Epidemiology and antifungal susceptibilities of clinically isolated Aspergillus species in South China.

Aspergillosis is a rising concern worldwide; however, its prevalence is not well documented in China. This retrospective study determined Aspergillus's epidemiology and antifungal susceptibilities at Meizhou People's Hospital, South China. From 2017 to 2022, the demographic, clinical, and laboratory data about aspergillosis were collected from the hospital's records and analysed using descriptive statistics, chi-square test, and ANOVA. Of 474 aspergillosis cases, A. fumigatus (75.32%) was the most common, followed by A. niger (9.92%), A. flavus (8.86%), and A. terreus (5.91%). A 5.94-fold increase in aspergillosis occurred during the study duration, with the highest cases reported from the intensive care unit (52.74%) - chronic pulmonary aspergillosis (79.1%) and isolated from sputum (62.93%). Only 38 (8.02%) patients used immunosuppressant drugs, while gastroenteritis (5.7%), haematologic malignancy (4.22%), and cardiovascular disease (4.22%) were the most prevalent underlying illnesses. In A. fumigatus, the wild-type (WT) isolates against amphotericin B (99.1%) were higher than triazoles (97-98%), whereas, in non-fumigatus Aspergillus species, the triazole (95-100%) WT proportion was greater than amphotericin B (91-95%). Additionally, there were significantly fewer WT A. fumigatus isolates for itraconazole and posaconazole in outpatients than inpatients. These findings may aid in better understanding and management of aspergillosis in the region.

miRNA-135a promotes hepatocellular carcinoma cell migration and invasion by targeting forkhead box O1.

AIMS: Hepatocellular carcinoma (HCC) is the third leading cause of cancer mortality worldwide. Many microRNAs (miRNAs), small non-coding RNAs, are involved in regulating cancer cell proliferation, metastasis, migration, invasion and apoptosis. MAIN METHODS: We investigated the expression of miR-135a in HCC cell lines and clinical tissues. The effect of miR-135a on migration and invasion of HepG2 and MHCC-97L were examined using wound healing and Transwell assay. We determined the expression of miR-135a, forkhead box O1 (FOXO1), matrix metalloproteinase-2 (MMP-2) and Snail using real-time PCR and western blotting. KEY FINDINGS: We found miR-135a was upregulated in HCC cell lines and tissues. miR-135a overexpression promoted HCC cells migration and invasion, whereas miR-135a inhibition suppressed HCC cells migration and invasion. miR-135a overexpression could upregulate the expression of MMP2, Snail and the phosphorylation of AKT, but decreased FOXO3a phosporylation. Tumor suppressor FOXO1 was the direct target for miR-135a. SIGNIFICANCE: Our results suggested that miR-135a might play an important role in promoting migration and invasion in HCC and presents a novel mechanism of miRNA-mediated direct suppression of FOXO1 in HCC cells.

LIM protein JUB promotes epithelial-mesenchymal transition in colorectal cancer.

Metastasis is the leading cause of cancer-related death in almost all types of cancers, including colorectal cancer (CRC). Metastasis is a complex, multistep, dynamic biological event, and epithelial-mesenchymal transition (EMT) is a critical process during the cascade. Ajuba family proteins are LIM domain-containing proteins and are reported to be transcription repressors regulating different kinds of physiological processes. However, the expression and pathological roles of Ajuba family proteins in tumors, especial in tumor metastasis, remain poorly studied. Here, we found that JUB, but not the other Ajuba family proteins, was highly upregulated in clinical specimens and CRC cell lines. Ectopic expression of JUB induced EMT and enhanced motility and invasiveness in CRC, and vice versa. Mechanistic study revealed that JUB induces EMT via Snail and JUB is also required for Snail-induced EMT. The expression of JUB shows an inverse correlation with E-cadherin expression in clinical specimens. Taken together, these findings revealed that the LIM protein JUB serves as a tumor-promoting gene in CRC by promoting EMT, a critical process of metastasis. Thus, the LIM protein JUB may provide a novel target for therapy of metastatic CRC.

