Leonurine alleviates vancomycin nephrotoxicity via activating PPARγ and inhibiting the TLR4/NF-κB/TNF-α pathway.

Vancomycin (VCM) is the first-line antibiotic for severe infections, but nephrotoxicity limits its use. Leonurine (Leo) has shown protective effects against kidney damage. However, the effect and mechanism of Leo on VCM nephrotoxicity remain unclear. In this study, mice and HK-2 cells exposed to VCM were treated with Leo. Biochemical and pathological analysis and fluorescence probe methods were performed to examine the role of Leo in VCM nephrotoxicity. Immunohistochemistry, q-PCR, western blot, FACS, and Autodock software were used to verify the mechanism. The present results indicate that Leo significantly alleviates VCM-induced renal injury, morphological damage, and oxidative stress. Increased intracellular and mitochondrial ROS in HK-2 cells and decreased mitochondrial numbers in mouse renal tubular epithelial cells were reversed in Leo-administrated groups. In addition, molecular docking analysis using Autodock software revealed that Leo binds to the PPARγ protein with high affinity. Mechanistic exploration indicated that Leo inhibited VCM nephrotoxicity via activating PPARγ and inhibiting the TLR4/NF-κB/TNF-α inflammation pathway. Taken together, our results indicate that the PPARγ inhibition and inflammation reactions were implicated in the VCM nephrotoxicity and provide a promising therapeutic strategy for renal injury.

Identification and validation of neutrophils-related subtypes and prognosis model in triple negative breast cancer.

BACKGROUND: Neutrophils are considered to be crucial players in the initiation and progression of cancer. However, the complex relationship between neutrophils and cancer prognosis remains elusive, mainly due to the significant plasticity and diversity exhibited by these immune cells. METHODS: As part of our thorough investigation, we examined 38 Neutrophils-Related Genes (NRGs) and the associated copy number variations (CNV), somatic mutations, and gene expression patterns in relation to triple negative breast cancer (TNBC). The interactions between these genes, their biological roles, and their possible prognostic significance were then examined. With the NRGs as our basis, we applied Lasso and Cox regression analyses to create a predictive model for overall survival (OS). Furthermore, TNBC tissue and a public database were used to assess changes in MYO1D expression (MYO1D is characterized as a member of the myosin-I family, a group of motor proteins based on actin), its connection to neutrophil infiltration, and the clinical importance of MYO1D in TNBC. RESULTS: Four neutrophil-related genes were included in the development of a prognostic model based on neutrophils. The model was further shown to be an independent predicted factor for overall survival by multivariate Cox regression analysis. According to this study, neutrophil subtype B as well as gene subtype B, were associated with activated cancer immunity and poor prognosis of TNBC patients. Furthermore, considering that poor OS was linked to increased MYO1D expression, MYO1D was increased in TNBC tissues and associated with neutrophil infiltration. In vitro experiments also confirmed that MYO1D facilitates breast cancer invasion and metastasis. CONCLUSION: Based on the degree of gene expression linked to neutrophils, a unique prognostic model was created. MYO1D could be a potential prognostic biomarker in TNBC patients and also a prospective target for therapy.

Integrative analysis of renal microRNA and mRNA to identify hub genes and pivotal pathways associated with cyclosporine-induced acute kidney injury in mice.

Cyclosporine (CsA) is an immunosuppressive agent that often causes acute kidney injury (AKI) in children. The specific mechanisms underlying CsA-induced AKI are currently unknown. This study used an integrated network analysis of microRNA (miRNA) and mRNA expression profiles, biochemical and pathological analyses to further investigate these potential mechanisms of CsA-induced AKI. Small RNA sequence analysis identified 25 differentially expressed miRNAs, RNA sequencing analysis identified 4,109 differentially expressed mRNAs. We obtained a total of 4,367 target genes from the 25 differentially expressed miRNAs based on three algorithms, including the Mirdb, Mirtarbase, and TargetScan. 971 target genes overlapped between the 4,367 target genes and 4,109 differentially expressed mRNAs were identified for further bioinformatics analysis. Finally, 30 hub genes and two main modules were recognized. Functional enrichment analysis of 30 hub genes indicated that inflammation and epithelial-mesenchymal transition (EMT) related genes were mainly concentrated together. Pathway analysis revealed that the PI3K-Akt signaling pathway plays an integral role in CsA-induced AKI. Network analysis identified 3 important miRNAs, mmu-miR-17b-5p, mmu-miR-19b-3p, and mmu-mir-423-5p that may further promote the development of inflammatory responses and EMT by mediating a complex network of factors. Our research provides a clearer understanding the molecular mechanism of this specific drug-induced AKI by CsA use, which is useful for discovering potential targets for gene therapies, and drug development in CsA-induced AKI.

