PRMT5 Mediated HIF1α Signaling and Ras-Related Nuclear Protein as Promising Biomarker in Hepatocellular Carcinoma.

Protein arginine N-methyltransferase 5 (PRMT5) has been identified as a potential therapeutic target for various cancer types. However, its role in regulating the hepatocellular carcinoma (HCC) transcriptome remains poorly understood. In this study, publicly available databases were employed to investigate PRMT5 expression, its correlation with overall survival, targeted pathways, and genes of interest in HCC. Additionally, we utilized in-house generated NGS data to explore PRMT5 expression in dysplastic nodules compared to hepatocellular carcinoma. Our findings revealed that PRMT5 is significantly overexpressed in HCC compared to normal liver, and elevated expression correlates with poor overall survival. To gain insights into the mechanism driving PRMT5 overexpression in HCC, we analyzed promoter CpG islands and methylation status in HCC compared to normal tissues. Pathway analysis of PRMT5 knockdown in the HCC cells revealed a connection between PRMT5 expression and genes related to the HIF1α pathway. Additionally, by filtering PRMT5-correlated genes within the HIF1α pathway and selecting up/downregulated genes in HCC patients, we identified Ras-related nuclear protein (RAN) as a target associated with overall survival. For the first time, we report that PRMT5 is implicated in the regulation of HIF1A and RAN genes, suggesting the potential prognostic utility of PRMT5 in HCC.

Vitamin D modulates systemic inflammation in patients with severe COVID-19.

AIMS: The ability of vitamin D (VitD) to modulate immune responses in the clinical setting of COVID-19 infection is not well investigated. This study aimed to evaluate the ability of VitD to attenuate inflammatory responses in patients with severe COVID-19. MATERIALS AND METHODS: Blood samples and nasopharyngeal swabs were obtained from patients with severe COVID-19 who had been treated (20 patients), or not (25 patients), with VitD, during their stay in the intensive care unit. Western blotting was used to evaluate the expressions of STAT3, JNK and AKT signaling pathways and ELISA was used to measure levels of IL-6, IL-17, and IL-1ß in blood of these patients. KEY FINDINGS: Reduced levels of STAT3, JNK and AKT pathways and lower levels of proinflammatory cytokines such as IL-6, IL-17, and IL-1ß were observed in VitD treated patients (50,000 IU of cholecalciferol weekly for 3 weeks), and in vitro following treatment of poly I:C stimulated PBMCs with VitD (50 nM of calcitriol). Moreover, lower circulatory levels of these proinflammatory cytokines following treatment with VitD were associated with lower serum levels of COVID-19-related severity markers such as D-dimer and C-reactive proteins (P < 0.001) which in overall resulted in shorter length of ICU stay for VitD treated compared to untreated patients (18 days for VitD treated vs. 28 days for VitD untreated; P = 0.01). SIGNIFICANCE: This study reveals that VitD plays immunomodulatory role during COVID-19 infection, which further emphasizes the importance of maintaining a normal level of this vitamin for the prevention of hyperinflammatory conditions associated with COVID-19.

Immunohistochemical Assessment of TNFAIP3/A20 Expression Correlates With Early Tumorigenesis in Breast Cancer.

BACKGROUND/AIM: Limited data exist on the expression pattern of TNFAIP3/A20, as assayed by immunohistochemistry (IHC), in breast cancer tissues. This study aimed to assess A20 expression pattern in breast cancer. MATERIALS AND METHODS: The expression of A20 was analysed using IHC in 50 breast cancer cases retrieved from the Sharjah Breast Cancer Center at the University Hospital Sharjah, United Arab Emirates. Omics survival data were also used to analyse its association with survival in endocrine-treated subgroups. RESULTS: A20 expression in breast cancer tissues was 'tumor-specific', and as compared to normal tissue areas, its expression was associated with both intensity and extent in early grade 1 (p<0.0001) in all molecular subtypes. In addition, using omics survival data from a cohort of 3,520 breast cancer patients, we showed that A20 overexpression associated with lower overall survival rate in the endocrine treated subgroups [hazard ratio (HR)=2.14, 95%CI=1.61-2.82, p<0.0001]. CONCLUSION: A20 can serve as a biomarker for early diagnosis of breast cancers.

Logistic regression prediction model identify type 2 diabetes mellitus as a prognostic factor for human papillomavirus-16 associated head and neck squamous cell carcinoma.