Distribution of Aspergillus species and risk factors for aspergillosis in mainland China: a systematic review.

Background: Aspergillus, a widespread fungus in the natural environment, poses a significant threat to human health by entering the human body via the airways and causing a disease called aspergillosis. This study comprehensively analyzed data on aspergillosis in published articles from mainland China to investigate the prevalence of Aspergillus, and risk factors, mortality rate, and underlying condition associated with aspergillosis. Methods: Published articles were retrieved from Google Scholar, PubMed, and Science Direct online search engines. In the 101 analyzed studies, 3558 Aspergillus isolates were meticulously collected and classified. GraphPad Prism 8 was used to statistically examine the epidemiology and clinical characteristics of aspergillosis. Results: Aspergillus fumigatus was prominently reported (n = 2679, 75.14%), followed by A. flavus (n = 437, 12.25%), A. niger (n = 219, 6.14%), and A. terreus (n = 119, 3.33%). Of a total of 9810 patients, 7513 probable cases accounted for the highest number, followed by confirmed cases (n = 1956) and possible cases (n = 341). In patients, cough emerged as the most common complaint (n = 1819, 18.54%), followed by asthma (n = 1029, 10.48%) and fever (1024, 10.44%). Of total studies, invasive pulmonary aspergillosis (IPA) was reported in 47 (45.53%) studies, exhibiting an increased prevalence in Beijing (n = 12, 25.53%), Guangdong (n = 7, 14.89%), and Shanghai (n = 6, 12.76%). Chronic pulmonary aspergillosis (CPA) was reported in 14 (13.86%) studies. Among the total of 14 studies, the occurrence of CPA was 5 (35.71%) in Beijing and 3 (21.42%) in Shanghai. Allergic bronchopulmonary aspergillosis (ABPA), was reported at a lower frequency (n = 8, 7.92%), Guangdong recorded a relatively high number (n = 3, 37.5%), followed by Beijing (n = 2, 25.0%), and Shanghai (n = 1, 12.5%). Percentage of death reported: IPA had the highest rate (n = 447, 68.87%), followed by CPA (n = 181, 27.88%) and ABPA (n = 14, 2.15%). Among the aspergillosis patients, 6220 had underlying conditions, including chronic lung disease (n = 3765, 60.53%), previous tuberculosis (n = 416, 6.68%), and organ transplant or organ failure (n = 648, 10.41%). Aspergillosis was also found in patients using corticosteroid therapy (n = 622, 10.0%). Conclusion: This review sheds light on the prevalence patterns of Aspergillus species, risk factors of aspergillosis, and gaps in surveillance that could be helpful for the control and treatment of aspergillosis and guide the researchers in future studies. Registration: This systematic review was prospectively registered on PROSPERO: Registration ID CRD42023476870.

Interleukin inhibitors and the associated risk of candidiasis.

Interleukins (ILs) are vital in regulating the immune system, enabling to combat fungal diseases like candidiasis effectively. Their inhibition may cause enhanced susceptibility to infection. IL inhibitors have been employed to control autoimmune diseases and inhibitors of IL-17 and IL-23, for example, have been associated with an elevated risk of Candida infection. Thus, applying IL inhibitors might impact an individual's susceptibility to Candida infections. Variations in the severity of Candida infections have been observed between individuals with different IL inhibitors, necessitating careful consideration of their specific risk profiles. IL-1 inhibitors (anakinra, canakinumab, and rilonacept), IL-2 inhibitors (daclizumab, and basiliximab), and IL-4 inhibitors (dupilumab) have rarely been associated with Candida infection. In contrast, tocilizumab, an inhibitor of IL-6, has demonstrated an elevated risk in the context of coronavirus disease 2019 (COVID-19) treatment, as evidenced by a 6.9% prevalence of candidemia among patients using the drug. Furthermore, the incidence of Candida infections appeared to be higher in patients exposed to IL-17 inhibitors than in those exposed to IL-23 inhibitors. Therefore, healthcare practitioners must maintain awareness of the risk of candidiasis associated with using of IL inhibitors before prescribing them. Future prospective studies need to exhaustively investigate candidiasis and its associated risk factors in patients receiving IL inhibitors. Implementing enduring surveillance methods is crucial to ensure IL inhibitors safe and efficient utilization of in clinical settings.