Diagnostic value of contrast-enhanced ultrasonography in the preoperative evaluation of lymph node metastasis in papillary thyroid carcinoma: a single-center retrospective study.

BACKGROUND: Contrast-enhanced ultrasound (CEUS) has been recently used for the assessment of cervical lymph node metastasis (LNM) to guide surgical operation in patients with papillary thyroid carcinoma (PTC). However, the specificity and sensitivity of CEUS reported from previous studies are not consistent. The objective of this study was to evaluate the diagnostic value of CEUS for the metastasis of cervical lymph nodes in PTC patients based on data from one regional central hospital. METHODS: The diagnostic value of CEUS in preoperative LNM of PTC patients was concluded by comparing the results of CEUS on lymph node status with postoperative pathology examination. In addition, this study conducted hierarchical analysis of PTC patients to explore whether tumor size, different lymph node regions, and Hashimoto's thyroiditis influence the assessment of CEUS. RESULTS: This research study ultimately enrolled 965 PTC patients, including 266 males and 699 females with a mean age of 42.27 ± 11.34 years. A total of 527 patients were considered clinical-node negative, and 438 were clinical-node positive before surgery. The specificity, sensitivity, positive predictive value (PPV), negative predictive value (NPV) and accuracy of CEUS in the assessment of LNM in PTC patients were 56.00%, 71.00%, 57.06%, 69.76% and 62.59%, respectively. For central and lateral lymph nodes, the accuracy of CEUS in PTC patients was 49.43% and 54.30%, respectively. In addition, it was shown that the accuracy of CEUS in PTC patients with Hashimoto's thyroiditis (HT) slightly decreased to 58.44%, and the accuracy of CEUS in PTC patients with non-HT in turn increased to 64.17%. The accuracy of CEUS in non-papillary thyroid microcarcinoma (PTMC) and PTMC patients was 65.68% and 61.24%, respectively. The accuracy of CEUS in predicting central LNM was significantly different between PTC patients with or without HT (P < 0.001) in this study but not for lateral lymph nodes (P = 0.114). CONCLUSION: The accuracy of CEUS in the assessment of LNM in PTC is not consistently satisfactory, especially for central lymph nodes, small tumor diameters, or patients with HT. More diagnostic technologies for abnormal lymph nodes should be considered in PTC patients.

Analysis of kidney proteomes to identify biological pathways associated with vancomycin-induced nephrotoxicity in mice by tandem mass tag-labeled quantitative and parallel reaction monitoring phosphoproteomics.

Vancomycin (VCM)-induced nephrotoxicity impedes its treatment applications. Thus, it is important to clarify the relevant mechanism. This study investigated phosphoprotein changes attributable to the VCM nephrotoxicity mechanisms. Biochemical, pathological and phosphoproteomic analyses based on C57BL/6 mice were performed to explore the mechanisms.VCM-treated mice showed increased levels of blood urea nitrogen and creatinine, and signs of acute tubular necrotic lesions. Phosphoproteomic profiling identified 3025 differentially phosphorylated phosphopeptides between the model and control group. Gene Ontology enrichment analysis demonstrated that Molecular Function "oxidoreductase activity" and Cellular Component "peroxisome" were markedly enriched. KEGG pathway analysis identified an enrichment in peroxisome pathway and PPAR (peroxisome proliferator-activated receptor) signaling pathways. Parallel reaction monitoring analysis revealed a significant downregulation of CAT, SOD-1, AGPS, DHRS4, and EHHADH at phosphorylation level by VCM. Notably, the phosphorylation of ACO, AMACR, and SCPX was downregulated by VCM, which are the fatty acid ß-oxidation-related proteins involved in PPAR signaling pathways. The phosphorylated PEX5 involved in peroxisome biogenesis was upregulated by VCM. Collectively, these findings indicated that VCM-induced nephrotoxicity is closely associated with peroxisome pathway and PPAR signaling pathways. The current study provides important insight into the mechanisms of VCM nephrotoxicity and will aid in the development of preventive and therapeutic strategies against this nephropathy.

