacer sequencing. Whereas voriconazole, terbinafine, and AmB, either alone or in combination, resulted in successful infection resolution in most cases (5/9; 55.5%), those suffering from invasive facial infections and CARD9 deficiency showed poor outcomes. Our patient is the third case of invasive facial infection caused by C. cassiicola and was successfully treated with intravenous LAmB followed by oral voriconazole combined with topical antifungal irrigation. Molecular identification of fungus and prompt antifungal treatment is pivotal in the clinical success of patients suspected to have phaeohyphomycosis. Moreover, as evidenced by our data, itraconazole treatment is not recommended.

XB130 inhibits healing of diabetic skin ulcers through the PI3K/Akt signalling pathway.

BACKGROUND: Diabetic skin ulcers, a significant global healthcare burden, are mainly caused by the inhibition of cell proliferation and impaired angiogenesis. XB130 is an adaptor protein that regulates cell proliferation and migration. However, the role of XB130 in the development of diabetic skin ulcers remains unclear. AIM: To investigate whether XB130 can regulate the inhibition of proliferation and vascular damage induced by high glucose. Additionally, we aim to determine whether XB130 is involved in the healing process of diabetic skin ulcers, along with its molecular mechanisms. METHODS: We conducted RNA-sequencing analysis to identify the key genes involved in diabetic skin ulcers. We investigated the effects of XB130 on wound healing using histological analyses. In addition, we used reverse transcription-quantitative polymerase chain reaction, Western blot, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining, immunofluorescence, wound healing, and tubule formation experiments to investigate their effects on cellular processes in human umbilical vein endothelial cells (HUVECs) stimulated with high glucose. Finally, we performed functional analysis to elucidate the molecular mechanisms underlying diabetic skin ulcers. RESULTS: RNA-sequencing analysis showed that the expression of XB130 was up-regulated in the tissues of diabetic skin ulcers. Knockdown of XB130 promoted the healing of skin wounds in mice, leading to an accelerated wound healing process and shortened wound healing time. At the cellular level, knockdown of XB130 alleviated high glucose-induced inhibition of cell proliferation and angiogenic impairment in HUVECs. Inhibition of the PI3K/Akt pathway removed the proliferative effects and endothelial protection mediated by XB130. CONCLUSION: The findings of this study indicated that the expression of XB130 is up-regulated in high glucose-stimulated diabetic skin ulcers and HUVECs. Knockdown of XB130 promotes cell proliferation and angiogenesis via the PI3K/Akt signalling pathway, which accelerates the healing of diabetic skin ulcers.

Diagnosis of invasive fungal infections: challenges and recent developments.

BACKGROUND: The global burden of invasive fungal infections (IFIs) has shown an upsurge in recent years due to the higher load of immunocompromised patients suffering from various diseases. The role of early and accurate diagnosis in the aggressive containment of the fungal infection at the initial stages becomes crucial thus, preventing the development of a life-threatening situation. With the changing demands of clinical mycology, the field of fungal diagnostics has evolved and come a long way from traditional methods of microscopy and culturing to more advanced non-culture-based tools. With the advent of more powerful approaches such as novel PCR assays, T2 Candida, microfluidic chip technology, next generation sequencing, new generation biosensors, nanotechnology-based tools, artificial intelligence-based models, the face of fungal diagnostics is constantly changing for the better. All these advances have been reviewed here giving the latest update to our readers in the most orderly flow. MAIN TEXT: A detailed literature survey was conducted by the team followed by data collection, pertinent data extraction, in-depth analysis, and composing the various sub-sections and the final review. The review is unique in its kind as it discusses the advances in molecular methods; advances in serology-based methods; advances in biosensor technology; and advances in machine learning-based models, all under one roof. To the best of our knowledge, there has been no review covering all of these fields (especially biosensor technology and machine learning using artificial intelligence) with relevance to invasive fungal infections. CONCLUSION: The review will undoubtedly assist in updating the scientific community's understanding of the most recent advancements that are on the horizon and that may be implemented as adjuncts to the traditional diagnostic algorithms.

Octreotide and Octreotide-derived delivery systems.

Pharmaceutical peptide Octreotide is a somatostatin analog with targeting and therapeutic abilities. Over the last decades, Octreotide has been developed and approved to treat acromegaly and neuroendocrine tumours, and Octreotide-based radioactive conjugates have been leveraged clinically to detect small neuroendocrine tumour sites. Meanwhile, variety of Octreotide-derived delivery strategies have been proposed and explored for tumour targeted therapeutics or diagnostics in preclinical or clinical settings. In this review, we especially focus on the preclinical development and applications of Octreotide-derived drug delivery systems, diagnostic nanosystems, therapeutic nanosystems and multifunctional nanosystems, we also briefly discuss challenges and prospects of these Octreotide-derived delivery systems.

