Naringenin Induces Cellular Apoptosis in Melanoma Cells via Intracellular ROS Generation.

BACKGROUND/AIM: Melanoma is a prevalent malignant tumor that arises from melanocytes. The treatment of malignant melanoma has become challenging due to the development of drug resistance. It is, therefore, imperative to identify novel therapeutic drug candidates for controlling malignant melanoma. Naringenin is a flavonoid abundant in oranges and other citrus fruits and recognized for its numerous medicinal benefits. The objective of the study was to assess the anti-carcinogenic potential of naringenin by evaluating its ability to regulate the cellular production of reactive oxygen species (ROS) and its effect on mitochondrial function and apoptosis in melanoma cells. MATERIALS AND METHODS: Cell viability, intracellular ROS levels, cell apoptosis, and mitochondrial functions were evaluated. RESULTS: Naringenin decreased melanoma cell viability and triggered generation of ROS, leading to cell apoptosis. In addition, it stimulated mitochondrial damage in melanoma cells by elevating the levels of Ca2+ and ROS in the mitochondria and decreasing cellular ATP. Naringenin stimulated the expression of proapoptotic proteins, including phospho p53, B-cell lymphoma-2 (Bcl-2)-associated X protein, cleaved caspase-3, and cleaved caspase-9, in melanoma cells in a time-dependent manner. Furthermore, it reduced the expression of the anti-apoptotic protein Bcl-2. Naringenin triggered cell apoptosis by phosphorylating c-Jun N-terminal kinase and stimulating cellular autophagy. CONCLUSION: Naringenin caused oxidative stress and mitochondrial damage, and activated autophagy in melanoma cells, leading to cell apoptosis. These findings indicate the potential of naringenin as a new therapeutic candidate for melanoma.

Mucosal Immunity Related to CD8+ T Lymphocytes in Children with Helicobacter pylori Gastritis.

Purpose: We investigated the role of CD8+T cells as host immune factors in pediatric patients with Helicobacter pylori gastritis. Methods: Gastric mucosal tissue and blood samples were collected from 39 children, including 11 children with H. pylori infection and 28 children as controls. Anti-CD8 and anti-T-bet antibodies were used for immunohistochemistry of the gastric mucosa. For the cell surface and intracellular staining, peripheral blood mononuclear cells were stained with anti-IL7Rα, anti-CX3CR1, anti-CD8, anti-T-bet, and anti-IFN-γ antibodies. Cytokines of sera such as tumor necrosis factor alpha (TNF-α) and CX3CL1 were analyzed using enzyme- linked immunosorbent assay (ELISA). Results: In the immunohistochemistry of gastric mucosa, the frequency of CD8+ and T-bet+ T cells cells was higher in the H. pylori-positive group than in the control group (26.9± 7.8% vs. 16.9±3.3%, p<0.001; 5.0±2.5% vs. 2.2±0.7%, p=0.001). Between the control and H. pylori-positive groups, the frequency of IL-7RαlowCX3CR1+ CD8+ and T-bet+ INF-γ+ CD8+ T cells were not significantly different between surface and intracellular staining, respectively (40.4±24.0% vs. 38.2±17.8%, p=0.914; 40.4±24.0% vs. 38.2±17.8%, p=0.914). In the ELISA, no significant differences in TNF-α and CX3CL1 concentrations were observed between the control and H. pylori-positive groups (34.3±12.1 pg/mL vs. 47.0±22.6 pg/mL, p=0.114/0.5± 0.1 pg/mL vs. 0.5±0.1 pg/mL, p=0.188). Conclusion: CD8+ T and Th1 cells, which secrete IFN-γ, might play important roles in the mucosal immunity of the stomach in children with H. pylori infection.

Diesel exhaust particulate matter impairs Toll-like receptor signaling and host defense against staphylococcal cutaneous infection in mice.