Targeting a novel circITCH/miR-421/BTG1 axis is effective to suppress the malignant phenotypes in hepatocellular carcinoma (HCC) cells.

Circular RNA-based competing endogenous RNA (ceRNA) networks contribute to the initiation and development of various types of cancer, including hepatocellular carcinoma (HCC). Although a novel circular RNA itchy E3 ubiquitin protein ligase (circITCH) is identified as a tumor suppressor in HCC, its detailed molecular mechanisms have not been fully delineated. The present study was designed to resolve this issue, and we firstly verified that circITCH suppressed the malignant phenotypes in HCC cells by regulating a novel miR-421/B-cell translocation gene 1 (BTG1) axis. Specifically, through performing the Real-Time qPCR analysis, we noticed that circITCH expression in HCC tumor tissues or cell lines were significantly lower than that in adjacent normal tissues or normal hepatocytes, and the expression levels of circITCH were negatively correlated with tumor size and TNM stage in HCC patients. Next, our functional experiments confirmed that overexpression of circITCH induced cell cycle arrest and apoptosis, and reduced cell viability and colony forming ability in Hep3B and Huh7 cells. Mechanically, bioinformatics analysis, RNA immunoprecipitation and luciferase reporter assay demonstrated that circITCH served as RNA sponges for miR-421 to elevate BTG1 levels in HCC cells. The rescuing experiments verified that upregulation of miR-421 promoted cell viability and colony formation, and reduced apoptosis, which were abrogated by overexpression of circITCH or BTG1. In conclusion, this study identified a novel circITCH/miR-421/BTG1 axis that restrained the development of HCC, and our findings provided novel biomarkers for the treatment of this disease.

Vancomycin Induced Ferroptosis in Renal Injury Through the Inactivation of Recombinant Glutathione Peroxidase 4 and the Accumulation of Peroxides.

Background: Vancomycin (VCM) has long been used clinically to fight against Gram-positive bacterial infections. In recent decades, an increased number of kidney injury cases caused by VCM overdose have been reported. In this study, we further investigated the mechanism of VCM-overdose-induced kidney injury. Methods: Immunohistochemistry (IHC) staining, RT-qPCR and Western blot assays were used to determine ki67, DDX5, PTGS2, GPX4 and SLC7A11 expressions in the kidney tissues of mice. CCK-8 and flow cytometry assays were used to determine HK2 cell viability and apoptosis. In addition, RT-qPCR and Western blot assays was applied to evaluate the expressions of ACSL4, PTGS2, GPX4, SLC7A11, DDX5 and Ki67 in HK2 cells. Results: We found that VCM induced ferroptosis in vitro and in vivo. Ferrostatin-1 (Fer-1) is a potent inhibitor of ferroptosis, Fer-1 rescued cell viability and renal function renal morphology in VCM-treated cells and mice, respectively. Further, GPX4, which plays an essential role in reducing lipid hydroperoxides and preventing ferroptosis, was observed to be downregulated by VCM treatment. Interestingly, we found that GPX4-knockdown HK-2 cells exhibited a similar phenotype and gene expression level of ACSL4, PTGS2, DDX5 and Ki67 compared with VCM-treated cells, which suggested that VCM could induce ferroptosis in HK2 cells by down-regulating GPX4. Conclusion: In conclusion, VCM induced renal injury in the kidney tissues of mice. In addition, VCM induced ferroptosis cell death in HK-2 cells and in the kidney tissues of mice by down-regulating GPX4 and causing the accumulation of peroxides. These data suggested that VCM could induce renal injury in vitro and in vivo via triggering ferroptosis. This study further elucidates the mechanism of VCM-induced renal injury and provides additional references for clinical use of VCM.

The impact of postmastectomy radiotherapy on cT1-2N1 breast cancer patients with ypN0 after neoadjuvant chemotherapy: a retrospective study based on real-world data.

