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Multidrug resistance (MDR) to anticancer drugs remains a serious obstacle to the success of cancer chemotherapy. Resveratrol, a polyphenol, present in natural products exerts anticancer activity and acts as a potential MDR inhibitor in various drug-resistant cancer cells. In the process of resensitization of drug-resistant cancer cells, resveratrol has been shown to interfere with ABC transporters and drug-metabolizing enzymes, increase DNA damage, inhibit cell cycle progression, and induce apoptosis and autophagy, as well as prevent the induction of epithelial to mesenchymal transition (EMT) and cancer stem cells (CSCs). This review summarizes the mechanisms by which resveratrol counteracts MDR in acquired drug-resistant cancer cell lines and provides a critical basis for understanding the regulation of MDR as well as the development of MDR-inhibiting drugs.

Extracellular acidity has been implicated in enhanced malignancy and metastatic features in various cancer cells. Gastric cancer cell lines (AGS and SNU601) maintained in an acidic medium have increased motility and invasiveness. In this study, we investigated the effect of ellagic acid, a plant-derived phenolic compound, on the acidity-promoted migration and invasion of gastric cancer cells. Treating cells maintained in acidic medium with ellagic acid inhibited acidity-mediated migration and invasion, and reduced the expression of MMP7 and MMP9. Examining regulatory factors contributing to the acidity-mediated invasiveness, we found that an acidic pH increased the expression of COX1 and COX2; importantly, expression decreased under the ellagic acid treatment. The general COX inhibitor, sulindac, also decreased acidity-mediated invasion and expression of MMP7 and MMP9. In addition, acidity increased the mRNA protein expression of transcription factors snail, twist1, and c-myc; these were also reduced by ellagic acid. Together, these results suggest that ellagic acid suppresses acidity-enhanced migration and invasion of gastric cancer cells via inhibition of the expression of multiple factors (COX1, COX2, snail, twist1, and c-myc); for this reason, it may be an effective agent for cancer treatment under acidosis.

We previously showed that oxaliplatin induces necrotic-like cell death in hepatocarcinomas, and combination with ursodexoycholic acid (UDCA) significantly shifts the necrotic-like death to apoptosis. Since cell death mode is crucial on inflammatory responses and chemotherapeutic efficacy, the mechanism underlying determination of cell death mode by UDCA was investigated in this study. Apoptosis or necrosis was determined by apoptotic body formation, caspase-8 activity, LDH release and PI inclusion. The involvement of lipid rafts and death receptors was examined by rafts fractionation, confocal microscopy and gene silencing assays. UDCA combination enhanced recruitment of death receptors and adaptors into cholesterol-enriched lipid rafts, and induced a stronger raft clustering. Lipid raft disruption decreased the UDCA/oxaliplatin-mediated apoptosis and increased necrotic-like death. UDCA promotes lipid raft localization of multiple death receptors, thereby contributing to a shift of cell death mode from oxaliplatin-induced necrotic death to apoptosis in HepG2 cells.

The acidic tumor environment has emerged as a crucial factor influencing the metastatic potential of cancer. We investigated the effect of an acidic environment on the acquisition of metastatic properties in MCF7 breast cancer cells and explored the inhibitory effects of gallic acid. Prolonged exposure to acidic culture conditions (over 12 weeks at pH 6.4) induced the acquisition of migratory and invasive properties in MCF7 cells, accompanied by increased expression of Matrix Metalloproteinase 2 and 9 (MMP2 and MMP9, respectively), together with alterations in E-cadherin, vimentin, and epithelial-to-mesenchymal transition markers. Gallic acid effectively inhibited the survival of acidity-adapted MCF7 (MCF7-6.4/12w) cells at high concentrations (>30 μM) and reduced metastatic characteristics induced by acidic conditions at low concentration ranges (5–20 μM). Moreover, gallic acid suppressed the PI3K/Akt pathway and the nuclear accumulation of β-catenin, which were elevated in MCF7-6.4/12w cells. These findings highlight the potential of gallic acid as a promising therapeutic agent for metastatic traits in breast cancer cells under acidic conditions.

Fascin, an actin-bundling protein, plays an essential role in cancer metastasis. The Hippo pathway is critical for carcinogenesis and cancer stem cell self-renewal. Mammalian STE20-like kinase (MST) is a core component of the Hippo pathway. However, whether fascin and MST2 affect melanoma remain largely unknown. This study aimed to investigate the role of fascin and MST2 in melanoma development. Surgically excised skin melanomas and the adjacent non-tumorous skin tissue from 30 cases were analyzed using immunohistochemistry for fascin and MST2. The melanoma cell line WM793 was employed for fascin and MST2 knock-down followed by western blotting, and melanoma xenografting in BALB/c mice. Immunohistochemistry revealed increased expression of fascin and decreased expression of MST2 in melanoma. The reverse correlation of fascin and MST2 was statistically significant. Fascin siRNA upregulated MST2 expression; however, MST2 siRNA did not significantly affect fascin expression in the WM793. WM793 xenografting followed by fascin knock-down inhibited tumor growth significantly in the animal study. Fascin is a regulator of the Hippo pathway and plays an important role in melanoma development. Therefore, fascin could be a potential therapeutic target for melanoma.