Risk of candidiasis associated with interleukin-17 inhibitors: Implications and management.

The application of interleukin-17 (IL-17) inhibitors, including secukinumab, ixekizumab, brodalumab, and bimekizumab, are associated with elevated risk of candidiasis. These medications interfere with the IL-17 pathway, which is essential for maintaining mucosal barriers and coordinating the immune response against Candida species. The observational data and clinical trials demonstrate the increased incidence of candidiasis in individuals treated with IL-17 inhibitors. Brodalumab and bimekizumab pose a greater risk than secukinumab in eliciting candidiasis, whereas the data regarding ixekizumab are equivocal. Higher doses and prolonged treatment duration of IL-17 inhibitors increase the risk of candidiasis by compromising the immune response against Candida species. Prior to prescribing IL-17 inhibitors, healthcare professionals should comprehensively evaluate patients' medical histories and assess their risk factors. Patients should be educated on the signs and symptoms of candidiasis to facilitate early detection and intervention. Future research should focus on identifying the risk factors associated with candidiasis in patients receiving IL-17 inhibitors. Prospective studies and long-term surveillance are required to explore the impact of specific inhibitors on the incidence and severity of candidiasis and to evaluate the effectiveness of combination therapies, such as concurrent use of IL-17 inhibitors and prophylactic antifungal agents.

Stabilization of Acne Vulgaris-Associated Microbial Dysbiosis with 2% Supramolecular Salicylic Acid.

Facial microbiota dysbiosis is an important factor in causing acne vulgaris. The present study aimed to analyze the effect of 2% Supramolecular Salicylic Acid (SSA) on acne-associated facial bacteria. In the current study, 30 acne vulgaris patients (treated with 2% SSA for eight weeks) and ten volunteers with no facial acne were selected. Samples from acne patients (before and after treatment) and volunteers (not treated) were analyzed via high throughput sequencing, Deblur algorithm, and R microbiome package. After treatment with 2% SSA, the total lesion count and global acne grading system (GAGS) score reduced significantly (p < 0.001). Metagenomic sequencing analysis revealed that the pre-treated acne group had low α and deviated ß diversity compared to the control and post-treated acne groups. Due to the treatment with 2% SSA, α diversity index was increased and ß diversity was stabilized significantly (p < 0.001). The relative abundance of bacterial genera in the pre-treated acne group was uneven and had a high proportion of Staphylococcus, Ralstonia, and Streptococcus. The proportion of these three genera was significantly decreased in the post-treated group, and overall bacteria genera distribution tends toward the healthy individual. It is concluded that 2% SSA normalizes the microbial communities associated with the skin.

Cryptococcosis in Southern China: Insights from a Six-Year Retrospective Study in Eastern Guangdong.