TREM2 as a Potential Immune-Related Biomarker of Prognosis in Patients with Skin Cutaneous Melanoma Microenvironment.

Background: The skin cutaneous melanoma (SKCM) is a devastating form of skin cancer triggered by genetic and environmental factors, and the incidence of SKCM has rapidly increased in recent years. Immune infiltration of the tumor microenvironment is positively associated with overall survival in many tumors. Triggering receptor expressed on myeloid cells 2 (TREM2) is a transmembrane receptor of the immunoglobulin superfamily and a crucial signaling hub for multiple pathological pathways that mediate immunity. Although numerous evidences suggest a crucial role for TREM2 in tumorigenesis of some tumors, no systematic SKCM analysis of TREM2 is available. Mehods. The relationship between TREM2 expression and diagnostic and prognostic value of SKCM patients via using The Cancer Genome Atlas (TCGA) data. The expression level of TREM2 and clinical characteristic correlation in SKCM patients were assessed by the Wilcoxon rank sum test. The cox regression methods, Kaplan-Meier (KM), and log-rank test were used to assess the impact of TREM2 expression on the overall survival (OS). Furthermore, the Gene Set Enrichment Analysis (GSEA) and TIMER were performed to evaluate the enrichment pathways and potential functions and quantify the immune cell infiltration level for TREM2 expression. Results: The TREM2 in SKCM sample expression levels was significantly higher than in normal tissues. Moreover, this expression level of TREM2 was also associated with the BMI of SKCM patients. KM overall survival analysis and OS curve displayed that a high-level TREM2 expression was significantly correlated with a better SKCM prognosis of patients as compared with a low level of TREM2 expression. The GSEA analysis also revealed that TREM2 was associated with immune functions, such as neutrophil activation. Conclusion: TREM2 played a crucial role in SKCM, which might be a prognostic biomarker and correlated with immune infifiltrates in SKCM patients.

Genotypic diversity and antifungal susceptibility of Scedosporium species from clinical settings in China.

BACKGROUND: Scedosporium species have drawn significant interest as inhabitants of polluted soil and water and as cause of high mortality in near-drowning patients. So far, most cases have been reported from Europe and Australia, while knowledge on their prevalence and genotypic diversity from Asia is scant. OBJECTIVES: To increase the knowledge of the genetic diversity and in vitro antifungal susceptibility of Scedosporium species involved in human infections from China. METHODS: Here, we applied the ISHAM-MLST consensus scheme for molecular typing of Scedosporium species and revealed both high species diversity and high genotypic diversity among 45 Chinese clinical Scedosporium isolates. RESULTS: Among the five species, Scedosporium boydii (n = 22) was the most common, followed by S. apiospermum (n = 18), S. aurantiacum (n = 4) and S. dehoogii (n = 1). S. aurantiacum was reported for the first time from clinical samples in China. The predominant sequence types (STs) were ST17 in S. apiospermum, ST4 in S. boydii and ST92 in S. aurantiacum, including four novel STs (ST40, ST41, ST42 and ST43) in S. apiospermum. Based on the CLSI-M38 A2 criterion, voriconazole was the only antifungal compound with low MIC values (MIC90 ≤ 1 µg/ml) for all Scedosporium isolates in our study. CONCLUSIONS: The genetic diversity of clinical isolates of Scedosporium species from China is extremely high, with S. boydii being predominant and S. aurantiacum being firstly reported here. VOR was the only antifungal compound with low MIC values for all Scedosporium isolates in our study, which should be recommended as the firstline antifungal treatment against scedosporiosis in China.

Functionalization of Nanomaterials for Skin Cancer Theranostics.

Skin cancer has drawn attention for the increasing incident rates and high morbidity worldwide. Timely diagnosis and efficient treatment are of paramount importance for prompt and effective therapy. Thus, the development of novel skin cancer diagnosis and treatment strategies is of great significance for both fundamental research and clinical practice. Recently, the emerging field of nanotechnology has profoundly impact on early diagnosis and better treatment planning of skin cancer. In this review, we will discuss the current encouraging advances in functional nanomaterials for skin cancer theranostics. Challenges in the field and safety concerns of nanomaterials will also be discussed.