Air pollution is an emerging cause of mortality, affecting nearly 5 million people each year. Exposure to diesel exhaust fine particulate matter (PM2.5) aggravates respiratory and skin conditions. However, its impact on the protective immunity of the skin remains poorly understood. This study aimed to investigate the underlying molecular mechanism for adverse effects of PM2.5 on the host protective immunity using in vitro cell and in vivo mouse model. Intracellular translocation of Toll-like receptor 9 (TLR9) and CpG-DNA internalization were assessed in dendritic cells without or with PM2.5 treatment using immunofluorescence staining. Cytokine and nitric oxide production were measured in dendritic cells and macrophages without or with PM2.5 treatment. NF-κB and MAPK signaling was determined using western blotting. Skin disease severity, bacterial loads, and cytokine production were assessed in cutaneous Staphylococcus aureus (S. aureus) infection mouse model. PM2.5 interfered with TLR9 activation by inhibiting both TLR9 trafficking to early endosomes and CpG-DNA internalization via clathrin-mediated endocytosis. In addition, exposure to PM2.5 inhibited various TLR-mediated nitric oxide and cytokine production as well as MAPK and NF-κB signaling. PM2.5 rendered mice more susceptible to staphylococcal skin infections. Our results suggest that exposure to PM impairs TLR signaling and dampens the host defense against staphylococcal skin infections. Our data provide a novel perspective into the impact of PM on protective immunity which is paramount to revealing air pollutant-mediated toxicity on the host immunity.

The feasibility of distance to the tumor of biopsy cores to estimate the extracapsular extension.

Background: To investigate the predictive capability of a new parameter, the distance between the fibromuscular capsule and the tumor as measured using a prostate biopsy core (referred to as "distance to the tumor" [DTT]), for the presence of extracapsular extension (ECE). Materials and methods: We analyzed specimens obtained from 246 patients diagnosed with prostate cancer. All patients underwent prebiopsy, prostate magnetic resonance imaging (MRI), and subsequent prostatectomy. DTT measurements were obtained for each prostate biopsy core, and the minimum (min) DTT was extracted. We assessed the relationship between min DTT, MRI-estimated ECE, and pathological ECE, considering factors such as the PI-RADS score and tumor location. Results: In this study of 246 patients, the mean age was 65.8 years, and the mean prostate-specific antigen (PSA) level was 18.9 ng/ml. Patients with suspicious lesions in the peripheral zone and pathological ECE displayed higher rates of positive digital rectal examination (DRE), elevated PSA levels, and shorter DTT values in the biopsy cores. DTT demonstrated an accurate estimation of the presence of ECE, similar to MRI findings. Min DTT exhibited higher accuracy for peripheral zone masses, with a cutoff value of 1.0 mm for min DTT predicting ECE (AUC: 0.84, sensitivity: 72.23%, specificity: 77.78%, P < 0.01). Of the 246 patients, 66 had no ECE on MRI; however, 18 of these patients displayed pathological ECE, with 14 having DTT values <1.0 mm. Conclusions: Min DTT, positive DRE results, and a higher Gleason grade were significantly associated with ECE. DTT measurements of <1 mm can provide a more accurate prediction of ECE in the peripheral zone of the prostate than MRI-based assessments.

Renal Epithelioid Angiomyolipoma with Epithelial Cysts Mimicking Cystic Renal Cell Carcinoma: A Case Report of Combination of Two Rare Entities.

Renal angiomyolipomas (AMLs) are typically solid tumors, but there have been few reports of a rare cystic variant of AML. AML with epithelial cysts, where the epithelial cyst has a cuboidal epithelial lining, account for the majority of them. Next, epithelioid AML (EAML) with cystic changes due to hemorrhage and necrosis, which is composed of epithelioid cells with abundant eosinophilic cytoplasm, have also been reported. These rare cystic types of AML can be mistaken for other cystic tumors, such as cystic renal cell carcinoma, in preoperative imaging. We report the imaging findings of a rare case of EAML with epithelial cysts.

The association between ephrin receptor-A1 expression and survival in patients with cancer: a meta-analysis.

Background: Ephrin receptor-A1 (EPHA1) participates in various developmental processes by engaging in cell adhesion, migration, and tissue boundary formation. EPHA1 is also associated with cancer progression and poor prognosis. However, the results of individual studies were inconsistent. Therefore, we aimed to systematically evaluate the association between survival and EPHA1 expression in patients with cancer. Methods: We searched electronic databases including PubMed, Embase, Scopus, and the Cochrane library until February 8, 2022. The pooled hazard ratio (HR) with 95% confidence interval (CI) was calculated to explore the relationship between EPHA1 expression and survival in patients with cancer. Funnel plots and Egger's regression tests were conducted to evaluate publication bias, and sensitivity analysis was performed to determine the reliability of the pooled results. Results: Eight studies with 1079 cancer patients were enrolled. EPHA1 expression was associated with progression-free survival (PFS) (HR 1.79, 95% CI: 1.49-2.15, P<0.001). EPHA1 expression was also associated with poor overall survival (HR 2.23, 95% CI: 1.42-3.51, P<0.001), higher tumor stage [odds ratio (OR) 1.74, 95% CI: 1.15-2.61, P=0.008], and lymph node metastasis (OR 1.88, 95% CI: 1.24-2.87, P=0.003) in patients with gastric cancer. Discussion: EPHA1 expression was significantly associated with PFS in patients with cancer.

