Role of E2F transcription factor in oral cancer: Recent insight and advancements.

The family of mammalian E2F transcription factors (E2Fs) comprise of 8 members (E2F1-E2F8) classified as activators (E2F1-E2F3) and repressors (E2F4-E2F8) primarily regulating the expression of several genes related to cell proliferation, apoptosis and differentiation, mainly in a cell cycle-dependent manner. E2F activity is frequently controlled via the retinoblastoma protein (pRb), cyclins, p53 and the ubiquitin-proteasome pathway. Additionally, genetic or epigenetic changes result in the deregulation of E2F family genes expression altering S phase entry and apoptosis, an important hallmark for the onset and development of cancer. Although studies reveal E2Fs to be involved in several human malignancies, the mechanisms underlying the role of E2Fs in oral cancer lies nascent and needs further investigations. This review focuses on the role of E2Fs in oral cancer and the etiological factors regulating E2Fs activity, which in turn transcriptionally control the expression of their target genes, thus contributing to cell proliferation, metastasis, and drug/therapy resistance. Further, we will discuss therapeutic strategies for E2Fs, which may prevent oral tumor growth, metastasis, and drug resistance.

Copresence of High-Risk Human Papillomaviruses and Epstein-Barr Virus in Colorectal Cancer: A Tissue Microarray and Molecular Study from Lebanon.

Colorectal cancer (CRC) is the third most common cause of cancer-related deaths worldwide. Human papillomaviruses (HPVs) and Epstein-Barr virus (EBV) have been reported to be present in different types of human cancers, including CRCs, where they can play a key role in the onset and/or progression of these cancers. Thus, we herein explored the prevalence of high-risk HPVs and EBV in a cohort of 94 CRC tissue samples and 13 colorectal normal tissues from the Lebanese population using polymerase chain reaction, immunohistochemistry, and tissue microarray methodologies. We found that high-risk HPVs are present in 64%, while EBV is present in 29% of our CRC samples. Additionally, our data showed that high-risk HPV types (16, 18, 35, 58, 51, 45, 52, 31, and 33) are the most frequent in CRC in the Lebanese cohort, respectively. Our data point out that HPVs and EBV are copresent in 28% of the samples. Thus, this study clearly suggests that high-risk HPVs and EBV are present/copresent in CRCs, where they could play an important role in colorectal carcinogenesis. Nevertheless, further investigations using a larger cohort are needed to elucidate the possible cooperation between these oncoviruses in the development of CRC.

Novel Nitrogen-Based Chalcone Analogs Provoke Substantial Apoptosis in HER2-Positive Human Breast Cancer Cells via JNK and ERK1/ERK2 Signaling Pathways.

Natural chalcones possess antitumor properties and play a role as inducers of apoptosis, antioxidants and cytotoxic compounds. We recently reported that novel nitrogen chalcone-based compounds, which were generated in our lab, have specific effects on triple-negative breast cancer cells. However, the outcome of these two new compounds on human epidermal growth factor receptor 2 (HER2)-positive breast cancer remains nascent. Thus, we herein investigated the effects of these compounds (DK-13 and DK-14) on two HER2-positive breast cancer cell lines, SKBR3 and ZR75. Our data revealed that these compounds inhibit cell proliferation, deregulate cell-cycle progression and significantly induce cell apoptosis in both cell lines. Furthermore, the two chalcone compounds cause a significant reduction in the cell invasion ability of SKBR3 and ZR75 cancer cells. In parallel, we found that DK-13 and DK-14 inhibit colony formation of both cell lines in comparison to their matched controls. On the other hand, we noticed that these two compounds can inhibit angiogenesis in the chorioallantoic membrane model. The molecular pathway analysis of chalcone compounds exposed cells revealed that these compounds inhibit the expression of both JNK1/2/3 and ERK1/2, the major plausible molecular pathways behind these events. Our findings implicate that DK-13 and DK-14 possess effective chemotherapeutic outcomes against HER2-positive breast cancer via the ERK1/2 and JNK1/2/3 signaling pathways.

