The SIX2/PFN2 feedback loop promotes the stemness of gastric cancer cells.

BACKGROUND: The roles of the transcriptional factor SIX2 have been identified in several tumors. However, its roles in gastric cancer (GC) progression have not yet been revealed. Our objective is to explore the impact and underlying mechanisms of SIX2 on the stemness of GC cells. METHODS: Lentivirus infection was employed to establish stable expression SIX2 or PFN2 in GC cells. Gain- and loss-of-function experiments were conducted to detect changes of stemness markers, flow cytometry profiles, tumor spheroid formation, and tumor-initiating ability. ChIP, RNA-sequencing, tissue microarray, and bioinformatics analysis were performed to reveal the correlation between SIX2 and PFN2. The mechanisms underlying the SIX2/PFN2 loop-mediated effects were elucidated through tissue microarray analysis, RNA stability assay, IP-MS, Co-Immunoprecipitation, and inhibition of the JNK signaling pathway. RESULTS: The stemness of GC cells was enhanced by SIX2. Mechanistically, SIX2 directly bound to PFN2's promoter and promoted PFN2 activity. PFN2, in turn, promoted the mRNA stability of SIX2 by recruiting RNA binding protein YBX-1, subsequently activating the downstream MAPK/JNK pathway. CONCLUSION: This study unveils the roles of SIX2 in governing GC cell stemness, defining a novel SIX2/PFN2 regulatory loop responsible for this regulation. This suggests the potential of targeting the SIX2/PFN2 loop for GC treatment (Graphical Abstracts).

ARHGAP9 knockdown promotes lung adenocarcinoma metastasis by activating Wnt/ß-catenin signaling pathway via suppressing DKK2.

This study aims to elucidate the effect of ARHGAP9 on lung adenocarcinoma (LUAD) metastasis, and preliminarily explore its molecular mechanism. As a result, we found that ARHGAP9 was downregulated and correlated with poor prognosis of LUAD. ARHGAP9 knockdown promoted LUAD cell proliferation, migration and invasion, inhibited cell apoptosis and reduced G0G1 cell cycle arrest, in contrast to the results of ARHGAP9 overexpression. Further RNA sequencing analysis demonstrated that ARHGAP9 knockdown in H1299 cells significantly reduced DKK2 (dickkopf related protein 2) expression. Silencing ARHGAP9 in H1299 cells while overexpressing DKK2, DKK2 reversed the promoted effects of ARHGAP9 knockdown on LUAD cell proliferation, migration and invasion. Meanwhile, the activity of Wnt/ß-catenin signaling pathway was also reduced. Taken together, these data indicated that ARHGAP9 knockdown promoted LUAD metastasis by activating Wnt/ß-catenin signaling pathway via suppressing DKK2. This may provide a new strategy for LUAD treatment.

Palladium-Catalyzed Reductive Double Carbonylation of Nitroarenes with Aryl Halides Using Mo(CO)6 as a Reductant and Carbonyl Source.

A new palladium-catalyzed reductive double carbonylation of nitroarenes with aryl halides for the synthesis of benzoxazin-4-ones has been reported. The key to success was the use of Mo(CO)6 as a reductant and bench-stable solid carbonyl sources. Various aryl iodides, bromides, and trifluoromethanesulfonates are suitable reaction partners and produce corresponding benzoxazin-4-one derivatives in moderate to good yields. Preliminary mechanistic studies indicate that nitrosoarene was first generated as the key intermediate through nitro reduction. Remarkably, this method avoids the use of toxic CO gas and is further applied to the late-stage modification of estrone.

The role of curcumin in the liver-gut system diseases: from mechanisms to clinical therapeutic perspective.