Cyclin-dependent kinase 8 (CDK8) is known to play an important role in the early development and progression of various cancers, and the Wnt/β-catenin pathway is also involved in cancer progression. Nevertheless, relatively little is known about the regulatory mechanisms of the β-catenin pathway in hepatocellular carcinoma (HCC). The complete clinicopathological features of 122 pairs of HCC and adjacent non-tumor tissues were analyzed and immunohistochemistry was used to detect the aberrant expression of CDK8 and β-catenin. Overall survival rates (OSRs) were evaluated using the Kaplan-Meier method and Cox multivariate analysis was used to assess the prognostic values. Aberrant expression of nuclear β-catenin and CDK8 are independent prognostic variables that negatively affect the OSR. The aberrant expression of CDK8 was associated with the dysregulated expression of β-catenin and correlated with a poor prognosis. Inhibition of CDK8 and/or nuclear β-catenin expression pattern could serve as a promising therapeutic strategy for the treatment of HCC.

We describe a case of a gastric submucosal tumor in a patient in South Korea infected with Dioctophyme renale roundworm. The patient had a history of consuming raw freshwater fish. Molecular and morphologic analyses confirmed D. renale Infection. Genetic testing should be used to diagnose rare parasitic infections with unusual clinical manifestations.

Bacterial co-infection has been associated with adverse outcomes in patients with COVID-19. Streptococcus pneumoniae is a common cause of community-acquired pneumonia and may contribute to poor clinical outcomes when co-detected in COVID-19 patients. This study aimed to investigate the clinical significance of pneumococcal positivity in hospitalized patients with COVID-19. We conducted a retrospective analysis of adult patients hospitalized with COVID-19 at two tertiary care centers. Pneumococcal positivity was defined by either a positive urinary antigen test or multiplex real-time polymerase chain reaction. Disease severity of COVID-19 pneumonia was assessed using the pneumonia severity index and CURB-65 scoring systems. Propensity score matching and multivariable logistic regression were used to adjust for confounders and identify independent risk factors for mortality. Among 280 patients, 65 pneumococcus-positive patients were matched with 65 pneumococcus-negative patients after propensity score matching. In the overall matched cohort, pneumococcal positivity was not significantly associated with in-hospital mortality. However, in patients with severe disease (n = 156), defined as pneumonia severity index >130 or CURB-65 ≥ 3, mortality was significantly higher in pneumococcus-positive patients (n = 39) than in pneumococcus-negative patients (53.8% vs. 29.1%, p = 0.009). In the multivariable analysis of this subgroup, pneumococcal positivity (odds ratio, 4.050; 95% confidence interval, 1.285-12.765; p = 0.017) and high-flow oxygen therapy (odds ratio, 6.510; 95% confidence interval, 1.847-22.944; p = 0.004) were independently associated with mortality. Detection of S. pneumoniae by urinary antigen test or multiplex polymerase chain reaction was associated with increased mortality in patients hospitalized with severe COVID-19.

Background/Aim: Renal-type clear cell carcinoma (RTCCC) occurring as a primary tumor in an extra-renal location, especially in the prostate, is very rare. In this report, we present a rare case of RTCCC of the prostate and review the current literature on this condition. Case Report: The patient was a 76-year-old man who presented with urinary symptoms. Cystoscopic findings showed tumor-like lesions in the dome, neck, and anterior wall of the urinary bladder. Biopsy revealed clear cell carcinoma (CCC). Transrectal needle biopsy of the prostate revealed prostatic adenocarcinoma with CCC features. Immunohistochemically, tumor cells of the bladder and prostate were compatible with prostatic carcinoma. The whole-body radiologic workup did not reveal any renal or other organ malignancies. Transurethral resection of the prostate and bladder tumor was performed. The patient underwent regular follow-up cystoscopic examination and urine cytology. No recurrence was observed 19 months after the diagnosis. Conclusion: This was a case of RTCCC arising in the prostate. RTCCC of the prostate is extremely rare and shows very similar histological and immunohistochemical features to those of CCC occurring in the kidney. Pathologists should be aware of such an entity whenever they see clear cells in urinary tract malignancies.

Abstrct Ephexin1 was reported to be highly upregulated by oncogenic Ras, but the functional consequences of this remain poorly understood. Here, we show that Ephexin1 is highly expressed in colorectal cancer (CRC) and lung cancer (LC) patient tissues. Knockdown of Ephexin1 markedly inhibited the cell growth of CRC and LC cells with oncogenic Ras mutations. Ephexin1 contributes to the positive regulation of Ras-mediated downstream target genes and promotes Ras-induced skin tumorigenesis. Mechanically, Akt phosphorylates Ephexin1 at Ser16 and Ser18 (pSer16/18) and pSer16/18 Ephexin1 then interacts with oncogenic K-Ras to promote downstream MAPK signaling, facilitating tumorigenesis. Furthermore, pSer16/18 Ephexin1 is associated with both an increased tumor grade and metastatic cases of CRC and LC, and those that highly express pSer16/18 exhibit poor overall survival rates. These data indicate that Ephexin1 plays a critical role in the Ras-mediated CRC and LC and pSer16/18 Ephexin1 might be an effective therapeutic target for CRC and LC.