Objective: Cryptococcosis is a fatal infection that can affect both immunocompetent and immunocompromised patients, and it is little understood in China's various regions. This research aimed to look at the epidemiology, risk factors, and antifungal susceptibility pattern of Cryptococcus neoformans in eastern Guangdong, China. Methods: A six-year (2016-2022) retrospective study was conducted at Meizhou People's Hospital, China. Demographical, clinical, and laboratory data of cryptococcal patients were collected from hospital records and statistically analyzed using the chi-square and ANOVA tests. Results: Overall, 170 cryptococcal infections were recorded, of which meningitis accounted for 78 (45.88%), cryptococcemia for 50 (29.41%), and pneumonia for 42 (24.7%). The number of cases increased 8-fold during the study duration. The median age of patients was 58 years (Inter quartile range: 47-66), and the high proportion of cases was from the male population (n = 121, 71.17%). The underlying diseases were identified only in 60 (35.29%) patients, of which 26 (15.29%) were severely immunocompromised, and 26 (15.29%) others were mildly immunocompromised. A statistically significant difference was reported for chronic renal failure, and anemia (p < 0.05) persisted in cases of three infection types. A high number of non-wild type (NWT) isolates were found against amphotericin B (n=13/145, 8.96%), followed by itraconazole (n=7/136, 5.15%) and voriconazole (n=4/158, 2.53%). Only six isolates (3.79%) were multidrug-resistant, four of which were from cryptococcemia patients. Compared to meningitis and pneumonia, cryptococcemia revealed a higher percentage of NWT isolates (p < 0.05). Conclusion: In high-risk populations, cryptococcal infections require ongoing monitoring and management.

Six-Year Retrospective Analysis of Epidemiology, Risk Factors, and Antifungal Susceptibilities of Candidiasis from a Tertiary Care Hospital in South China.

Candidiasis is a life-threatening disease that increases mortality in critically ill patients. However, such epidemiological data are still lacking in underdeveloped regions of China. A retrospective analysis (2016 to 2021) was conducted in Meizhou People's Hospital, China to study the burden of candidiasis, particularly candidemia, and antifungal susceptibilities of the species among hospitalized patients. Of the 7,864 candidiasis cases, 461 (5.86%) were candidemia cases. Candida albicans (64.25%) was the most identified species, followed by C. tropicalis (12.61%), C. glabrata (10.79%), and C. parapsilosis (9.79%). In non-C. albicans (NCA) candidemia cases, the number of C. glabrata cases was higher (102/461, 22.37%) than C. tropicalis (64/461, 14.04%). Gastrointestinal pathology, respiratory dysfunctions, septic shock, and malignancies were common underlying comorbidities, respectively. A central venous catheter was an independent risk factor for both C. albicans and NCA candidemia. The mortality rate was not statistically significant for either C. albicans or NCA. Amphotericin B and 5-flucytosine were highly effective (98 to 100%), while azoles were least effective (67.74 to 95.66%). Candidemia cases caused by C. tropicalis and C. glabrata had significantly lower azole susceptibility than non-candidemia-causing isolates. This study provides valuable information for prescribers to choose the right empirical therapy, for researchers to explore different resistance mechanisms, and for health care managers to control candidiasis better. IMPORTANCE This study provides important information on the burden of candidiasis, particularly candidemia, and the antifungal susceptibility of Candida species among hospitalized patients in an underdeveloped region of China. First, the finding that azoles were least effective against Candida species causing candidemia is particularly noteworthy, as it suggests the possibility of resistance to this class of antifungal agents. This information can guide the choice of empirical therapy and help in the selection of appropriate antifungal agents for the treatment of candidemia, thereby reducing the risk of resistance development. Second, the study provides important information for researchers to explore different resistance mechanisms in Candida species. Finally, the study has important implications for health care managers in controlling the spread of candidiasis. The high prevalence of candidemia cases in the study highlights the need for appropriate infection control measures to prevent the spread of the disease.

Antifungal susceptibility pattern of Candida isolated from cutaneous candidiasis patients in eastern Guangdong region: A retrospective study of the past 10 years.