Natural products have provided abundant sources of lead compounds for new drug discovery and development over the past centuries. Curcumin is a lipophilic polyphenol isolated from turmeric, a plant used in traditional Asian medicine for centuries. Despite the low oral bioavailability, curcumin exhibits profound medicinal value in various diseases, especially liver and gut diseases, bringing an interest in the paradox of its low bioavailability but high bioactivity. Several latest studies suggest that curcumin's health benefits may rely on its positive gastrointestinal effects rather than its poor bioavailability solely. Microbial antigens, metabolites, and bile acids regulate metabolism and immune responses in the intestine and liver, suggesting the possibility that the liver-gut axis bidirectional crosstalk controls gastrointestinal health and diseases. Accordingly, these pieces of evidence have evoked great interest in the curcumin-mediated crosstalk among liver-gut system diseases. The present study discussed the beneficial effects of curcumin against common liver and gut diseases and explored the underlying molecular targets, as well as collected evidence from human clinical studies. Moreover, this study summarized the roles of curcumin in complex metabolic interactions in liver and intestine diseases supporting the application of curcumin in the liver-gut system as a potential therapeutic option, which opens an avenue for clinical use in the future.

Mangrovimonas aestuarii sp. nov., isolated from tidal flat sediment.

A Gram-stain-negative, rod-shaped and light yellow-pigmented strain designated MBT5T was isolated from tidal flat sediment of an oyster farming area in Quanzhou Bay, PR China. Catalase activity and oxidase activity were positive. Flexirubin-type pigment was absent. Growth was observed at 10-40 °C (optimum, 35 °C), pH 6-9 (optimum, pH 7), and with 1-7 % NaCl (optimum, 2 %, w/v). The 16S rRNA gene of strain MBT5T had maximum sequence similarity values with Meridianimaribacter flavus NH57NT, Mangrovimonas yunxiaonensis LYYY01T and Mangrovimonas futianensis AS18T of 95.6, 95.4 and 94.9 %, respectively. Phylogenetic analysis based on 16S rRNA gene sequences and 120 conserved concatenated proteins indicated that strain MBT5T was affiliated to the genus Mangrovimonas and formed a distinct monophyletic branch. The digital DNA-DNA hybridization, average nucleotide identity and average amino acid identity values between strain MBT5T and the type strains of Mangrovimonas were estimated to be 17.3-18.7 %, 70.9-71.5 % and 66.4-68.2 %, respectively. The respiratory quinone was menaquinone-6. The major fatty acids were iso-C15 : 0 and iso-C15 : 1 G. The draft genome size was 2 952 053 bp with a DNA G+C content of 36.5 %. Based on phenotypic, physiological, phylogenetic and genomic data, together with chemotaxonomic characteristics, strain MBT5T represents a novel species, for which the name Mangrovimonas aestuarii sp. nov. is proposed. The type strain is MBT5T (=MCCC 1K06186T=KCTC 92888T=GDMCC 1.3851T).

Phenazine derivatives attenuate the stemness of breast cancer cells through triggering ferroptosis.

Breast cancer stem cells (BCSCs) are positively correlated with the metastasis, chemoresistance, and recurrence of breast cancer. However, there are still no drugs targeting BCSCs in clinical using for breast cancer treatment. Here, we tried to screen out small-molecule compounds targeting BCSCs from the phenazine library established by us before. We focused on the compounds without affecting cell viability and screened out three potential compounds (CPUL119, CPUL129, CPUL149) that can significantly attenuate the stemness of breast cancer cells, as evident by the decrease of stemness marker expression, CD44+/CD24- subpopulation, mammary spheroid-formation ability, and tumor-initiating capacity. Additionally, these compounds suppressed the metastatic ability of breast cancer cells in vitro and in vivo. Combined with the transcriptome sequencing analysis, ferroptosis was shown on the top of the most upregulated pathways by CPUL119, CPUL129, and CPUL149, respectively. Mechanistically, we found that these three compounds could trigger ferroptosis by accumulating and sequestering iron in lysosomes through interacting with iron, and by regulating the expression of proteins (IRP2, TfR1, ferritin) engaged in iron transport and storage. Furthermore, inhibition of ferroptosis rescued the suppression of these three compounds on breast cancer cell stemness. This study suggests that CPUL119, CPUL129, and CPUL149 can specifically inhibit the stemness of breast cancer cells through triggering ferroptosis and may be the potential compounds for breast cancer treatment.

