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Colorectal cancer (CRC) is one of the most common cancers and is the second leading cause of cancer-related death in the world. Due to the westernization of diets, young patients with CRC are often diagnosed at advanced stages with an associated poor prognosis. Improved lifestyle choices are one way to minimize CRC risk. Among diet choices is the inclusion of bee propolis, long recognized as a health supplement with anticancer activities. Understanding the effect of propolis on the gut environment is worth exploring, and especially its associated intratumoral immune changes and its anticancer effect on the occurrence and development of CRC. In this study, early stage CRC was induced with 1,2-dimethylhydrazine (DMH) and dextran sulfate sodium (DSS) for one month in an animal model, without and with propolis administration. The phenotypes of early stage CRC were evaluated by X-ray microcomputed tomography and histologic examination. The gut immunity of the tumor microenvironment was assessed by immunohistochemical staining for tumor-infiltrating lymphocytes (TILs) and further comparative quantification. We found that the characteristics of the CRC mice, including the body weight, tumor loading, and tumor dimensions, were significantly changed due to propolis administration. With further propolis administration, the CRC tissues of DMH/DSS-treated mice showed decreased cytokeratin 20 levels, a marker for intestinal epithelium differentiation. Additionally, the signal intensity and density of CD3+ and CD4+ TILs were significantly increased and fewer forkhead box protein P3 (FOXP3) lymphocytes were observed in the lamina propria. In conclusion, we found that propolis, a natural supplement, potentially prevented CRC progression by increasing CD3+ and CD4+ TILs and reducing FOXP3 lymphocytes in the tumor microenvironment of early stage CRC. Our study could suggest a promising role for propolis in complementary medicine as a food supplement to decrease or prevent CRC progression. [ABSTRACT FROM AUTHOR]

Inflammatory bowel disease (IBD) is associated with dysbiosis and intestinal barrier dysfunction, as indicated by epithelial hyperpermeability and high levels of mucosal-associated bacteria. Changes in gut microbiota may be correlated with IBD pathogenesis. Additionally, microbe-based treatments could mitigate clinical IBD symptoms. Plasmon-activated water (PAW) is known to have an anti-inflammatory potential. In this work, we studied the association between the anti-inflammatory ability of PAW and intestinal microbes, thereby improving IBD treatment. We examined the PAW-induced changes in the colonic immune activity and microbiota of mice by immunohistochemistry and next generation sequencing, determined whether drinking PAW can mitigate IBD induced by 2,4,6-trinitrobenzene sulfonic acid (TNBS) and dysbiosis through mice animal models. The effects of specific probiotic species on mice with TNBS-induced IBD were also investigated. Experimental results indicated that PAW could change the local inflammation in the intestinal microenvironment. Moreover, the abundance of Akkermansia spp. was degraded in the TNBS-treated mice but elevated in the PAW-drinking mice. Daily rectal injection of Akkermansia muciniphila, a potential probiotic species in Akkermansia spp., also improved the health of the mice. Correspondingly, both PAW consumption and increasing the intestinal abundance of Akkermansia muciniphila can mitigate IBD in mice. These findings indicate that increasing the abundance of Akkermansia muciniphila in the gut through PAW consumption or other methods may mitigate IBD in mice with clinically significant IBD. [ABSTRACT FROM AUTHOR]