Differential epithelial and stromal LGR5 expression in ovarian carcinogenesis.

Lgr5 has been identified as a marker of the stem/progenitor cells in the murine ovary and oviduct by lineage tracing. However, little is known regarding LGR5 expression or its functional significance in human ovary tissues. Here, using RNA in situ hybridization and/or immunohistochemistry, we thoroughly investigated LGR5 expression in normal human ovaries, fallopian tubes and various ovarian tumors. We discovered that LGR5 expression is negligible in the human ovary surface epithelium, whereas ovarian stromal cells normally express low levels of LGR5. Remarkably, fallopian tube epithelium, inclusion cysts and serous cystadenomas with a Müllerian phenotype expressed high levels of LGR5, and LGR5 expression was restricted to PAX8+/FOXJ1- secretory cells of the tubal epithelium. Strong stromal LGR5 expression without epithelial LGR5 expression was consistently observed in the path from serous cystadenoma to serous borderline tumor to low grade serous carcinoma (LGSC). Unlike LGSC, high grade serous carcinoma (HGSC), clear cell carcinoma, endometrioid carcinomas displayed various epithelial-stromal LGR5 expression. Notably, high levels of LGR5 expression were observed in serous tubal intraepithelial carcinoma, which slightly declined in invasive HGSC. LGR5 expression was significantly associated with improved progression-free survival in HGSC patients. Moreover, in vitro assays demonstrated that LGR5 expression suppressed tumor proliferation and migratory capabilities. Taken together, these findings indicate a tumor-suppressive role for LGR5 in the progression of HGSC.

Prognostic Value of NOX4 Expression in Cancer Patients: A Systematic Review and Meta-analysis.

Background: Recent studies have shown that nicotinamide adenosine dinucleotide phosphate oxidase 4 (NOX4) is related to cancer development, proliferation, invasion, epithelial-to-mesenchymal transition, and metastasis. The prognostic value of NOX4 expression although has been reported in various cancers, it remains unclear as several studies have reported conflicting results. Therefore, the purpose of this study was to systematically investigate the prognostic value of NOX4 expression in cancer patients. Method: Appropriate studies were collected by searching the PubMed, EMBASE, and Cochrane library databases, and the prognostic value of NOX4 expression in cancer patients was assessed through a meta-analysis. Results: Nine eligible studies involving 2675 cancer patients were included in this meta-analysis. We found that NOX4 expression is related to prognosis in cancer patients. In particular, high expression of NOX4 was significantly associated with overall survival in patients with gastrointestinal cancer (hazard ratio [HR]: 1.83, 95% confidence interval [CI]: 1.39-2.42, p < 0.001). Conclusion: NOX4 expression is significantly correlated with overall survival in patients with gastrointestinal cancer, indicating that it could be a potential prognostic marker.

Increased CD9 expression predicts favorable prognosis in human cancers: a systematic review and meta-analysis.

BACKGROUND: CD9 is implicated in cancer progression and metastasis by its role in suppressing cancer cell proliferation and survival. However, the prognostic and clinicopathological significance of CD9 expression is controversial. Therefore, the current meta-analysis was conducted to determine the prognostic and clinicopathological significance of CD9 expression in cancer patients. METHODS: Eligible studies were selected through database search of PubMed, Embase and Cochrane library up to April 5 2020. The necessary data were extracted from the included studies. Pooled hazard ratio (HR) and odds ratio (OR) with 95% confidence interval (CI) were calculated to evaluate the prognostic and clinicopathological significance of CD9 expression in cancer patients. RESULTS: A total of 17 studies consisting of 3456 cancer patients were included in this meta-analysis. An increased CD9 expression was significantly associated with a more favorable overall survival (OS) (HR 0.47, 95% CI 0.31-0.73, p = 0.001) and disease-free survival (DFS) (HR 0.48, 95% CI 0.30-0.79, p = 0.003). In subgroup analysis of cancer type, an increased CD9 expression was associated with increased OS in breast cancer and digestive system cancer, and with increased DFS in head and neck cancer and leukemia/lymphoma. Additionally, an increased CD9 expression significantly correlated with lower overall stage (OR 0.45, 95% CI 0.29-0.72, p = 0.001). CONCLUSION: An increased CD9 expression was associated with favorable survival in cancer patients suggesting that CD9 expression could be a valuable survival factor in cancer patients.