Cutaneous candidiasis is one of the most prevalent mycotic infections caused by Candida species. The severity of infection mounts faster when the species shows antifungal resistance. In the current retrospective study, we aimed to analyze the occurrence, causes of cutaneous candidiasis, and antifungal susceptibility pattern of Candida isolates from Skin and Venereal Diseases Prevention and Control Hospital of Shantou, located in eastern Guangdong, China. The laboratory data of all patients (n = 3,113) suffering from various skin and venereal infections during January 2012 to December 2021 was analyzed through Excel and GraphPad prism. Our analysis indicate that cutaneous candidiasis was 22.29% (n = 694), of which 78.53% (n = 554) of patients were males and 21.47% (n = 149) of patients were females. The median age of patients with cutaneous candidiasis was 38-year [interquartile range (30-48)]. Most cases occurred in the adult age group (19-50 years). Regarding the species type, the Candida albicans were prominently detected (n = 664, 95.68%), while non-C. albicans were found only in 30 (4.32%) patients, which were C. glabrata (n = 18), C. krusei (n = 8), C. tropicalis (n = 3), and C. parapsilosis (n = 1). The C. albicans susceptibility rate for terbinafine, miconazole, voriconazole, itraconazole, fluconazole, ketoconazole, nystatin, 5-flucytosine and amphotericin B were 10.83, 29.32, 59.39, 78.53, 85.28, 87.75, 99.59, 99.41, and 100%, respectively. Finally, all C. glabrata isolates were found susceptible to all tested azole drugs with exception to miconazole against which 8.33% of isolates showed resistance. The findings of this study will help healthcare officials to establish better antifungal stewardship in the region.

Distribution and antifungal susceptibility pattern of Candida species from mainland China: A systematic analysis.

Antifungal resistance to Candida pathogens increases morbidity and mortality of immunosuppressive patients, an emerging crisis worldwide. Understanding the Candida prevalence and antifungal susceptibility pattern is necessary to control and treat candidiasis. We aimed to systematically analyse the susceptibility profiles of Candida species published in the last ten years (December 2011 to December 2021) from mainland China. The studies were collected from PubMed, Google Scholar, and Science Direct search engines. Out of 89 included studies, a total of 44,716 Candida isolates were collected, mainly comprising C. albicans (49.36%), C. tropicalis (21.89%), C. parapsilosis (13.92%), and C. glabrata (11.37%). The lowest susceptibility was detected for azole group; fluconazole susceptibilities against C. parapsilosis, C. albicans, C. glabrata, C. tropicalis, C. guilliermondii, C. pelliculosa, and C. auris were 93.25%, 91.6%, 79.4%, 77.95%, 76%, 50%, and 0% respectively. Amphotericin B and anidulafungin were the most susceptible drugs for all Candida species. Resistance to azole was mainly linked with mutations in ERG11, ERG3, ERG4, MRR1-2, MSH-2, and PDR-1 genes. Mutation in FKS-1 and FKS-2 in C. auris and C. glabrata causing resistance to echinocandins was stated in two studies. Gaps in the studies' characteristics were detected, such as 79.77%, 47.19 %, 26.97%, 7.86%, and 4.49% studies did not mention the mortality rates, age, gender, breakpoint reference guidelines, and fungal identification method, respectively. The current study demonstrates the overall antifungal susceptibility pattern of Candida species, gaps in surveillance studies and risk-reduction strategies that could be supportive in candidiasis therapy and for the researchers in their future studies.

Synergistic Activity of Tetrandrine and Colistin against mcr-1-Harboring Escherichia coli.

Before the emergence of plasmid-mediated colistin resistance, colistin was once considered the last drug of choice for infections caused by carbapenem-resistant bacteria. Currently, researchers are relentlessly exploring possible alternative therapies that could efficiently curb the spread of drug resistance. In this study, we aim to investigate the synergistic antibacterial activity of tetrandrine in combination with colistin against mcr-1-harboring Escherichia coli. We examined the antibacterial activity of tetrandrine in combination with colistin in vivo and in vitro and examined the bacterial cells by fluorescence, scanning, and transmission electron microscopy (TEM) to explore their underlying mechanism of action. We further performed a computational analysis of MCR-1 protein and tetrandrine to determine the interaction interface of these two molecules. We confirmed that neither colistin nor tetrandrine could, on their own, inhibit the growth of mcr-1-positive E. coli. However, in combination, tetrandrine synergistically enhanced colistin activity to inhibit the growth of E. coli both in vivo and in vitro. Similarly, molecular docking showed that tetrandrine interacted with the three crucial amino acids of the MCR-1 protein in the active site, which might inhibit MCR-1 from binding to its substrates, cause MCR-1 to lose its ability to confer resistance. This study confirmed that tetrandrine and colistin have the ability to synergistically overcome the issue of colistin resistance in mcr-1-harboring E. coli.

