Establishment of a trastuzumab-resistant extramammary Paget disease model: loss of PTEN as a potential mechanism.

BACKGROUND/OBJECTIVES: Extramammary Paget disease (EMPD) is a rare, cutaneous intraepithelial adenocarcinoma typically treated with wide local excision. Unfortunately, a number of patients with metastases show poor responses to chemotherapy. While some studies have explored trastuzumab's effectiveness against EMPD positive for human epidermal growth factor receptor 2 (HER2), trastuzumab resistance (TR) may emerge after anti-HER2 therapy. METHODS/SUBJECTS: In this study, we established TR EMPD patient-derived xenografts (PDX) that replicated the histological and HER2 expression traits of naive EMPD tumours. RESULTS: Cancer gene analyses revealed a loss of the PTEN gene in TR tumours, which was further confirmed by immunohistochemical staining and immunoblotting to test for protein expression levels. Reduced PTEN levels correlated with increased protein kinase B (Akt) phosphorylation and p27 downregulation, suggesting a potential mechanism for trastuzumab resistance in EMPD cells. In the trastuzumab-sensitive EMPD-PDX mouse model, PTEN inhibitors partially restored trastuzumab-mediated tumour regression. The TR EMPD-PDX responded favourably to targeted therapy (lapatinib, abemaciclib, palbociclib) and chemotherapy (eribulin, docetaxel, trastuzumab deruxtecan). CONCLUSIONS: This study demonstrates an innovative TR EMPD-PDX model and introduces promising antineoplastic effects with various treatments for TR EMPD tumours.

Association Between Serum Total IgE Levels and Clinical Response to Omalizumab for Chronic Spontaneous Urticaria: A Systematic Review and Meta-Analysis.

BACKGROUND: Omalizumab is the only biological agent approved for patients with chronic spontaneous urticaria (CSU), but no biomarker is well established for predicting clinical response to omalizumab. OBJECTIVE: We aimed to determine the association between baseline total serum IgE levels and the effects of omalizumab in patients with CSU. METHODS: PubMed, Web of Science, Scopus, and Cochrane Library were systematically searched for relevant studies from inception to August 23, 2022. The research protocol was registered on PROSPERO (CRD42022355592). No language restrictions were applied. A random-effects model was used for meta-analysis. RESULTS: Ten interventional studies, including 1 randomized controlled trial, were included in the final meta-analysis, and a total of 866 patients with CSU were included. A pooled analysis showed significantly higher serum total IgE levels in complete responders (CRs) than in nonresponders (NRs) (mean difference [MD]: 56.509 IU/mL; 95% confidence interval [CI]: 24.230-88.789) and in partial responders (PRs) than in NRs (MD: 62.688 IU/mL; 95% CI: 32.949-92.427), but no significant difference was detected between CRs and PRs. The mean total IgE levels for CRs, PRs, and NRs were 163.154, 179.926, and 51.535 IU/mL, respectively. Further, the serum total IgE levels in early CRs were significantly higher compared with late CRs (MD: 55.194 IU/mL; 95% CI: 13.402-96.986). The sensitivity analyses with the leave-one-out method validated the robustness of all findings. CONCLUSIONS: This systematic review and meta-analysis provide convincing evidence that pretreatment total serum IgE levels in patients with CSU are associated with clinical responses to omalizumab.

Eribulin inhibits growth of cutaneous squamous cell carcinoma cell lines and a novel patient-derived xenograft.

Advanced cutaneous squamous cell carcinoma (cSCC) is treated with chemotherapy and/or radiotherapy, but these typically fail to achieve satisfactory clinical outcomes. There have been no preclinical studies to evaluate the effectiveness of eribulin against cSCC. Here, we examine the effects of eribulin using cSCC cell lines and a novel cSCC patient-derived xenograft (PDX) model. In the cSCC cell lines (A431 and DJM-1 cells), eribulin was found to inhibit tumor cell proliferation in vitro as assessed by cell ATP levels. DNA content analysis by fluorescence-activated cell sorting (FACS) showed that eribulin induced G2/M cell cycle arrest and apoptosis. In xenograft models of cSCC cell lines, the administration of eribulin suppressed tumor growth in vivo. We also developed a cSCC patient-derived xenograft (PDX) which reproduces the histological and genetic characteristics of a primary tumor. Pathogenic mutations in TP53 and ARID2 were detected in the patient's metastatic tumor and in the PDX tumor. The cSCC-PDX responded well to the administration of eribulin and cisplatin. In conclusion, the present study shows the promising antineoplastic effects of eribulin in cSCC. Also, we established a novel cSCC-PDX model that preserves the patient's tumor. This PDX could assist researchers who are exploring innovative therapies for cSCC.