Use of prebiotics is a growing topic in healthcare. A lightweight molecule and water-soluble fiber ingredient, longish glucomannan hydrolysates (LGH), has been developed to improve the intestinal mucosal barrier and confer gut health benefits. This study aims to investigate the implications of continuous LGH intervening in intestinal epithelium integrity and protective immunity against chemical dextran sodium sulfate (DSS)-induced colitis. Twelve male BALB/c mice were randomly arranged into four groups. The LGH/DSS group had results in bodyweight variance, epithelial cell density, and aberrancy score as good as the LGH group, and both were equivalent to the control group. LGH consumption effectively protects the distal intestinal epithelium by activating innate T lymphocytes. Meanwhile, T-cell subsets in subepithelial interspersion take a bystander role in these microenvironmental alterations. Under this stress, the cluster of differentiation 3 (CD3)+ T cells infiltrate the epithelium, while CD4+ T cells inversely appear in submucosal large lymphoid aggregates/isolated lymphoid follicles (ILFs) in which significant CD3+, CD4+, and CD8+ T-cell populations agglomerate. Moreover, forkhead box P3 (Foxp3) and interleukin 17 (IL-17) are observed in these ILFs. Agglomerated CD4+ T-cell lineages may have roles with proinflammatory T helper 17 cells and anti-inflammatory regulatory T cells in balancing responses to intraluminal antigens. Collectively, LGH administration may function in immune modulation to protect against DSS-induced inflammation. [ABSTRACT FROM AUTHOR]

Pancreatic adenocarcinoma (PAC) is the 8th leading cause of cancer-related deaths in Taiwan, and its incidence is increasing. The development of PAC involves successive accumulation of multiple genetic alterations. Understanding the molecular pathogenesis and heterogeneity of PAC may facilitate personalized treatment for PAC and identify therapeutic agents. We performed tumor-only next-generation sequencing (NGS) with targeted panels to explore the molecular changes underlying PAC patients in Taiwan. The Ion Torrent Oncomine Comprehensive Panel (OCP) was used for PAC metastatic lesions, and more PAC samples were sequenced with the Ion AmpliSeq Cancer Hot Spot (CHP) v2 panel. Five formalin-fixed paraffin-embedded (FFPE) metastatic PAC specimens were successfully assayed with OCP, and KRAS was the most prevalent alteration, which might contraindicate the use of anti-EGFR therapy. One PAC patient harbored a FGFR2 p. C382R mutation, which might benefit from FGFR tyrosine kinase inhibitors. An additional 38 samples assayed with CHP v2 showed 100 hotspot variants, collapsing to 54 COSMID IDs. The most frequently mutated genes were TP53, KRAS, and PDGFRA (29, 23, 10 hotspot variants), impacting 11, 23, and 10 PAC patients. Highly pathogenic variants, including COSM22413 (PDGFRA, FATHMM predicted score: 0.88), COSM520, COSM521, and COSM518 (KRAS, FATHMM predicted score: 0.98), were reported. By using NGS with targeted panels, somatic mutations with therapeutic potential were identified. The combination of clinical and genetic information is useful for decision making and precise selection of targeted medicine. [ABSTRACT FROM AUTHOR]

Periodontal disease (PD) is one of the most prevalent disorders globally and is strongly associated with many other diseases. Inflammatory bowel disease (IBD), an inflammatory condition of the colon and the small intestine, is reported to be associated with PD through undetermined mechanisms. We analyzed taxonomic assignment files from the Crohn's Disease Viral and Microbial Metagenome Project (PRJEB3206). The abundance of Porphyromonadaceae in fecal samples was significantly different between patients with Crohn's disease and control volunteers. Dextran sulfate sodium was used to induce colitis in mice to reveal the effect of this periodontopathic pathogen in vivo. After intrarectal implantation of Porphyromonas gingivalis (Pg)—the primary pathogen causing PD—the disease activity index score, colonic epithelial loss, and inflammatory cell infiltration were intensified. In addition, tumor necrosis factor-α and interleukin-6 showed the highest levels in Pg-infected colons. This revealed the importance of Pg in the exacerbation of IBD. Thus, simultaneous treatment of PD should be considered for people with IBD. Moreover, implantation of Pg in the rectum worsened the clinical symptoms of colitis in mice. Because Pg participates in the pathogenesis of IBD, reducing the chances of it entering the intestine might prevent the worsening of this disorder. [ABSTRACT FROM AUTHOR]