AKR1C1 connects autophagy and oxidative stress by interacting with SQSTM1 in a catalytic-independent manner.

Targeting autophagy might be a promising anticancer strategy; however, the dual roles of autophagy in cancer development and malignancy remain unclear. NSCLC (non-small cell lung cancer) cells harbour high levels of SQSTM1 (sequestosome 1), the autophagy receptor that is critical for the dual roles of autophagy. Therefore, mechanistic insights into SQSTM1 modulation may point towards better approaches to treat NSCLC. Herein, we used multiple autophagy flux models and autophagy readouts to show that aldo-keto reductase family 1 member C1 (AKR1C1), which is highly expressed in NSCLC, promotes autophagy by directly binding to SQSTM1 in a catalytic-independent manner. This interaction may be strengthened by reactive oxygen species (ROS), important autophagy inducers. Further mechanistic research demonstrated that AKR1C1 interacts with SQSTM1 to augment SQSTM1 oligomerization, contributing to the SQSTM1 affinity for binding cargo. Collectively, our data reveal a catalytic-independent role of AKR1C1 for interacting with SQSTM1 and promoting autophagy. All these findings not only reveal a novel functional role of AKR1C1 in the autophagy process but also indicate that modulation of the AKR1C1-SQSTM1 interaction may be a new strategy for targeting autophagy.

Advances in targeted therapy in non-small cell lung cancer with actionable mutations and leptomeningeal metastasis.

WHAT IS KNOWN AND OBJECTIVE?: Leptomeningeal metastasis (LM) is a serious complication of advanced non-small cell lung cancer (NSCLC) that is diagnosed in approximately 3%-5% of patients. LM occurs more frequently in patients with NSCLC harbouring epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) rearrangements and is usually accompanied by a poor prognosis, with a median overall survival (OS) of several months if patients receive conventional treatments. However, tyrosine kinase inhibitor (TKI) therapy after LM diagnosis is an independent predictive factor for extended survival. Here, we aim to summarize the latest advances in targeted therapy for LM and provide patients with better treatment options. METHODS: By reviewing the recent progress of targeted therapy in NSCLC with LM, especially the efficacy of newer generation TKIs, we aim to provide clinicians with a reference to further optimize patient treatment plans. RESULTS AND DISCUSSION: Osimertinib was confirmed to have a several-fold higher CNS permeability than other EGFR-TKIs and was recommended as the preferred choice for patients with EGFR-positive LM whether or not they harboured the T790M mutation. Second-generation ALK-TKIs have a higher rate of intracranial response and can be positioned as front-line drugs in NSCLC with LM. However, the sequence in which ALK-TKIs are administered for effective disease control requires further evaluation. In addition, targeted therapy revealed a potential choice in patients with LM and rare mutations, such as ROS1 and BRAF. WHAT IS NEW AND CONCLUSIONS?: The development of therapeutic agents with greater CNS penetration is vital for the management of CNS metastasis from NSCLC, particularly in the EGFR-mutant and ALK-rearranged subtypes. Systemic therapy with newer generation TKIs is preferred as the initial intervention. This is because newer generation TKIs are designed to penetrate the blood-brain barrier and possess significantly higher intracranial activities. However, their further effectiveness is limited by inadequate blood-brain barrier penetration and acquired drug resistance. Further studies are needed to further understand the mechanisms underlying resistance to treatment.

Emerging role of m6A methylation modification in ovarian cancer.

m6A (N6-methyladenosine) methylation, a well-known modification in tumour epigenetics, dynamically and reversibly fine tunes the entire process of RNA metabolism. Aberrant levels of m6A and its regulators, which can predict the survival and outcomes of cancer patients, are involved in tumorigenesis, metastasis and resistance. Ovarian cancer (OC) ranks first among gynaecological tumours in the causes of death. At first diagnosis, patients with OC are usually at advanced stages owing to a lack of early biomarkers and effective targets. After treatment, patients with OC often develop drug resistance. This article reviews the recent experimental advances in understanding the role of m6A modification in OC, raising the possibility to treat m6A modification and its regulators as promising diagnostic markers and therapeutic targets for OC.