Co-prevalence of human Papillomaviruses (HPV) and Epstein-Barr virus (EBV) in healthy blood donors from diverse nationalities in Qatar.

BACKGROUND: Infections by both human oncoviruses, human Papillomaviruses (HPV) and Epstein-Barr virus (EBV) are very common in the adult human population and are associated with various malignancies. While HPV is generally transmitted sexually or via skin-to-skin contact, EBV is frequently transmitted by oral secretions, blood transfusions and organ transplants. This study aims to determine the prevalence and circulating genotypes of HPV and EBV in healthy blood donors in Qatar. METHODS: We explored the co-prevalence of high-risk HPVs and EBV in 378 males and only 7 females blood donors of different nationalities (mainly from Qatar, Egypt, Syria, Jordan, Pakistan, and India) residing in Qatar, using polymerase chain reaction (PCR). DNA was extracted from the buffy coat and genotyping was performed using PCR and nested-PCR targeting E6 and E7 as well as LMP-1 of HPV and EBV, respectively. RESULTS: We found that from the total number of 385 cases of healthy blood donors studied, 54.8% and 61% of the samples are HPVs and EBV positive, respectively. Additionally, our data revealed that the co-presence of both high-risk HPVs and EBV is 40.4% of the total samples. More significantly, this study pointed out for the first time that the most frequent high-risk HPV types in Qatar are 59 (54.8%), 31 (53.7%), 52 (49.1%), 51 (48.6%), 58 (47%) and 35 (45.5%), while the most commonly expressed low-risk HPV types are 53 (50.6%), 11 (45.5), 73 (41.7%) and 6 (41.3%), with all the cases showing multiple HPVs infection. CONCLUSION: In this study, we demonstrated for the first time that HPV and EBV are commonly co-present in healthy blood donors in Qatar. On the other hand, it is important to highlight that these oncoviruses can also be co-present in several types of human cancers where they can cooperate in the initiation and/or progression of these cancers. Therefore, more studies regarding the co-presence of these oncoviruses and their interaction are necessary to understand their cooperative role in human diseases.

Circulating miRNAs in HER2-Positive and Triple Negative Breast Cancers: Potential Biomarkers and Therapeutic Targets.

Breast cancer is one of the most prevalent diseases among women worldwide and is highly associated with cancer-related mortality. Of the four major molecular subtypes, HER2-positive and triple-negative breast cancer (TNBC) comprise more than 30% of all breast cancers. While the HER2-positive subtype lacks estrogen and progesterone receptors and overexpresses HER2, the TNBC subtype lacks estrogen, progesterone and HER2 receptors. Although advances in molecular biology and genetics have substantially ameliorated breast cancer disease management, targeted therapies for the treatment of estrogen-receptor negative breast cancer patients are still restricted, particularly for TNBC. On the other hand, it has been demonstrated that microRNAs, miRNAs or small non-coding RNAs that regulate gene expression are involved in diverse biological processes, including carcinogenesis. Moreover, circulating miRNAs in serum/plasma are among the most promising diagnostic/therapeutic tools as they are stable and relatively easy to quantify. Various circulating miRNAs have been identified in several human cancers including specific breast cancer subtypes. This review aims to discuss the role of circulating miRNAs as potential diagnostic and prognostic biomarkers as well as therapeutic targets for estrogen-receptor negative breast cancers, HER2+ and triple negative.

Elaeagnus angustifolia Plant Extract Inhibits Angiogenesis and Downgrades Cell Invasion of Human Oral Cancer Cells via Erk1/Erk2 Inactivation.