BACKGROUND: The role of postmastectomy radiation therapy (PMRT) in clinical T1-2N1 breast cancer patients who achieve axillary pathological complete response (ypN0) after neoadjuvant chemotherapy (NAC) is controversial. METHODS: Data from cT1-2N1 breast cancer patients who converted to ypN0 after NAC and subsequent surgery were retrospectively analyzed. Disease-free survival (DFS) and overall survival (OS) were estimated using the Kaplan‒Meier method. Univariate and multivariate Cox regression models were applied to investigate the correlations between clinical or pathological parameters and survival. RESULTS: From 2012-2019, we identified 116 cases for analysis, including 31 (26.7%) who received PMRT and 85 (73.3%) who did not. At a median follow-up time of 56.4 months, the 5-year DFS and OS rates were 90.2% and 96.7% with PMRT and 93.7% and 97.3% without PMRT, respectively. PMRT did not affect either DFS (p = 0.234) or OS (p = 0.878). On multivariate analyses, no differences in DFS or OS between the two groups were detected, taking into consideration the following factors: age, molecular subtype, Ki67 index, cT stage, and in-breast pathologic complete response (DFS: HR 2.260; 95% CI 0.465-10.982; p = 0.312. OS: HR 1.400; 95% CI 0.138-14.202; p = 0.776). This nonsignificant difference was also consistent in subgroup analyses (all p > 0.05). CONCLUSIONS: PMRT has limited ability to confer DFS or OS benefits for cT1-2N1 breast cancer patients who achieved axillary pathological complete response after NAC and total mastectomy. It is imperative to conduct prospective studies to investigate the safety and feasibility of omitting PMRT. TRIAL REGISTRATION: This research was approved by the Ethics Committee of The First Affiliated Hospital of Chongqing Medical University (ID: No. 2021-442).

Delayed cutaneous hypersensitivity reactions following the use of infliximab or adalimumab in patients with coronavirus disease 2019.

Recent evidence has emerged concerning delayed cutaneous hypersensitivity reactions after infliximab or adalimumab applications in patients with coronavirus disease 2019 (COVID-19). A few real-world studies compared the events, clinical features, and prognosis of infliximab- or adalimumab-related delayed cutaneous hypersensitivity reactions in COVID-19 patients. Disproportionality analysis and Bayesian analysis were utilized to determine the suspected adverse events of delayed cutaneous hypersensitivity reactions after infliximab or adalimumab use based on the Food and Drug Administration's Adverse Event Reporting Systems (FAERS) from May 2020 to December 2021. Additionally, the times to onset and fatality rates of delayed cutaneous hypersensitivity reactions following infliximab or adalimumab were compared. In total, 475 reports of delayed cutaneous hypersensitivity reactions were associated with infliximab or adalimumab. Females were affected almost twice more than males. Among the two therapies, infliximab had the highest association with delayed cutaneous hypersensitivity reactions based on the highest reporting odds ratio (2.14, 95% two-sided confidence interval [CI] = 1.2-3.81), proportional reporting ratio (1.95, χ2 = 7.03), and empirical Bayesian geometric mean (1.94, 95% one-sided CI = 1.2). Infliximab-related delayed cutaneous hypersensitivity reactions had earlier onset (0 [interquartile range (IQR): 0-0] days vs. 166.5 (IQR: 18-889.5) days, p < 0.05), while adalimumab-related delayed cutaneous hypersensitivity reactions have higher fatality rate (0.44% vs. 0.00%). Based on the FAERS database, we profiled delayed cutaneous hypersensitivity reactions related to infliximab or adalimumab application in patients with COVID-19 with more points of occurrences, clinical characteristics, and prognosis.

Circular RNA ITCH increases sorafenib-sensitivity in hepatocellular carcinoma via sequestering miR-20b-5p and modulating the downstream PTEN-PI3K/Akt pathway.

BACKGROUNDS: Sorafenib-resistance leads to poor prognosis and high mortality in advanced hepatocellular carcinoma (HCC), and this study aims to investigate the functional role of a circular RNA ITCH (circITCH) in regulating the sorafenib-resistance of HCC and its underlying mechanisms. METHODS: The expression of circITCH in HCC tissues and cell lines were detected by performing quantitative real-time polymerase chain reaction. Sorafenib-resistant HCC cells were transfected with PLCDH-circITCH to upregulate circITCH and intervened with sorafenib, and MTT assay, flow cytometry and transwell assay were used to test the cell viability, apoptosis and migration ability, respectively. The downstream target of circITCH were explored by using bioinformatic analysis, dual luciferase reporter system and Western blot. RESULTS: CircITCH was significantly down-regulated in HCC tissues and cell lines, compared with their normal counterparts. Especially, in contrast with the sorafenib-sensitive HCC cells, continuous sorafenib treatment decreased the expression levels of circITCH in the sorafenib-resistant HCC cells. Overexpression of circITCH increased sorafenib-sensitivity, promoted cell apoptosis and reduced cell migration abilities in the sorafenib-resistant HCC cells. Mechanically, circITCH elevated PTEN expression to inactivate the PI3K/Akt signals through negatively regulating miR-20b-5p in HCC, and upregulating miR-20b-5p or inhibiting PTEN abolished the enhancing effect of circITCH overexpression on sorafenib-induced cytotoxicity in sorafenib-resistant HCC cells. CONCLUSION: Taken together, this study proves that circITCH enhances sorafenib-sensitivity in sorafenib-resistant HCC cells via regulating the miR-20b-5p/PTEN/PI3K/Akt signaling cascade, which highlights the potential value of circITCH as a target for enhancing the sorafenib-sensitivity in HCC.