Chaetoglobosin G inhibits proliferation, autophagy and cell cycle of lung cancer cells through EGFR/MEK/ERK signaling pathway.

Chaetoglobosin G (CG) is a fungal secondary metabolite and shows anti-tumor effects. However, the mechanisms behind the anti-tumor effect is still unclear. In this study, we evaluated the anti-proliferation effect of CG on human NSCLC A549 cells and explored the underlying mechanisms. The anti-proliferation effect of CG on A549 cells was evaluated by MTT. The targets of CG were screened through transcriptome sequencing. A flow cytometer was used to detect cell cycle and apoptosis. Western blotting was used to analyze apoptosis, cell cycle and autophagy related protein expression. Our results showed that CG had a dose-dependent inhibitory effect on proliferation of A549 cells. Transcriptome sequencing analysis found that CG obviously induced cell cycle arrest. Flow cytometry analysis and western blot showed that CG induced G2/M arrest with p21 protein upregulation and cyclinB1 protein downregulation. Western blot analysis also indicated that p-EGFR, EGFR, p-MEk and p-ERK protein expressions decreased and autophagy protein LC3II expression increased, indicating that CG can promote autophagy through EGFR/MEK/ERK/LC3 pathway. Moreover, CG can induce apoptosis with bcl-2 protein decrease. In conclusion, this study indicated that CG obviously inhibited A549 cell proliferation, and its mechanism may induce autophagy of A549 cells through EGFR/MEK/ERK/LC3 pathway to upregulate the expression of P21, thus lead to G2/M phase arrest to exert an anti-tumor role.

A dormant BODIPY-acrolein singlet oxygen photosensitizer intracellularly activated upon adduct formation with cysteine residues.

Here we report the activatable photosensitizer BromoAcroB, a brominated BODIPY dye incorporating a reactive acrolein warhead. The acrolein moiety serves as an intramolecular switch, deactivating the BODIPY dye in its singlet and triplet excited states via internal conversion. Thiolate addition to this moiety disables the intramolecular quenching mechanism restoring the photosensitizing properties of the parent dye, characterized by a quantum yield of singlet oxygen photosensitization of 0.69 ± 0.02. In cell cultures, and upon thiol adduct formation, BromoAcroB induced light-dependent cell death in MRC-5 and HeLa cell lines. Using fluorescence microscopy and upon measuring the low yet non-negligible emission of the activated compound, we show that the phototoxicity of the dormant photosensitizer correlated with the quantity of BromoAcroB adducts generated. BromoAcroB thus serves as a dormant photosensitizer sensitive to intracellular electrophile response. Our results highlight the effective control of a triplet state process by modulation of an unsaturated moiety on the BODIPY scaffold and underscore the mechanistic opportunities arising for controlled singlet oxygen production in cells specifically sensitive to electrophile stress.

Biopharmaceutics classification and intestinal absorption of chikusetsusaponin IVa.