In bladder cancer, urothelial carcinoma is the most common histologic subtype, accounting for more than 90% of cases. Pathogenic effects due to the dysbiosis of gut microbiota are localized not only in the colon, but also in regulating bladder cancer distally. Butyrate, a short-chain fatty acid produced by gut microbial metabolism, is mainly studied in colon diseases. Therefore, the resolution of the anti-cancer effects of butyrate-producing microbes on bladder urothelial cells and knowledge of the butyrate-responsive molecules must have clinical significance. Here, we demonstrate a correlation between urothelial cancer of the bladder and Butyricicoccus pullicaecorum. This butyrate-producing microbe or their metabolite, butyrate, mediated anti-cancer effects on bladder urothelial cells by regulating cell cycle, cell growth, apoptosis, and gene expression. For example, a tumor suppressor against urothelial cancer of the bladder, bladder cancer-associated protein, was induced in butyrate-treated HT1376 cells, a human urinary bladder cancer cell line. In conclusion, urothelial cancer of the bladder is a significant health problem. To improve the health of bladder urothelial cells, supplementation of B. pullicaecorum may be necessary and can further regulate butyrate-responsive molecular signatures. [ABSTRACT FROM AUTHOR]

Simple Summary: Although the incidence of thyroid cancer is increasing, improvements in treatment have resulted in more patients being confirmed to have a second primary cancer. However, studies on potential biomarkers for predicting the risk of second primary malignancy are extremely limited. Therefore, our objective was to establish molecular biomarkers for the risk prediction of second primary malignancy using routinely collected formalin-fixed paraffin-embedded tissue specimens. Our results suggest that the deficient mismatch repair phenotype, the expression of pRb, and the lack of CDK4 or CDK6 are significantly associated with co-occurrence of nonthyroid malignancy. The predictive value of these immunohistochemical profiles for the co-occurrence of nonthyroid malignancy was also assessed. The combined evaluation of a four-biomarker signature model may provide the most important predictive innovation. Our study proposes the first tissue-based screening tool for risk stratification and further active surveillance in patients with thyroid cancer. Some patients with thyroid cancer develop a second primary cancer. Defining the characteristics of patients with double primary cancers (DPCs) is crucial and needs to be followed. In this study, we examine molecular profiles in DPC. We enrolled 71 patients who received thyroid cancer surgery, 26 with single thyroid cancer (STC), and 45 with DPC. A retrograde cohort was used to develop immunohistochemical expressions of mismatch repair (MMR) proteins and cell-cycle-related markers from tissue microarrays to produce an equation for predicting the occurrence of DPC. The multivariate logistic model of 67 randomly selected patients (24 with STC and 43 with DPC) identified that the expression of deficient MMR (dMMR) (odds ratio (OR), 10.34; 95% confidence interval (CI), 2.17–49.21) and pRb (OR, 62.71; 95% CI, 4.83–814.22) were significantly associated with a higher risk of DPC. In contrast, the expression of CDK4 (OR, 0.19; 95% CI, 0.04–0.99) and CDK6 (OR, 0.03; 95% CI, 0.002–0.44) was significantly associated with a lower risk of DPC. Collectively, dMMR, pRb, CDK4, and CDK6 have a sensitivity of 88.9% (95% CI, 75.1–95.8) and a specificity of 69.2% (95% CI, 48.1–84.9) for occurrence of DPC in all 71 patients. This is the first report to demonstrate the molecular differentiation of STC and DPC. Overall, the integral molecular profile performed excellent discrimination and denoted an exponential function to predict the probability of DPC. [ABSTRACT FROM AUTHOR]