Smoking Cessation Rate and Its Predictors among Heavy Smokers in a Smoking-Free Hospital in Taiwan.

Smoking poses critical risks for heart disease and cancers. Heavy smokers, defined as smoking more than 30 pack-year, are the most important target for smoking cessation. This study aimed to obtain the cessation rate and its predictors among heavy smokers. We collected data from heavy smokers who visited a smoking-free hospital in Taiwan during 2017. All patients were prescribed either varenicline or nicotine replacement therapy (NRT) for smoking cessation, and their smoking status was followed for six months. Successful smoking cessation was defined by self-reported no smoking over the preceding seven days (7-day point abstinence). In total, 280 participants with a mean aged of 53.5 years were enrolled, and 42.9% of participants successfully stopped smoking in 6 months. The results revealed that quitters were older, with hypertension, fewer daily cigarettes, and being prescribed with varenicline. Multiple logistic regressions analyses identified that fewer daily cigarettes and being prescribed with varenicline were predictors of successful smoking cessation. Therefore, we suggest that varenicline use may help heavy smokers in smoking cessation.

TRIM29 in Cutaneous Squamous Cell Carcinoma.

Tripartite motif (TRIM) proteins play important roles in a wide range of cell physiological processes, such as signal transduction, transcriptional regulation, innate immunity, and programmed cell death. TRIM29 protein, encoded by the ATDC gene, belongs to the RING-less group of TRIM protein family members. It consists of four zinc finger motifs in a B-box domain and a coiled-coil domain, and makes use of the B-box domain as E3 ubiquitin ligase in place of the RING. TRIM29 was found to be involved in the formation of homodimers and heterodimers in relation to DNA binding; additional studies have also demonstrated its role in carcinogenesis, DNA damage signaling, and the suppression of radiosensitivity. Recently, we reported that TRIM29 interacts with keratins and FAM83H to regulate keratin distribution. Further, in cutaneous SCC, the expression of TRIM29 is silenced by DNA methylation, leading to the loss of TRIM29 and promotion of keratinocyte migration. This paper reviews the role of TRIM family proteins in malignant tumors, especially the role of TRIM29 in cutaneous SCC.

Gut Microbiome in Psoriasis is Perturbed Differently During Secukinumab and Ustekinumab Therapy and Associated with Response to Treatment.

BACKGROUND AND OBJECTIVE: Immunotherapy could change the complex host-microbial interactions. We aimed to investigate the dynamics of gut microbiome in response to secukinumab [an interleukin (IL)-17 inhibitor] and ustekinumab (an IL-12/23 inhibitor) therapy and its association with treatment response in psoriasis. METHODS: This observational, longitudinal study collected a total of 114 fecal samples from 12 healthy controls and 34 patients with psoriasis at baseline and 3 and 6 months after secukinumab (n = 24) or ustekinumab treatment (n = 10) and gut microbiomes were investigated using next-generation sequencing targeting 16S ribosomal RNA. RESULTS: Secukinumab treatment causes more profound alterations in gut microbiome, including increases in the relative abundance of phylum Proteobacteria and decreases in Bacteroidetes and Firmicutes, than ustekinumab treatment. The relative abundance of family Pseudomonadaceae, family Enterobacteriaceae and order Pseudomonadales also increased significantly following secukinumab therapy. In contrast, there was no significant change in gut microbiome composition following ustekinumab treatment, and only genus Coprococcus significantly increased after 6 months of ustekinumab therapy. Moreover, we observed significant differences in baseline gut microbiome between responders and non-responders to secukinumab treatment. CONCLUSION: These results indicate that gut microbiome is altered differently after anti-IL17 and anti-IL12/23 treatment. Secukinumab (anti-IL17) therapy is associated with distinct and more profound gut microbiome shifts than ustekinumab therapy (anti-IL 12/23) in patients with psoriasis. Moreover, gut microbiome would serve as potential biomarkers of response to secukinumab treatment.

Immunopathological effects of Agaricus blazei Murill polysaccharides against Schistosoma mansoni infection by Th1 and NK1 cells differentiation.