The objective of this study was to investigate the absorption behavior of chikusetsusaponin IVa (CHS-IVa) in the rat intestine using single-pass intestinal perfusion (SPIP) and to classify CHS-IVa into the biopharmaceutics classification system (BCS). The equilibrium solubility of CHS-IVa was determined by the shaker method. The absorption mechanism of CHS-IVa in the intestine was studied by comparing the Peff of different concentrations of CHS-IVa. The intestinal site dependence of CHS-IVa absorption was studied by comparing the Peff of the same concentration of CHS-IVa in different intestinal segments. The relationship between CHS-IVa and intestinal efflux protein was studied by perfusion with an efflux protein inhibitor. The permeability of CHS-IVa was investigated by comparing the Peff of CHS-IVa and the reported value. The solubility of CHS-IVa over the pH range 1.0-7.5 was 14.4 ± 0.29 to 16.9 ± 0.34 mg/ml. The Peff of CHS-IVa in the duodenum was 1.76 × 10-3 to 2.00 × 10-3  cm/min. The Peff of CHS-IVa in the jejunum was 1.26 × 10-3 to 1.39 × 10-3  cm/min. The Peff of CHS-IVa in the ileum was 1.25 × 10-3 to 1.31 × 10-3  cm/min. The Peff of CHS-IVa in the colon was 1.02 × 10-3 to 1.08 × 10-3  cm/min. There was no statistical difference of the Peff in the four segments at different CHS-IVa concentrations. The Peff of CHS-IVa (0.07, 0.7 and 7.0 mg/ml) were all notably smaller than the reported Peff (3.00 × 10-3  cm/min) in the jejunum. The Peff of CHS-IVa was not influenced by verapamil (P-gp inhibitor), indomethacin (MRP inhibitor) and pantoprazole (BCRP inhibitor). CHS-IVa was classified as high solubility, low permeability and BCS III. The main absorptive tracts were the upper intestinal tracts and the rank order of intestinal permeability was duodenum > jejunum ≈ ileum > colon. The transport mechanism of CHS-IVa in all intestinal segments might be primarily passive transport. CHS-IVa was not a substrate of P-gp, MRP and BCRP.

Association between UDP-glucuronosyltransferase 2B7 tagSNPs and breast cancer risk in Chinese females.

This retrospective study was performed to evaluate the association between the UGT2B7 tagSNPs (rs12233719, rs4356975, rs7435335 and rs7441774) and breast cancer in Chinese females. Blood samples were collected from 672 patients with breast cancer and 670 healthy controls for DNA extraction. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) was used to analyze UGT2B7 polymorphisms. Dual-luciferase reporter assays were further performed to investigate the regulatory function of UGT2B7 tagSNPs. The frequency of rs7441774 G allele in the breast cancer cases was statistically significantly higher than in the controls (0.412 vs 0.358, P = .006; odds ratio [OR] = 1.27, 95% CI = 1.08-1.48). After adjusting for conventional risk factors, individuals with the GG genotype had a higher breast cancer risk than those with the AA genotype (adjusted OR = 1.63, 95% CI = 1.18-2.26; P = .008). The GCGG haplotype of UGT2B7 was also associated with breast cancer (OR = 1.22, 95% CI = 1.04-1.45; P = .027). Meanwhile, the rs7441774 G allele could significantly decrease the transcriptional activity of the UGT2B7 gene. This study indicates that UGT2B7 polymorphisms may play a crucial role in the occurrence and development of breast cancer in the Han Chinese population.

Mitochondria Alkylation and Cellular Trafficking Mapped with a Lipophilic BODIPY-Acrolein Fluorogenic Probe.

Protein and DNA alkylation by endogenously produced electrophiles is associated with the pathogenesis of neurodegenerative diseases, to epigenetic alterations and to cell signaling and redox regulation. With the goal of visualizing, in real-time, the spatiotemporal response of the cell milieu to electrophiles, we have designed a fluorogenic BODIPY-acrolein probe, AcroB, that undergoes a >350-fold fluorescence intensity enhancement concomitant with protein adduct formation. AcroB enables a direct quantification of single post-translational modifications occurring on cellular proteins via recording fluorescence bursts in live-cell imaging studies. In combination with super-resolution imaging, protein alkylation events may be registered and individually counted, yielding a map of protein-electrophile reactions within the cell lipid milieu. Alkylation is predominantly observed within mitochondria, a source, yet not a sink, of AcroB adducts, illustrating that a mitochondrial constitutive excretion mechanism ensures rapid disposal of compromised proteins. Sorting within the Golgi apparatus and trafficking along microtubules and through the cell endo- and exocytic pathways can be next visualized via live-cell imaging. Our results offer a direct visualization of cellular response to a noncanonical acrolein warhead. We envision AcroB will enable new approaches for diagnosis of pathologies associated with defective cellular trafficking. AcroB may help elucidate key aspects of mitochondria electrophile adduct excretion and cell endocytic and exocytic pathways. Conceptually, AcroB provides a new paradigm on fluorescence microscopy studies where chemical perturbation is achieved and simultaneously reported by the probe.