Drug-induced liver injury following the use of tocilizumab or sarilumab in patients with coronavirus disease 2019.

BACKGROUNDS: Interleukin-6 (IL-6) blockers including tocilizumab and sarilumab were approved by the U.S. Food and Drug Administration (FDA) in June 2021 for the treatment of patients with moderate to severe COVID-19. The use of sarilumab or tocilizumab in COVID-19 patients has been related to a reduction in mortality compared to standard care. Recent evidence has emerged concerning drug-induced liver injury (DILI) after sarilumab or tocilizumab applications in COVID-19 patients. AIMS: The study aimed to estimate DILI associated with sarilumab or tocilizumab in treating moderate to severe patients infected with SARS-Cov-2. METHODS: We conducted a retrospective pharmacovigilance study by data mining of the FDA's adverse event reporting systems (FAERS) database from the first quarter of 2004 to the fourth quarter of 2021 in confirmed COVID-19 patients. We analyzed DILI cases associated with tocilizumab or sarilumab in treating COVID-19 patients from the FAERS during this period. Disproportionality analysis and Bayesian analysis of COVID-19 patients were utilized for case analysis, and we also next compared the onset time and fatality rates of DILI following tocilizumab or sarilumab. RESULTS: A total of 275 cases of TCZ or SAR-related DILI reports were extracted. A total of 192 AEs cases were related to tocilizumab (TCZ), and 83 were related to sarilumab (SAR). In patients treated with TCZ, most were < 75 years old (51.57%), with more male than female (46.35% vs. 13.02%). The correlation between IL-6 receptor antagonists and DILI was stronger in SAR (ROR = 12.94; 95%CI 9.6-17.44) than in TCZ (ROR = 1.33; 95%CI 1.14-1.55). The onset time of DILI was different between TCZ and SAR, and a significant difference was observed in TCZ than SAR (P < 0.0001). A significant difference was observed in the mortality rate of TCZ and SAR (P = 0.0009). DILI associated with COVID-19 patients treated with TCZ appeared to have earlier onset-time (1(0-46) day) VS. SAR (3.5(0-27) day). CONCLUSION: This study shows strict monitor ought to be paid for TCZ or SAR when used for COVID-19 patients with poor liver function.

The Regulatory Effects of Traditional Chinese Medicine on Ferroptosis.

Traditional Chinese medicine (TCM) has significantly contributed to protecting human health and promoting the progress of world civilization. A total of 2,711 TCMs are included in the 2020 version of the Chinese Pharmacopoeia, which is an integral part of the world's medical resources. Tu Youyou and her team discovered and purified artemisinin. And their contributions made the values and advantageous effects of TCM more and more recognized by the international community. There has been a lot of studies on TCM to treat diseases through antioxidant mechanisms, the reports on the new mechanisms beyond antioxidants of TCM has also increased year by year. Recently, many TCMs appear to have significant effects in regulating ferroptosis. Ferroptosis is an iron-dependent, non-apoptotic, regulated cell death characterized by intracellular lipid peroxide accumulation and oxidative membrane damage. Recently, accumulating studies have demonstrated that numerous organ injuries and pathophysiological process of many diseases are companied with ferroptosis, such as cancer, neurodegenerative disease, acute renal injury, arteriosclerosis, diabetes, and ischemia-reperfusion injury. This work mainly introduces dozens of TCMs that can regulate ferroptosis and their possible mechanisms and targets.

FGFR blockade boosts T cell infiltration into triple-negative breast cancer by regulating cancer-associated fibroblasts.