BACKGROUND: HPV-16-positive HNSCC and HPV-16-negative HNSCC have different clinical factors, representing distinct forms of cancers. The study aimed to identify patient-specific factors for HPV-16-positive HNSCC based on baseline clinical data. METHOD: Factors associated with HPV-16-positive HNSCC were identified using the data from 210 patients diagnosed with HNSCC at University College of London Hospital between January 1, 2003, and April 30, 2015, inclusive. A series of models were developed using logistic regression methods, and the overall model fit was compared using Akaike Information Criterion. Survival analysis was carried with Cox proportional hazards model for survival-time outcomes. The survival time for individual patients was defined as the time from diagnosis of HNSCC to the date of death from any cause. For patients who did not die, they were censored at the end of study on April 30, 2015. RESULTS: Of the 210 patients, 151 (72%) were found to have HPV-16-positive HNSCC. The logistic regression model showed that the prevalence of developing HPV-16-positive HNSCC was 3.79 times higher in patients with Type 2 Diabetes Mellitus (T2DM) (odd ratio [OR], 3.79; 95% CI, 1.70-8.44) than in those without T2DM, and 8.84 times higher in patients with history of primary HNSCC (OR, 8.84; 95% CI, 2.30-33.88) than in those without a history of primary HNSCC. HPV-16-positive HNSCC was also observed more in tonsils (OR, 4.02; 95% CL, 1.56-10.36) and less in non-alcohol drinker's oral cavity (OR, 0.14; 95% CI, 0.03-0.56). Furthermore, individual patients were followed-up for 1 to 13 years (median of 1 year). Patients with HPV-positive HNSCC had a median survival of 5 years (95% CI, 2.6-7.3 years). Among HPV-16-positive HNSCC cohort, T2DM was a risk for poorer prognosis (hazard ratio, 2.57; 95% Cl, 1.09-6.07), and had lower median survival of 3 years (95% CI, 1.8-4.1 years), as compared to 6 years (95% CI, 2.8-9.1 years) in non-T2DM. CONCLUSIONS: Patient-specific factors for HPV-positive HNSCC are T2DM, history of primary HNSCC and tonsillar site. T2DM is associated with poorer prognosis. These findings suggest that it might be beneficial if routine HPV-16 screening is carried out in T2DM patients which can provide better therapeutic and management strategies.

Cytoplasmic E-Cadherin Expression Is Associated With Higher Tumour Level of VEGFA, Lower Response Rate to Irinotecan-based Treatment and Poorer Prognosis in Patients With Metastatic Colorectal Cancer.

BACKGROUND: The prognostic value of vascular endothelial growth factor-A (VEGFA) and epithelial cadherin (E-cadherin) expression in patients with metastatic colorectal cancer (mCRC) is controversial. MATERIALS AND METHODS: In this prospective study, patients diagnosed with mCRC between August 1, 1998, and August 30, 2003, at the Turku University Hospital, Finland were included. Expression of E-cadherin (membranous and cytoplasmic pattern) and VEGFA in tumour samples was assessed by immunohistochemistry. Tumours were classified as E-cadherin expressers if they demonstrated moderate or strong cytoplasmic or membranous staining, while those positive for VEGFA expression showed a moderate or strong cytoplasmic staining. Of particular interest was the association between membranous or cytoplasmic expression of E-cadherin and VEGFA. The value of strong VEGF-A staining and membranous or cytoplasmic expression of E-cadherin as a predictor of disease outcome over a 6-year period was another point of interest in this study. RESULTS: Of the 67 patients with mCRC, 43 (64%) had tumours positive for cytoplasmic E-cadherin, while in 24 cases (36%), E-cadherin expression was membranous. Strong VEGFA staining was present in half of the cases (n=36, 54% of all 67 mCRC cases). VEGFA expression was significantly correlated with cytoplasmic E-cadherin expression in that 28/36 cases of VEGFA-positive tumours were also positive for cytoplasmic E-cadherin (p=0.012). In addition, among the patients with intense VEGFA expression (n=36), those who had positive cytoplasmic E-cadherin in their tumours had a lower response-rate to first-line therapy with irinotecan, fluorouracil and leucovorin regimen: 5 out of 36 (14%) were chemosensitive. This is in contrast to the patients with VEGFA-positive tumours and membranous E-cadherin (8/36, 22% chemosensitive (p=0.004). The former group also had more ominous prognosis (p<0.001). CONCLUSION: Reduced membranous expression of E-cadherin and increased cytoplasmic E-cadherin expression predict poor survival in mCRC.

Patients with hMLH1 or/and hMSH2-deficient Metastatic Colorectal Cancer Are Associated with Reduced Levels of Vascular Endothelial Growth Factor-1 Expression and Higher Response Rate to Irinotecan-based Regimen.

BACKGROUND/AIM: The benefit of IFL (irinotecan, fluorouracil and leucovorin) regimen for metastatic colorectal cancer patients (mCRCs) with high levels of microsatellite instability (MSI-H) or loss of mismatch repair (dMMR) protein expression, is uncertain. This study investigated the association of tumour MMR-status and VEGF-1 expression with response to first-line IFL regimen in mCRCs. PATIENTS AND METHODS: This prospective study analyzed patients diagnosed with mCRC between August 1st, 1998, and August 30th, 2003, at the Turku University Hospital, Finland. All patients received postoperative IFL regimen. Tumour expression of the MMR proteins, hMLH1 and hMSH2, and VEGF-1 expression were assessed by immunohistochemistry (IHC). Tumours with dMMR were those demonstrating loss of MMR protein expression, and tumours with high VEGF-1 expression were those showing moderate or strong cytoplasmic staining. The primary endpoint was the association between tumour hMLH1 or/and hMSH2-deficient and VEGF-1 expression; the relation between tumour MMR-status and IFL response rate was the secondary endpoint. RESULTS: Of the 67 mCRCs patients, 29 (43%) were hMLH1 or/and hMSH2-deficient and 15 (22%) were pMMR mCRCs. At diagnosis, patients with hMLH1 or/and hMSH2-deficient tumours expressed lower levels of VEGF-1 compared to pMMR tumour patients (p=0.01). More than half (n=17, 59%) of those with dMMR were chemosensitive to first-line IFL regimen, while just one-fifth (n=3, 20%) of those with pMMR were chemosensitive to the IFL regimen (p=0.045). CONCLUSION: Association between MMR-status and VEGF-1 expression predicts clinical outcome in mCRC patients.