Breast cancer is the most common female malignancy in Taiwan, while conventional clinical and pathological factors fail to provide full explanation for prognostic heterogeneity. The aim of the study was to evaluate the feasibility of targeted sequencing combined with concurrent genes signature to identify somatic mutations with clinical significance. The extended concurrent genes signature was based on the coherent patterns between genomic and transcriptional alterations. Targeted sequencing of 61 Taiwanese breast cancers revealed 1036 variants, including 76 pathogenic and 545 likely pathogenic variants based on the ACMG classification. The most frequently mutated genes were NOTCH, BRCA1, AR, ERBB2, FANCA, ATM, and BRCA2 and the most common pathogenic deletions were FGFR1, ATM, and WT1, while BRCA1 (rs1799965), FGFR2 (missense), and BRCA1 (rs1799949) were recurrent pathogenic SNPs. In addition, 38 breast cancers were predicted into 12 high-risk and 26 low-risk cases based on the extended concurrent genes signature, while the pathogenic PIK3CA variant (rs121913279) was significantly mutated between groups. Two deleterious SH3GLB2 mutations were further revealed by multivariate Cox's regression (hazard ratios: 29.4 and 16.1). In addition, we identified several significantly mutated or pathogenic variants associated with differentially expressed signature genes. The feasibility of targeted sequencing in combination with concurrent genes risk stratification was ascertained. Future study to validate clinical applicability and evaluate potential actionability for Taiwanese breast cancers should be initiated. [ABSTRACT FROM AUTHOR]

Introduction: Coxsackievirus/adenovirus receptors (CARs) and desmoglein-2 (DSG2) are similar molecules to adenovirus-based vectors in the cell membrane. They have been found to be associated with lung epithelial cell tumorigenesis and can be useful markers in predicting survival outcome in lung adenocarcinoma (LUAD). Methods: A gene ontology enrichment analysis disclosed that DSG2 was highly correlated with CAR. Survival analysis was then performed on 262 samples from the Cancer Genome Atlas, forming "Stage 1A" or "Stage 1B". We therefore analyzed a tissue microarray (TMA) comprised of 108 lung samples and an immunohistochemical assay. Computer counting software was used to calculate the H-score of the immune intensity. Cox regression and Kaplan–Meier analyses were used to determine the prognostic value. Results: CAR and DSG2 genes are highly co-expressed in early stage LUAD and associated with significantly poorer survival (p = 0.0046). TMA also showed that CAR/DSG2 expressions were altered in lung cancer tissue. CAR in the TMA was correlated with proliferation, apoptosis, and epithelial–mesenchymal transition (EMT), while DSG2 was associated with proliferation only. The Kaplan–Meier survival analysis revealed that CAR, DSG2, or a co-expression of CAR/DSG2 was associated with poorer overall survival. Conclusions: The co-expression of CAR/DSG2 predicted a worse overall survival in LUAD. CAR combined with DSG2 expression can predict prognosis. [ABSTRACT FROM AUTHOR]