Background: Since T cell exclusion contributes to tumor immune evasion and immunotherapy resistance, how to improve T cell infiltration into solid tumors becomes an urgent challenge. Methods: We employed deep learning to profile the tumor immune microenvironment (TIME) in triple negative breast cancer (TNBC) samples from TCGA datasets and noticed that fibroblast growth factor receptor (FGFR) signaling pathways were enriched in the immune-excluded phenotype of TNBC. Erdafitinib, a selective FGFR inhibitor, was then used to investigate the effect of FGFR blockade on TIME landscape of TNBC syngeneic mouse models by flow cytometry, mass cytometry (CyTOF) and RNA sequencing. Cell Counting Kit-8 (CCK-8) assay and transwell migration assay were carried out to detect the effect of FGFR blockade on cell proliferation and migration, respectively. Cytokine array, western blot, enzyme-linked immunosorbent assay (ELISA) and immunofluorescence (IF) were employed to investigate the potential mechanism by which FGFR inhibition enhanced T cell infiltration. Results: Blocking FGFR pathway by Erdafitinib markedly suppressed tumor growth with increased T cell infiltration in immunocompetent mouse models of TNBC. Mechanistically, FGFR blockade inhibited cancer-associated fibroblasts (CAFs) proliferation, migration and secretion of vascular cell adhesion molecule 1 (VCAM-1) by down-regulating MAPK/ERK pathway in CAFs, thus promoting T cell infiltration by breaking physical and chemical barriers built by CAFs in TIME. Furthermore, we observed that FGFR inhibition combined with immune checkpoint blockade therapy (ICT) greatly improved the therapeutic response of TNBC tumor models. Conclusions: FGFR blockade enhanced ICT response by turning immune "cold" tumor into "hot" tumor, providing remarkable implications of FGFR inhibitors as adjuvant agents for combinatorial immunotherapy.

Antifungal Drugs and Drug-Induced Liver Injury: A Real-World Study Leveraging the FDA Adverse Event Reporting System Database.

Aims: We aimed to estimate the risk of drug-induced liver injury (DILI) from various antifungal treatments with azoles and echinocandins causing in real-world practice. Methods: We performed disproportionality and Bayesian analyses based on data from the first quarter in 2004 to the third quarter in 2021 in the Food and Drug Administration Adverse Event Reporting System to characterize the signal differences of antifungal drugs-related DILI. We also compared the onset time and mortality differences of different antifungal agents. Results: A total of 2943 antifungal drugs-related DILI were identified. Affected patients tended to be aged >45 years (51.38%), with more males than females (49.03% vs. 38.09%). Antifungal drug-induced liver injury is most commonly reported with voriconazole (32.45%), fluconazole (19.37%), and itraconazole (14.51%). Almost all antifungal drugs were shown to be associated with DILI under disproportionality and Bayesian analyses. The intraclass analysis of correlation between different antifungal agents and DILI showed the following ranking: caspofungin (ROR = 6.12; 95%CI: 5.36-6.98) > anidulafungin (5.15; 3.69-7.18) > itraconazole (5.06; 4.58-5.60) > voriconazole (4.58; 4.29-4.90) > micafungin (4.53; 3.89-5.27) > posaconazole (3.99; 3.47-4.59) > fluconazole (3.19; 2.93-3.47) > ketoconazole (2.28; 1.96-2.64). The onset time of DILI was significantly different among different antifungal drugs (p < 0.0001), and anidulafungin result in the highest mortality rate (50.00%), while ketoconazole has the lowest mortality rate (9.60%). Conclusion: Based on the Food and Drug Administration Adverse Event Reporting System database, antifungal drugs are significantly associated with DILI, and itraconazole and voriconazole had the greatest risk of liver injury. Due to indication bias, more clinical studies are needed to confirm the safety of echinocandins.

Stevens-Johnson Syndrome Following Vancomycin and Linezolid: A Real-World Analysis of Post-Marketing Surveillance Data.