Oral cancer is a common malignancy in both men and women worldwide; this cancer is characterized by a marked propensity for invasion and spreading to local lymph nodes. On the other hand, Elaeagnus angustifolia (EA) is a medicinal plant that has been used for centuries for treating many human diseases in the Middle East. However, the effect of EA plant extract on human cancers especially oral has not been investigated yet. Thus, first we examined the outcome of EA flower extract on angiogenesis, using the chorioallantoic membrane (CAM) of the chicken embryo; we found that EA extract reduces blood vessel development of the CAM. Then, we investigated the effect of EA flower extract on selected parameters in FaDu and SCC25 oral cancer cell lines. Our results show that EA extract inhibits cell proliferation and colony formation, in addition to the initiation of S cell cycle arrest and reduction of G1/G2 phase. In parallel, EA extract provokes differentiation to an epithelial phenotype "mesenchymal-to-epithelial transition: MET" which is the opposite of "epithelial-to-mesenchymal transition, EMT": an important event in cell invasion and metastasis. Thus, EA plant extract causes a dramatic decrease in cell invasion and motility abilities of FaDu and SCC25 cancer cells in comparison with their controls. These changes are accompanied by an upregulation of E-cadherin expression. The molecular pathway analysis of the EA flower extract reveals that it can inhibit the phosphorylation of Erk1/Erk2, which could be behind the inhibition of angiogenesis, the initiation of MET event, and the overexpression of E-cadherin. Our findings indicate that EA plant extract can reduce human oral cancer progression by the inhibition of angiogenesis and cell invasion via Erk1/Erk2 signaling pathways.

Electrospun polyvinyl alcohol membranes incorporated with green synthesized silver nanoparticles for wound dressing applications.

Electrospun membranes have the potential to act as an effective barrier for wounds from the external environment to prevent pathogens. In addition, materials with good antibacterial properties can effectively fight off the invading pathogens. In this paper, we report the development of a novel electrospun polyvinyl alcohol (PVA) membrane containing biosynthesized silver nanoparticle (bAg) for wound dressing applications. Plant extract from a medicinal plant Mimosa pudica was utilized for the synthesis of bAg. Synthesized bAg were characterized by Ultraviolet-Visible (UV) Spectroscopy and Fourier Transform Infrared Spectroscopy (FTIR). The morphology of bAg was obtained from Transmission Electron Microscopy (TEM) and found that they were spherical in morphology with average particle size 7.63 ± 1.2 nm. bAg nanoparticles incorporated PVA membranes were characterized using several physicochemical techniques such as Scanning Electron Microscopy (SEM), Energy Dispersive X-Ray Spectroscopy (EDS) and X-Ray Diffraction (XRD) analysis. Experimental results confirmed the successful incorporation of bAg in PVA fibers. PVA nanofiber membranes incorporated with bAg showed good mechanical strength, excellent exudate uptake capacity, antibacterial activity, blood compatibility and cytocompatibility.

The effect of novel nitrogen-based chalcone analogs on colorectal cancer cells: Insight into the molecular pathways.

In colorectal cancer (CRC), aberrations in KRAS are associated with aggressive tumorigenesis and an overall low survival rate because of chemoresistance and adverse effects. Ergo, complementary, and integrative medicines are being considered for CRC treatment. Among which is the use of natural chalcones that are known to exhibit anti-tumor activities in KRAS mutant CRC subtypes treatment regimens. Consequently, we examine the effect of two novel compounds (DK13 and DK14) having chalcones with nitrogen mustard moiety on CRC cell lines (HCT-116 and LoVo) with KRAS mutation. These compounds were synthesized in our lab and previously reported to exhibit potent activity against breast cancer cells. Our data revealed that DK13 and DK14 treatment suppress cell growth, disturb the progression of cell cycle, and trigger apoptosis in CRC cell lines. Besides, treatment with both compounds impedes cell invasion and colony formation in both cell lines as compared to 5-FU; this is accompanied by up and down regulations of E-cadherin and Vimentin, respectively. At the molecular level, both compounds deregulate the expression and phosphorylation of ß-catenin, Akt and mTOR, which are the main likely molecular mechanisms underlying these biological occurrences. Our findings present DK13 and DK14 as novel chemotherapies against CRC, through ß-catenin/Akt/mTOR signaling pathways.

Metformin and HER2-positive breast cancer: Mechanisms and therapeutic implications.