In this study, we examined the ability of A. blazei Murill polysaccharides (AB-PS) to activate the immune system in vivo and the protective activity exhibited against parasitic S. mansoni in the murine model. AB-PS treatment significantly reduced the worm and egg burden in infected BALB/c and C57BL/6 mice with dose- and time-dependent manners. Additionally, a dose- and time-dependent expression of IL-2, INF-γ, and TNF-α cytokines was also observed in both strains of mice treatments. Using T1/T2 doubly transgenic mice, we demonstrated that AB-PS-treated mice splenocytes initiated early differentiation of Th1 and NK1 cells, which was consistent with the reduction course of Schistosoma infection. Although AB-PS treatment enhanced the Th1 response, it did not suppress Th2 cell activity in treated mice. Histopathological data of the livers showed AB-PS treatment significantly attenuated the liver fibrosis induced by S. mansoni eggs. AB-PS augmented type-1 responses by inducing Th1 and NK1 cell differentiation to effectively decrease the infection rate of S. mansoni. Furthermore, AB-PS treatment may not only inhibit the schistosome infection, but also improving the pathological effects of granulomas formation. This study provides evidence for a novel therapeutic potential, by which A. blazei Murill may be used to treat or prevent schistosome infection.

Utility of Gram staining for diagnosis of Malassezia folliculitis.

Malassezia folliculitis (MalF) mimics acne vulgaris and bacterial folliculitis in clinical presentations. The role of Gram staining in rapid diagnosis of MalF has not been well studied. In our study, 32 patients were included to investigate the utility of Gram staining for MalF diagnosis. The final diagnoses of MalF were determined according to clinical presentation, pathological result and treatment response to antifungal agents. Our results show that the sensitivity and specificity of Gram staining are 84.6% and 100%, respectively. In conclusion, Gram staining is a rapid, non-invasive, sensitive and specific method for MalF diagnosis.

In vivo immunomodulatory effects of Antrodia camphorata polysaccharides in a T1/T2 doubly transgenic mouse model for inhibiting infection of Schistosoma mansoni.

Antrodia camphorata (A. camphorata) is a fungus commonly used for treatment of viral hepatitis and cancer in Chinese folk medicine. Extract of A. camphorate is reported to possess anti-inflammatory, antihepatitis B virus and anticancer activities. In this study, we tested the in vivo effects of polysaccharides derived from A. camphorata (AC-PS) on immune function by detection of cytokine expression and evaluation of the immune phenotype in a T1/T2 doubly transgenic mouse model. The protective effect of AC-PS in mice was tested by infection with Schistosoma mansoni. The induction of large amounts of IFN-gamma, IL-2 and TNF-alpha mRNA were detected after 2 and 4 weeks of oral AC-PS administration in BALB/c and C57BL/6 mice. In transgenic mice, 3 to 6 weeks of oral AC-PS administration increased the proportion of CD4(+) T cells and B cells within the spleen. More specifically, there was an increase of Th1 CD4(+) T cells and Be1 cells among spleen cells as observed by detection the of Type1/Type2 marker molecules. By using a disease model of parasitic infection, we found that AC-PS treatment inhibited infection with S. mansoni in BALB/C and C57BL/6 mice. AC-PS appears to influence the immune system of mice into developing Th1 responses and have potential for preventing infection with S. mansoni.

Negative regulation of protease-activated receptor 1-induced Src kinase activity by the association of phosphocaveolin-1 with Csk.

Protease-activated receptor 1 (PAR1), a G protein-coupled receptor (GPCR) for thrombin, has been correlated with cell proliferation. PAR1 is activated by the irreversibly proteolytic cleavage, internalized via clathrin-coated pits, and then sorted to lysosomes for degradation. Caveolae play important roles in both signaling transduction and internalization of several GPCRs. However, the role of caveolae in cellular signaling and trafficking of PAR1 is still unclear. In this study, we show that PAR1 was partially localized in caveolae. Disruption of caveolae by cholesterol depletion did not inhibit PAR1 internalization, indicating that internalization of PAR1 was not via caveolae. Of interest, activation of PAR1 resulted in the phosphorylation of caveolin-1, a principal component of caveolae, on tyrosine 14 by a Gi-linked Src kinase pathway and p38 mitogen-activated protein kinase. Analysis of immunoprecipitates from cells stimulated by PAR1 showed that phosphocaveolin-1 but not caveolin-1 with mutation at tyrosine 14 could bind to Csk. In addition, phosphocaveolin-1 could not bind to CskS109C mutant with the defective SH2 domain. These results indicated that phosphocaveolin-1 was associated with the SH2 domain of Csk in response to PAR1 activation. The association further resulted in a rapid decrease in Src kinase activity. Thus, PAR1-induced Src activation is negatively regulated by recruiting Csk through phosphocaveolin-1. Our results also reveal that phosphocaveolin-1 represents a novel effector of PAR1 to downregulate Src kinase activity. The downregulation of PAR1-induced Src activation mediated by phosphocaveolin-1 provides an additional mechanism for the termination of PAR1 signaling at its downstream molecules.