Background: Stevens-Johnson syndrome (SJS) has been reported as a serious adverse effect in patients treated with vancomycin or linezolid, and there is currently a lack of real-world studies comparing specific differences in adverse effects of SJS. Methods: According to the FDA's Adverse Event Reporting System (FAERS), from January 2004 to July 2021, the data of suspected SJS after the use of vancomycin and linezolid were analyzed by imbalance and Bayesian analysis. The onset time, fatality rate and hospitalization rate of vancomycin-associated SJS and linezolid-associated SJS were also investigated. Results: 276 cases of vancomycin-related SJS reports and 63 cases of linezolid-related SJS reports were identified. These two drugs are more common in middle-aged patients (45-64 years) than other age groups, and less common in underage children (<18). Among them, linezolid-related SJS is more common in middle-aged and elderly patients (45-74 years old) than other groups. Except for unspecified data, in vancomycin-associated SJS cases, there are more men than women (49.28% vs 43.84%), while in linezolid-associated SJS cases, the proportion of men and women is almost equal (44.44%). From the point of view of the areas where adverse reactions were reported, about 1/2 of the reports on Vancomycin-related SJS came from North America, and 1/3 of the reports came from Europe. The median onset time of Linezolid-related SJS was 5 days (interquartile range [IQR] 2-7.75), which was significantly earlier than that of Vancomycin-related SJS (12 days, IQR 4-20) (Mann-Whitney test, p < 0.0001). There were no significant differences in mortality and hospitalization rates after vancomycin and linezolid caused SJS. Conclusion: The analysis of faers data provides a comprehensive overview of the adverse reactions of SJS caused by the use of vancomycin and linezolid, and can warn clinical workers to timely intervene and continuously monitor the patients at risk of SJS when using such drugs.

Stevens-Johnson Syndrome Following Non-steroidal Anti-inflammatory Drugs: A Real-World Analysis of Post-marketing Surveillance Data.

Background: The Stevens-Johnson syndrome (SJS) is a severe skin reaction to non-steroidal anti-inflammatory drugs (NSAIDs), and can even be life-threatening. However, there are still few real-world studies to compare the specific differences in the adverse effects of skin and mucosal invasion. Methods: Disproportionality analysis and Bayesian analysis were devoted to data-mining of the suspected SJS after using NSAIDs based on the FDA's Adverse Event Reporting System (FAERS) from January 2004 to March 2021. The times to onset, fatality, and hospitalization rates of antipyretic analgesic-associated SJS were also investigated. Results: A total of 1,868 reports of SJS adverse events were identified with NSAIDs. Among 5 NSAIDs monotherapies we studied (acetaminophen, ibuprofen, aspirin, diclofenac and celecoxib), ibuprofen had the highest association with SJS based on the highest reporting odds ratio (ROR = 7.06, 95% two-sided CI = 6.59-7.56), proportional reporting ratio (PRR = 6.98, χ2 = 4201.14) and empirical Bayes geometric mean (EBGM = 6.78, 95% one-sided CI = 6.40). However, ibuprofen-associated SJS had the lowest fatality rate (6.87%, p < 0.0001) and the highest hospitalization rate (79.27%, p < 0.0001). Celecoxib-associated SJS had the latest time to onset (317.56 days, p < 0.0001). Diclofenac-associated SJS cases appeared to be associated with the highest risk of death (25.00%, p < 0.0001). Conclusions: The analysis of FAERS data provides a more accurate profile of the incidence and prognosis of SJS after NSAIDs treatment, enabling continued surveillance and timely intervention in patients at risk of SJS following these NSAIDs.

Severe Bilateral Hyperkeratosis of the Nipples and Areolae: A Case Report and Literature Review.

Background: Hyperkeratosis of the nipple and areola (HNA) is a rare skin disease with unknown etiology. Some patients are misdiagnosed or never diagnosed, especially during the early stage of this disease. In addition, the mechanism involved in the development of HNA is still unknown, and genomic alterations have not been reported anywhere. Case Information: A 26-year-old female suffered gradual bilateral areola thickening and enlargement, with accompanying intense itching, and was diagnosed with HNA at the First Affiliated Hospital of Chongqing Medical University. No obvious abnormalities were found in laboratory test examinations such as hormone testing for estrogen, progesterone, or prolactin. Typical papillomatous skin with orthokeratotic hyperkeratosis and numerous infiltrating lymphocytes was detected through a histopathological examination. The results from RNA-sequencing showed that the molecular expression between HNA and a normal nipple and areola (NNA) was obviously different. No significant difference was found in the bilateral lesions. In addition, immune-related cell signaling pathways were overactivated in HNA compared to the control HNA. Conclusion: The typical symptoms, clinical features, and histopathological alterations presented in this case lead to a profound understanding of HNA, which can avoid the misdiagnosis and missed diagnosis of this disease at an early stage. The dysfunction of the local immune system, which was demonstrated by pathological examination and genomic analysis, suggests that anti-autoimmune therapy, such as steroid medication, may be an effective treatment for HNA at an early stage.

The allergy mediator histamine confers resistance to immunotherapy in cancer patients via activation of the macrophage histamine receptor H1.