Due to the strong association between diabetes and cancer incidents, several anti-diabetic drugs, including metformin, have been examined for their anticancer activity. Metformin is a biguanide antihyperglycemic agent used as a first-line drug for type II diabetes mellitus. It exhibits anticancer activity by impacting different molecular pathways, such as AMP-inducible protein kinase (AMPK)-dependent and AMPK-independent pathways. Additionally, Metformin indirectly inhibits IGF-1R signaling, which is highly activated in breast malignancy. On the other hand, breast cancer is one of the major causes of cancer-related morbidity and mortality worldwide, where the human epidermal growth factor receptor-positive (HER2-positive) subtype is one of the most aggressive ones with a high rate of lymph node metastasis. In this review, we summarize the association between diabetes and human cancer, listing recent evidence of metformin's anticancer activity. A special focus is dedicated to HER2-positive breast cancer with regards to the interaction between HER2 and IGF-1R. Then, we discuss combination therapy strategies of metformin and other anti-diabetic drugs in HER2-positive breast cancer.

Incidence and association of high-risk HPVs and EBV in patients with advanced stages of colorectal cancer from Qatar.

High-risk Human Papillomaviruses (HPVs) and Epstein - Barr virus (EBV) are present and involved in several types of human carcinomas, including cervical and, head and neck cancers. Nevertheless, their presence and association in the pathogenesis of colorectal cancer is still nascent. The current study explored the association between the high-risk HPVs and EBV and tumor phenotype in colorectal cancers (CRCs) in the Qatari population. We found that high-risk HPVs and EBV are present in 69/100 and 21/100 cases, respectively. Additionally, 17% of the cases showed a copresence of high-risk HPVs and EBV, with a significant correlation only between the HPV45 subtype and EBV (p = .004). While the copresence did not significantly associate with clinicopathological characteristics, we identified that coinfection with more than two subtypes of HPV is a strong predictor of advanced stage CRC, and the confounding effect of the copresence of EBV in such cases strengthens this association. Our results indicate that high-risk HPVs and EBV can co-present in human CRCs in the Qatari population where they could plausibly play a specific role in human colorectal carcinogenesis. However, future studies are essential to confirm their copresence and synergistic role in developing CRCs.

Effect of Water-Pipe Smoking on the Normal Development of Zebrafish.

BACKGROUND: Among all types of tobacco consumption, Water-Pipe Smoking (WPS) is the most widely used in the Middle East and second-most in several other countries. The effect of WPS on normal development is not yet fully understood, thus the aim of this study is to explore the acute toxicity effects of WPS extract on zebrafish larvae. METHODS: In this study, we compared the effects of WPS smoke condensates at concentrations varying from 50 to 200 µg/mL on developmental, cardiac, and behavioural (neurotoxicity) functions. Gene expression patterns of cardiac biomarkers were also evaluated by RT-qPCR. RESULTS: Exposing zebrafish embryos to 50, 100, 150 and 200 µg/mL WPS for three days did not affect the normal morphology of Zebrafish embryos, as the tail flicking, behavioural and locomotion assays did not show any change. However, WPS deregulated cardiac markers including atrial natriuretic peptide (ANP/NPPA) and brain natriuretic peptide (BNP/NPPB). Furthermore, it induced apoptosis in a dose-dependent manner. CONCLUSION: Our data demonstrate that WPS can significantly affect specific cardiac parameters during the normal development of zebrafish. Further investigations are necessary to elucidate the pathogenic outcome of WPS on different aspects of human life, including pregnancy.

SnoRNAs and miRNAs Networks Underlying COVID-19 Disease Severity.

There is a lack of predictive markers for early and rapid identification of disease progression in COVID-19 patients. Our study aims at identifying microRNAs (miRNAs)/small nucleolar RNAs (snoRNAs) as potential biomarkers of COVID-19 severity. Using differential expression analysis of microarray data (n = 29), we identified hsa-miR-1246, ACA40, hsa-miR-4532, hsa-miR-145-5p, and ACA18 as the top five differentially expressed transcripts in severe versus asymptomatic, and ACA40, hsa-miR-3609, ENSG00000212378 (SNORD78), hsa-miR-1231, hsa-miR-885-3p as the most significant five in severe versus mild cases. Moreover, we found that white blood cell (WBC) count, absolute neutrophil count (ANC), neutrophil (%), lymphocyte (%), red blood cell (RBC) count, hemoglobin, hematocrit, D-Dimer, and albumin are significantly correlated with the identified differentially expressed miRNAs and snoRNAs. We report a unique miRNA and snoRNA profile that is associated with a higher risk of severity in a cohort of SARS-CoV-2 infected patients. Altogether, we present a differential expression analysis of COVID-19-associated microRNA (miRNA)/small nucleolar RNA (snoRNA) signature, highlighting their importance in SARS-CoV-2 infection.