Genotypic diversity and antifungal susceptibility of environmental isolates of Cryptococcus neoformans from the Yangtze River Delta region of East China.

Although cryptococcosis is widely recognized as infection by Cryptococcus neoformans sensu lato from environmental sources, information concerning the characteristics of environmental isolates of C. neoformans s. l. and how they are related to clinical isolates is very limited, especially in East China. In this study, 61 environmental isolates of C. neoformans were recovered from pigeon (Columba livia) droppings from the Yangtze River Delta region of East China. These isolates were genotyped using the ISHAM-MLST consensus scheme and their antifungal drug susceptibilities were determined following the CLSI M27-A3 guidelines. The 61 isolates were found belonging to 13 sequence types (STs), including several novel STs such as ST254 and ST194. The dominant ST in this environmental sample was ST31, different from that of clinical strains (ST5) in this region. Azole-resistance, such as fluconazole (FLU)-resistance, was observed among our environmental C. neoformans isolates. The findings of this study expand our understanding of ecological niches, population genetic diversity, and azole-resistance characteristics of the yeast in East China. Our research lays the foundation for further comparative analysis the potential mechanisms for the observed differences between environmental and clinical populations of C. neoformans in China. LAY SUMMARY: Cryptococcosis is widely recognized as infection by Cryptococcus neoformans sensu lato from environmental sources. However, there is currently limited information about the genetic diversity and antifungal susceptibility of environmental C. neoformans s. l. isolates, including how they may differ from clinical samples. In this study, we collected 61 environmental C. neoformans isolates from domestic pigeon droppings from the Yangtze River Delta region of East China. These isolates were genotyped using multi-locus sequencing. We found a high genotypic diversity in this population of C. neoformans, with several novel genotypes and a distribution of genotypes different from that of clinical strains in this region. Azole-resistance, such as fluconazole (FLU)-resistance, was observed among our environmental C. neoformans isolates. The findings of this study expand our understanding of ecological niches, genetic diversity, and azole-resistance characteristics of the yeast in East China. Our research lays the foundation for phylogenomic analysis investigating why and how disparate population structures of C. neoformans isolates formed between environmental and clinical sources in the region.

Molecular identification of Cryptococcus gattii from cerebrospinal fluid using single-cell sequencing: A case study.

A 31-year-old man presented with cryptococcal meningitis (CM) without typical clinical characteristics, but with abnormal walking, difficult leg lifting and frequent falling. He was admitted to Peking Union Medical College Hospital. After multiple tests failed to identify the pathogen, single-cell sequencing (scS) was used to test the cerebrospinal fluid (CSF). Comparing the sequence obtained from single-cell sequencing with the reference database, it was found that the infection was caused by Cryptococcus gattii sensu stricto (AFLP4/VGI genotype). Cryptococcus is difficult to cultivate from complex body fluids. The etiological agent of this patient was identified and the patient was treated. This is the first case in which scS was used to detect and identify fungal pathogen after conventional testing failed to identify the cause of the disease. This report demonstrates that the scS approach can be used to generate fungal genome sequences directly from the CSF of a CM patient. The scS technology could become a powerful tool to precise detect microscopically visible but uncultured pathogens in clinical samples.

Evaluation of genetic susceptibility loci for chronic hepatitis B in Chinese: two independent case-control studies.

BACKGROUND: A recent genome-wide scan has identified two genetic variants in the HLA-DP region strongly associated with hepatitis B infection in Japanese. This study evaluates the effects of these risk variants in Chinese, where the HBV infection is the most popular in the world. METHODS AND FINDINGS: We have assessed the relationship between these two single nucleotide polymorphisms (rs3077 and rs9277535) and chronic hepatitis B infection in two independent case-control studies. The first population in Chinese Han included 736 patients and 782 spontaneously recovered controls. The second set was established in Chinese Zhuang minority of 177 patients and 208 controls. Both A alleles of rs3077 and rs9277535 significantly deceased the risk to CHB in Chinese Han (OR = 0.540, 95%CI: 0.464-0.628, P = 4.068×10(-16) and OR = 0.696, 95%CI: 0.601-0.806, P = 1.062×10(-6), respectively). Conceivably, rs9277535 was found to be associated with decreased risk of the disease in Chinese Zhuang, with an OR of 0.606 (95%CI, 0.441-0.833, P = 0.002). CONCLUSION: Chronic hepatitis B susceptibility loci in HLA-DP region (rs3077 and rs9277535) identified by genome-wide scan in Japanese population were validated in Chinese population. These findings might provide clues to develop screening and surveillance strategies.