The Intestinal Stem Cell Marker SMOC2 Is an Independent Prognostic Marker Associated With Better Survival in Gastric Cancer.

BACKGROUND/AIM: SPARC-related modular calcium-binding protein 2 (SMOC2), a secreted matricellular protein, is reported to be involved in cancer progression such as cell cycle, angiogenesis, and invasion. In this study, we aimed to investigate the expression of SMOC2 in various gastric lesions and assessed its prognostic value in a large cohort of gastric cancer (GC) patients. PATIENTS AND METHODS: SMOC2 mRNA levels were measured by quantitative real-time PCR using 26 matched fresh-frozen GC samples. SMOC2 protein expression was determined by immunohistochemistry on tissue microarrays including 734 GC specimens and its correlations with clinicopathological features and survival were evaluated. RESULTS: The transcription level of SMOC2 was higher in GC samples compared to normal mucosa (p=0.006). Its expression levels were associated with the intestinal stem cell (ISC) marker, LGR5, but there were no correlations with EPHB2 and OLFM4 or the candidate cancer stem cell markers CD133 and CD44. SMOC2 expression was significantly increased in the intestinal metaplasia and was further increased in gastric adenomas and early gastric cancers (EGC). In total, 34% of GCs were positive for SMOC2, and SMOC2 positivity was higher in old (p=0.001) and male (p<0.001) patients, and in well-differentiated GC (p<0.001). SMOC2 expression had a negative association with perineural invasion (p<0.001) and tumor stage (p<0.001). In survival analysis, SMOC2-positive GC patients had much better clinical outcomes in overall survival rates (p<0.001) compared to SMOC2-negative GC patients. The prognostic impact of SMOC2 remained significant both in intestinal (p<0.001) and diffuse-type GC (p<0.001). Remarkably, a multivariate analysis demonstrated SMOC2 as an independent prognostic marker [hazard ratio (HR)=0.732, p=0.045] along with venous invasion (p=0.012), tumor stage (p<0.001) and CDX2 (p=0.028). CONCLUSION: Our results suggest that SMOC2 can be a prognostic marker for better clinical outcomes in GC.

[Multicentric Florid Cystic Endosalpingiosis in Different Anatomical Spaces: A Case Report]. / 서로 다른 í•´ë¶€í•™ì  공간에 발생한 다발성 개화성 낭성 ë‚´ë‚œê´€ì¢ : 증례 ë³´ê³ .

Endosalpingiosis is a condition that causes the non-neoplastic proliferation of ectopic tubal epithelium. Florid cystic endosalpingiosis is an atypical subtype that is very rarely reported. It presents as a mass-like feature and therefore needs to be differentiated from tumorous conditions. Here, we report the imaging findings of a case of multicentric florid cystic endosalpingiosis in the extraperitoneal pelvic cavity and the retroperitoneal spaces.

CXCR3 expression as a prognostic factor in gastric cancer: a meta-analysis.

BACKGROUND: CXC chemokine receptor 3 (CXCR3) plays a critical role in tumorigenesis, and CXCR3 expression is associated with prognosis in many cancers. Recently, CXCR3 expression is recognized as a potential prognostic factor for patients with gastric cancer. In this study, we analyzed the prognostic significance of CXCR3 expression in gastric cancer. METHODS: We conducted a meta-analysis after selecting eligible studies through a literature search. We calculated pooled results to assess the associations between CXCR3 expression and overall survival (OS) and clinicopathological factors for gastric cancer. RESULTS: The pooled hazard ratio (HR) with 95% confidence interval (CI) between high expression of CXCR3 and OS was 0.46 (95% CI 0.30-0.71, P<0.001), suggesting that high expression of CXCR3 was associated with a favorable OS. High expression of CXCR3 was significantly correlated with younger age [odds ratio (OR) 0.67, 95% CI: 0.49-0.91, P=0.011], lower tumor grade (OR 0.46, 95% CI: 0.29-0.73, P=0.001), absence of lymph node metastasis (OR 0.47, 95% CI: 0.31-0.71, P<0.001), and lower Tumor-Node-Metastasis stage (OR 0.51, 95% CI: 0.35-0.74, P<0.001). CONCLUSIONS: High expression of CXCR3 was associated with better survival and may be a potential prognostic factor for patients with gastric cancer patients.

Diffuse alveolar hemorrhage from metastatic cardiac angiosarcoma of the lung successfully treated with paclitaxel chemotherapy: A case report and brief literature review.