Preferential binding of Inorganic Mercury to specific lipid classes and its competition with Cadmium.

Upon uptake of Hg and Cd into living systems, possible targets for metal induced toxicity include the membranes surrounding nervous, cardiovascular and renal cells. To further our understanding of the interactions of Hg and Cd with different lipid structures under physiologically relevant chloride and pH conditions (100 mM NaCl pH 7.4), we used fluorescence spectroscopy and dynamic light scattering to monitor changes in membrane fluidity and phase transition and liposome size. The metal effects were studied on zwitterionic, cationic and anionic lipids to elucidate electrostatically driven metal-lipid interactions. The effect of Hg-catalyzed cleavage of the vinyl ether bond in plasmalogens on these aforementioned properties was studied in addition to a thermodynamic characterization of this interaction by Isothermal Titration Calorimetry. The negatively charged Hg-chloride complexes formed under our experimental conditions induce membrane rigidity in membranes containing cationic lipids and plasmalogens while this effect is heavily reduced and entirely absent with zwitterionic and anionic lipids respectively. The KD for the interaction of Hg with plasmalogen containing liposomes was between 4-30 µM. Furthermore, the presence of Cd affected the interaction of Hg with plasmalogen when negatively charged PS was also present. In this case, even the order of the metal addition was important.

The role of E2F2 in cancer progression and its value as a therapeutic target.

The E2F family of transcription factors plays a crucial role in the regulation of cell cycle progression and cell proliferation. Accumulative evidence indicates that aberrant expression or activation of E2F2 is a common phenomenon in malignances. E2F2 has emerged as a key player in the development and progression of various types of tumors. A wealth of research has substantiated that E2F2 could contribute to the enhancement of tumor cell proliferation, angiogenesis, and invasiveness. Moreover, E2F2 exerts its influence on a myriad of cellular processes by engaging with a spectrum of auxiliary factors and downstream targets, including apoptosis and DNA repair. The dysregulation of E2F2 in the context of carcinogenesis may be attributable to a multitude of mechanisms, which encompass modifications in upstream regulatory elements or epigenetic alterations. This review explores the function of E2F2 in cancer progression and both established and emerging therapeutic strategies aiming at targeting this oncogenic pathway, while also providing a strong basis for further research on the biological function and clinical applications of E2F2.

Individualized gray matter morphological abnormalities uncover two robust transdiagnostic biotypes.

Psychiatric disorders exhibit a shared neuropathology, yet the diverse presentations among patients necessitate the identification of transdiagnostic subtypes to enhance diagnostic and treatment strategies. This study aims to unveil potential transdiagnostic subtypes based on personalized gray matter morphological abnormalities. A total of 496 patients with psychiatric disorders and 255 healthy controls (HCs) from three distinct datasets (one for discovery and two for validation) were enrolled. Individualized gray matter morphological abnormalities were determined using normative modeling to identify transdiagnostic subtypes. In the discovery dataset, two transdiagnostic subtypes with contrasting patterns of structural abnormalities compared to HCs were identified. Reproducibility and generalizability analyses demonstrated that these subtypes could be generalized to new patients and even to new disorders in the validation datasets. These subtypes were characterized by distinct disease epicenters. The gray matter abnormal pattern in subtype 1 was mainly linked to excitatory receptors, whereas subtype 2 showed a predominant association with inhibitory receptors. Furthermore, we observed that the gray matter abnormal pattern in subtype 2 was correlated with transcriptional profiles of inflammation-related genes, while subtype 1 did not show this association. Our findings reveal two robust transdiagnostic biotypes, offering novel insights into psychiatric nosology.

Antibiotics-associated pseudomembranous colitis: a disproportionality analysis of the US food and drug administration adverse event reporting system (FAERS) database.