Reinvigoration of antitumor immunity remains an unmet challenge. Our retrospective analyses revealed that cancer patients who took antihistamines during immunotherapy treatment had significantly improved survival. We uncovered that histamine and histamine receptor H1 (HRH1) are frequently increased in the tumor microenvironment and induce T cell dysfunction. Mechanistically, HRH1-activated macrophages polarize toward an M2-like immunosuppressive phenotype with increased expression of the immune checkpoint VISTA, rendering T cells dysfunctional. HRH1 knockout or antihistamine treatment reverted macrophage immunosuppression, revitalized T cell cytotoxic function, and restored immunotherapy response. Allergy, via the histamine-HRH1 axis, facilitated tumor growth and induced immunotherapy resistance in mice and humans. Importantly, cancer patients with low plasma histamine levels had a more than tripled objective response rate to anti-PD-1 treatment compared with patients with high plasma histamine. Altogether, pre-existing allergy or high histamine levels in cancer patients can dampen immunotherapy responses and warrant prospectively exploring antihistamines as adjuvant agents for combinatorial immunotherapy.

Gut Microbiome and Serum Metabolome Profiles of Capsaicin with Cognitive Benefits in APP/PS1 Mice.

Capsaicin, a natural bioactive component, has been reported to improve cognition and ameliorate the pathology of Alzheimer's disease (AD). Studies have linked AD to alterations in gut microbiota composition and serum metabolites. In the present study, we examined the alterations in serum metabolome and gut microbiome in APPswe/PS1dE9 (APP/PS1) mice treated with capsaicin. Capsaicin treatments resulted in a significant increase in the abundance of Akkermansia, Faecalibaculum, Unclassified_f_Atopobiaceae, and Gordonibacter and a significant decrease in the abundance of Adlercreutzia, Peptococcaceae, Alistipes, Oscillibacter and Erysipelatoclostridium. Furthermore, the species Akkermansia muciniphila (A. muciniphila) was significantly enriched in capsaicin-treated APP/PS1 mice (p = 0.0002). Serum metabolomic analysis showed that capsaicin-treated APP/PS1 mice had a significant higher level of tryptophan (Trp) metabolism and a significantly lower level of lipid metabolism compared with vehicle-treated mice. Capsaicin altered serum metabolites, including Kynurenine (Kyn), 5-Hydroxy-L-tryptophan (5-HIT), 5-Hydroxyindoleacetic acid (5-HIAA), indoxylsulfuric acid, lysophosphatidyl cholines (LysoPCs), and lysophosphatidyl ethanolamine (LysoPE). Significant correlations were observed between the gut bacteria and serum metabolite. With regard to the increased abundance of A. muciniphila and the ensuing rise in tryptophan metabolites, our data show that capsaicin alters both the gut microbiota and blood metabolites. By altering the gut microbiome and serum metabolome, a diet high in capsaicin may reduce the incidence and development of AD.

AMPD1 Is Associated With the Immune Response and Serves as a Prognostic Marker in HER2-Positive Breast Cancer.

BACKGROUND: Although immunotherapy has been used in the treatment of metastatic triple negative breast cancer (TNBC), its therapeutic influence on human epidermal growth factor receptor 2 (HER2)-positive subtype remains controversial. It is therefore imperative to find biomarkers that can predict the immune response in HER2+ BC. METHODS: ESTIMATE was utilized to compute the ImmuneScore and StromalScore from data obtained from TCGA database, and differentially expressed genes (DEGs) were identified. In addition, univariate Cox regression was used to assess candidate genes such as AMPD1, CD33, and CCR5. Gene set enrichment analysis (GSEA) was used to further understand AMPD1-associated pathways. Moreover, immunohistochemical analyses were performed to further reveal the relationship among AMPD1, CD4 and CD8 genes. RESULTS: The expression of AMPD1 was markedly associated with disease outcome and tumor-infiltrating immune cells (TICs). In addition, AMPD1 was associated with lymph node status, age and the expression of PD-L1 and PD-L2. High AMPD1 expression was linked to longer overall survival (OS). Upregulated expression of AMPD1 correlated with the enrichment of immune-related signaling pathways. In addition, immunohistochemical analyses demonstrated a co-expression profile among AMPD1, CD4 and CD8 genes. CONCLUSIONS: Taken together, our data demonstrated that AMPD1 might serve as a novel biomarker for predicting the immune response and disease outcome in HER2+ BC.