Diffuse alveolar hemorrhage (DAH) is a life-threatening syndrome caused by various etiologies. DAH has rarely been reported to be associated with metastatic angiosarcoma. However, due to the rarity of complications, it may not be well-recognized by most clinicians. Herein, we report the case of a 70-year-old man with newly diagnosed metastatic cardiac angiosarcoma presenting with DAH. After an immediate bronchoalveolar lavage study and bronchoscopic biopsy, the patient was successfully treated with paclitaxel chemotherapy. Although most patients with this phenomenon have an extremely grave prognosis in previous literature, our experience showed that appropriate evaluation and treatment may be beneficial.

The relationship between hepatoma-derived growth factor and prognosis in non-small cell lung cancer: A systematic review and meta-analysis.

BACKGROUND: Hepatoma-derived growth factor (HDGF) promotes cancer progression and metastasis by interacting with vascular endothelial growth factor, thereby inducing epithelial-to-mesenchymal transition and angiogenesis. Recent studies have correlated increased HDGF levels with poor prognosis in various malignancies, including lung cancer. This meta-analysis systematically assessed the prognostic significance of HDGF expression in patients with non-small cell lung cancer (NSCLC). METHODS: Eligible studies were identified by searching literature in PubMed, Embase, Scopus, and the Cochrane library until June 2020. The pooled hazard ratio (HR) or odds ratio (OR) with 95% confidence interval (CI) was determined to assess the relationship between HDGF expression and clinical outcome in patients with NSCLC. RESULTS: The pooled HRs between high HDGF expression and clinical outcome were 2.20 (95% CI 1.75-2.76, P < .001) and 2.77 (95% CI 1.79-4.29, P < .001) for overall survival and disease-free survival, respectively. High HDGF expression was significantly correlated with a larger tumor size (OR 1.59, 95% CI 1.02-2.46, P = .040). CONCLUSION: HDGF expression is related to clinical outcome and may be a prognostic marker in patients with NSCLC.

Acute Cholangitis Caused by Boryong Strain of Orientia tsutsugamushi.

Scrub typhus present with a variety clinical manifestations caused by Orientia tsutsugamushi, it is sometimes accompanied by severe complications. The clinical course of this complication is not well clear. Herein, we first report a case with acute cholangitis and acalculous cholecystitis caused by the Boryong genotype of O. tsutsugamushi. A 82-year-old woman presented with fever and acute abdominal pain on the right upper quadrant. Initially, the patient showed an abnormality of liver enzymes of cholestatic pattern. An acute cholangitis and cholecystitis were suspected on the enhanced computed tomography (CT), and emergent endoscopic retrograde cholangiopancreatography (ERCP) performed. However, neither ERCP nor CT detected common bile duct stones or sludge. The patient's illness progressed despite bile drainage and antibiotic therapy. On the fifth day in hospital, an immunofluorescence IgG assay for O. tsutsugamushi was positive, and the patient newly developed a skin rash and an eschar lesion on the right abdomen. The polymerase chain reaction amplification of Orientia genes from blood and bile was positive, genotype of both samples was identified the Boryong type. The presentation of scrub typhus as an acute cholangitis is not reported till now. In endemic areas, scrub typhus would be considered a rare etiology of acute cholangitis.

Prognostic and clinicopathological roles of programmed death-ligand 1 (PD-L1) expression in thymic epithelial tumors: A meta-analysis.

BACKGROUND: Programmed death-ligand 1 (PD-L1) is one of the immune checkpoint proteins, and plays an important role in the progression and microenvironment of cancer. PD-L1 expression has been associated with poor survival in many cancers. Several studies have also shown an association between PD-L1 expression and the prognosis of patients with thymic epithelial tumors (TETs). In this study, we systematically evaluated the prognostic and clinicopathological roles of PD-L1 expression in TETs. METHODS: We searched the literature through PubMed, Embase and Cochrane library and chose the eligible studies, and subsequently performed a meta-analysis to evaluate the prognostic and clinicopathological roles of PD-L1 expression in TETs. RESULTS: Six of the 75 articles found in the literature were selected. PD-L1 expression was significantly related to unfavorable overall survival (hazard ratio 1.52, 95% confidence interval [CI]: 1.01-2.30, P = 0.046) in TETs. PD-L1 expression was significantly associated with male gender (odds ratio [OR] 1.55, 95% CI: 1.08-2.22, P = 0.017) and higher Masaoka stage (OR 3.93, 95% CI: 2.44-6.32, P < 0.001). CONCLUSIONS: PD-L1 expression was correlated with unfavorable prognosis in TETs, indicating PD-L1 expression could help determine the prognosis of TET patients.