Simple Summary: This study investigated the association between survival outcome and the new grading system among advanced stage lung adenocarcinoma (LADC) (stages IIIA, IIIB and IV) patients who were diagnosed as LADC with a pathologic report according to a new grading system by the International Association for the Study of Lung Cancer (IASLC) pathology committee. The results indicate that the poorly differentiated group had a poorer prognosis in PFS, as did patients with wild-type EGFR who were treated with chemotherapy. No survival difference could be found among EGFR mutation patients. Older age and a lower body mass index also led to worse survival. Patients with poorly differentiated adenocarcinoma likewise had worse survival, especially compared to those with moderately differentiated adenocarcinoma. Our findings highlight that the therapeutic regimen should be adjusted for wild-type EGFR patients with poorly differentiated adenocarcinoma treated with chemotherapy to provide better outcomes. No survival difference could be seen among EGFR mutation patients. The impact of the new International Association for the Study of Lung Cancer pathology committee grading system for advanced lung adenocarcinoma (LADC) on survival is unclear, especially in Asian populations. In this study, we reviewed the prognostic outcomes of patients with late-stage disease according to the new grading system. We reviewed 136 LADC cases who underwent a small biopsy from 2007 to 2018. Tumors were classified according to the new grading system for LADC. Baseline characteristics (age, sex, smoking status, body mass index, and driver gene mutations) were analyzed. Kaplan–Meier and Cox regression analyses were used to determine correlations with the new grading system and prognosis. Patients with poorly differentiated adenocarcinoma were significantly correlated with a poor progression-free survival (PFS) (p = 0.013) but not overall survival (OS) (p = 0.154). Subgroup analysis showed that wild-type EGFR patients with poorly differentiated adenocarcinoma treated with chemotherapy had significantly worse PFS (p = 0.011). There was no significant difference in survival among the patients with epidermal growth factor receptor mutations who were treated with tyrosine kinase inhibitors. Patients aged >70 years and those with a BMI ≤ 25 kg/m2 and wild-type patients had significantly worse OS in both univariate (HR = 1.822, p = 0.006; HR = 2.250, p = 0.004; HR = 1.537, p = 0.046, respectively) and multivariate analyses (HR = 1.984, p = 0.002; HR = 2.383, p = 0.002; HR = 1.632, p = 0.028, respectively). Despite therapy, patients with poorly differentiated tumors still fared worse than those with better differentiated tumors. No differences were found among the EGFR mutations treated with TKI. Our findings highlight that the therapeutic regimen should be adjusted for EGFR Wild-type patients with poorly differentiated adenocarcinoma treated with chemotherapy to provide better outcomes. [ABSTRACT FROM AUTHOR]

Psoriasis is a chronic inflammatory skin disorder with a pathogenesis involving the interleukin-23/interleukin-17 axis. Salvianolic acid B exerts several pharmacological effects, such as antioxidation, anti-inflammation, and antitumor effects. The anti-psoriatic effects of salvianolic acid B have not been reported. In this study, we aimed to determine the optimum vehicle for salvianolic acid B, investigate its therapeutic effect on psoriatic-like skin conditions, and explore its underlying mechanisms of action. BALB/c mice were administered topical imiquimod to induce psoriasis-like skin and were then randomly assigned to control, vehicle control, salvianolic acid B in vehicles, and 0.25% desoximetasone ointment treatment groups. Barrier function, cytokine expression, histology assessment, and disease severity were evaluated. The results showed that salvianolic acid B-containing microemulsion alleviated disease severity, reduced acanthosis, and inhibited interleukin-23/interleukin-17 (IL-23/IL-17) cytokines, epidermal proliferation, and increased skin hydration. Our study suggests that salvianolic acid B represents a possible new therapeutic drug for the treatment of psoriasis. In addition, such formulation could obtain high therapeutic efficacy in addition to providing sufficient hydration for dry skin. [ABSTRACT FROM AUTHOR]

Pulsed radiofrequency (PRF) is effective in the treatment of neuropathic pain in clinical practice. Its application to sites proximal to nerve injury can inhibit the activity of extra-cellular signal-regulated kinase (ERK) for up to 28 days. The spared nerve injury (SNI)+ immPRF group (immediate exposure to PRF for 6 min after SNI) exhibited a greater anti-allodynic effect compared with the control group (SNI alone) or the SNI + postPRF group (application of PRF for 6 min on the 14th day after SNI). Insulin-like growth factor 2 (IGF2) was selected using microarray assays and according to web-based gene ontology annotations in the SNI + immPRF group. An increase in IGF2 and activation of ERK1/2 were attenuated by the immPRF treatment compared with an SNI control group. Using immunofluorescent staining, we detected co-localized phosphorylated ERK1/2 and IGF2 in the dorsal horn regions of rats from the SNI group, where the IGF2 protein predominantly arose in CD11b- or NeuN-positive cells, whereas IGF2 immunoreactivity was not detected in the SNI + immPRF group. Taken together, these results suggest that PRF treatment immediately after nerve injury significantly inhibited the development of neuropathic pain with a lasting effect, most likely through IGF2 down-regulation and the inhibition of ERK1/2 activity primarily in microglial cells.