BACKGROUND: Evaluating antibiotics most commonly associated with pseudomembranous colitis (PMC) based on the real-world data is of great significance. RESEARCH DESIGN AND METHODS: We used the data from FAERS to evaluate the potential association between antibiotics and PMC by disproportionality analyzes. RESULTS: Eighty-one antibiotics which met the three algorithms simultaneously were enrolled. There were 1683 reports of PMC associated with the enrolled antibiotics. In the top 24 antibiotics, cefoxitin, streptomycin, fosfomycin, and micafungin had a high risk of PMC, but there were few reports in the literature. CONCLUSIONS: This study was of great significance for healthcare professionals to realize the potential PMC risks of antibiotics.

Evaluating cardiac disorders associated with triazole antifungal agents based on the US Food and Drug Administration Adverse Event reporting system database.

Introduction: Triazole antifungal agents are widely used to treat and prevent systemic mycoses. With wide clinical use, the number of reported adverse events has gradually increased. The aim of this study was to analyze the cardiac disorders associated with TAAs (fluconazole, voriconazole, itraconazole, posaconazole and isavuconazole) based on data from the US Food and Drug Administration Adverse Event Reporting System FDA Adverse Event Reporting System. Methods: Data were extracted from the FAERS database between the first quarter of 2004 and third quarter of 2022. The clinical characteristics in TAA-associated cardiac AE reports were analyzed. Disproportionality analysis was performed to evaluate the potential association between AEs and TAAs using the reporting odds ratio (ROR) and proportional reporting ratio (PRR). Results: Among 10,178,522 AE reports, 1719 reports were TAA-associated cardiac AEs as primary suspect drug. Most reports were related to fluconazole (38.34%), voriconazole (28.56%) and itraconazole (26.76%). Itraconazole (N = 195, 42.39%) and isavuconazole (N = 2, 14.29%) had fewer serious outcome events than three other drugs including fluconazole, voriconazole, and posaconazole. 13, 11, 26, 5 and 1 signals were detected for fluconazole, voriconazole, itraconazole, posaconazole and isavuconazole, respectively. The number of new signals unrecorded in the drug label was 9, 2, 13, 2 and 0 for fluconazole, voriconazole, itraconazole, posaconazole and isavuconazole, respectively. Conclusion: Isavuconazole might be the safest of the five TAAs for cardiac AEs. TAA-associated cardiac disorders may result in serious adverse outcomes. Therefore, in addition to AEs on the drug label, we should pay attention to new AEs unrecorded on the drug label during the clinical use of TAAs.

Infection associated with CDK4/6 inhibitors: a pharmacovigilance analysis of the FDA adverse event reporting system database.

Introduction: Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors are first-line treatments for hormone receptor-positive/human epidermal growth factor receptor 2-negative breast cancer. With their increasing clinical use, infection-related adverse events (AEs) associated with CDK4/6 inhibitors have been widely reported in recent years. This study aimed to analyze the occurrence of infections associated with the CDK4/6 inhibitors (palbociclib, ribociclib and abemaciclib) based on the real-world data from the US Food and Drug Administration Adverse Event Reporting System (FAERS) database. Methods: Data were extracted from the FAERS database between 2015Q1 and 2022Q3. The clinical characteristics of patients with primary suspected infection-related AEs were analyzed. A disproportionality analysis was performed to investigate the potential association between AEs and CDK4/6 inhibitors. The influencing factors were evaluated using Pearson's chi-square test. Results: Reports of infection-related AEs associated with ribociclib accounted for 8.58% of the total reports of AEs associated with ribociclib, followed by palbociclib (2.72%) and abemaciclib (1.24%). Ribociclib (67.65%) was associated with more serious outcome events than palbociclib (30%) or abemaciclib (48.08%). The sex and age were not associated with outcome severity. Disproportionality analysis showed that fourteen, sixteen and two infection-related preferred terms were detected for palbociclib, ribociclib and abemaciclib, respectively. Conclusion: Infection-related AEs were highly associated with three CDK4/6 inhibitors, especially palbociclib and ribociclib, based on the real-world data from the FAERS database. However, further causality assessment is required.