Genome-wide expression profiling of the response to terbinafine in Candida albicans using a cDNA microarray analysis.

BACKGROUND: Candida albicans is the most frequently seen opportunistic human fungal pathogen. Terbinafine is an allylamine antifungal agent that has been proven to have high clinical efficacy in the therapy of fungal infections, the mechanism of action of terbinafine involves the specific inhibition of fungal squalene epoxidase, resulting in ergosterol deficiency and accumulation of intracellular squalene. We used cDNA microarray analysis technology to monitor global expression profile changes of Candida albicans genes in response to terbinafine treatment, and we anticipated a panoramic view of the responses of Candida albicans cells to the representatives of allylamine antifungal agents at the molecular level in an effort to identify drug class-specific and mechanism-independent changes in gene expression. METHODS: Candida albicans strain ATCC 90028 was exposed to either medium alone or terbinafine at a concentration equivalent to the 1/2 minimal inhibitory concentrations (MICs, 4 mg/L) for 90 minutes. RNA was isolated and gene expression profiles were compared to identify the changes in the gene expression profile using a cDNA microarray analysis. Differential expression of 10 select genes detected by cDNA microarray analysis was confirmed by semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: A total of 222 genes were found to be responsive to terbinafine, including 121 up-regulated genes and 101 down-regulated genes. These included genes encoding membrane transport proteins belonging to the members of the ATP-binding cassette (ABC) or major facilitator superfamily (MFS; CDR1, AGP2, GAP6, PHO84, HOL3, FCY23, VCX1), genes involved in stress response and detoxification (CDR1, AGP2, HOL3), and gene involved in the ergosterol biosynthesis pathway (ERG12). The results of semi-quantitative RT-PCR were consistent with that of the cDNA microarray analysis. CONCLUSIONS: The up-regulation of the gene encoding the multidrug resistance efflux pump CDR1 may contribute to the terbinafine resistance in Candida albicans. However, the precise roles of other affected genes remain unclear, further studies of these genes and their respective products that play roles in the context of antifungal resistance are warranted.

Defect detection in slab surface: a novel dual Charge-coupled Device imaging-based fuzzy connectedness strategy.

To provide an accurate surface defects inspection system and make the automation of robust image segmentation method a reality in routine production line, a general approach is presented for continuous casting slab (CC-slab) surface defects extraction and delineation. The applicability of the system is not tied to CC-slab exclusively. We combined the line array CCD (Charge-coupled Device) traditional scanning imaging (LS-imaging) and area array CCD laser three-dimensional (3D) scanning imaging (AL-imaging) strategies in designing the system. Its aim is to suppress the respective imaging system's limitations. In the system, the images acquired from the two CCD sensors are carefully aligned in space and in time by maximum mutual information-based full-fledged registration schema. Subsequently, the image information is fused from these two subsystems such as the unbroken 2D information in LS-imaging and 3D depressed information in AL-imaging. Finally, on the basis of the established dual scanning imaging system the region of interest (ROI) localization by seed specification was designed, and the delineation for ROI by iterative relative fuzzy connectedness (IRFC) algorithm was utilized to get a precise inspection result. Our method takes into account the complementary advantages in the two common machine vision (MV) systems and it performs competitively with the state-of-the-art as seen from the comparison of experimental results. For the first time, a joint imaging scanning strategy is proposed for CC-slab surface defect inspection that allows a feasible way of powerful ROI delineation strategies to be applied to the MV inspection field. Multi-ROI delineation by using IRFC in this research field may further improve the results.