Cerium Oxide Nanoparticle Incorporated Electrospun Poly(3-hydroxybutyrate-co-3-hydroxyvalerate) Membranes for Diabetic Wound Healing Applications.

Insufficient cell proliferation, cell migration, and angiogenesis are among the major causes for nonhealing of chronic diabetic wounds. Incorporation of cerium oxide nanoparticles (nCeO2) in wound dressings can be a promising approach to promote angiogenesis and healing of diabetic wounds. In this paper, we report the development of a novel nCeO2 containing electrospun poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) membrane for diabetic wound healing applications. In vitro cell adhesion studies, chicken embryo angiogenesis assay, and in vivo diabetic wound healing studies were performed to assess the cell proliferation, angiogenesis, and wound healing potential of the developed membranes. The experimental results showed that nCeO2 containing PHBV membranes can promote cell proliferation and cell adhesion when used as wound dressings. For less than 1% w/w of nCeO2 content, human mammary epithelial cells (HMEC) were adhered parallel to the individual fibers of PHBV. For higher than 1% w/w of nCeO2 content, cells started to flatten and spread over the fibers. In ovo angiogenic assay showed the ability of nCeO2 incorporated PHBV membranes to enhance blood vessel formation. In vivo wound healing study in diabetic rats confirmed the wound healing potential of nCeO2 incorporated PHBV membranes. The study suggests that nCeO2 incorporated PHBV membranes have strong potential to be used as wound dressings to enhance cell proliferation and vascularization and promote the healing of diabetic wounds.

Water-pipe smoking and serum testosterone levels in adult males in Qatar.

INTRODUCTION: Water-pipe (WP) smoking is the most common method of tobacco consumption in the Middle-East and is rapidly spreading on a global scale. Although, water-pipe smoking is linked to various diseases, such as emphysema and various types of cancers, its effect on testosterone levels has yet to be investigated. This study explores the effect of water-pipe smoking on serum testosterone levels in males in Qatar. METHODS: In this cross-sectional sample within a cohort study, we retrieved data for a total of 1000 male volunteers from the Qatar BioBank (QBB) project. A self-reported questionnaire was used to determine the water-pipe smoking status of participants. Moreover, participants were stratified based on the frequency of smoking. Total testosterone and sex hormone binding globulin (SHBG) were measured clinically, whereas free testosterone and bioavailable testosterone were calculated using Vermeulen's equation. Hormone values of 541 males (277 water-pipe smokers and 264 non-smokers) were compared using multiple regression analysis based on water-pipe smoking status after adjusting for confounding factors. RESULTS: No statistically significant difference was observed between WP smokers and non-water-pipe smokers in the likelihood of having lower or higher total testosterone, after adjustment for confounding factors. Similar results were found in free testosterone, bioavailable testosterone, and sex hormone binding globulin (all p>0.05). When compared with the reference group, both light and heavy water-pipe smokers had a similar likelihood of circulating low total testosterone levels (OR=0.83, 95% CI: 0.46-1.49; and OR=0.80, 95% CI: 0.43-1.49; respectively). CONCLUSIONS: Our results reveal, for the first time, that there is no significant change in total testosterone, free testosterone, bioavailable testosterone and sex hormone binding globulin in waterpipe smokers compared to non-water-pipe smokers. Therefore, we believe that further studies are needed to confirm the effect of water-pipe smoking on testosterone in different populations.

Effect of cell-phone radiofrequency on angiogenesis and cell invasion in human head and neck cancer cells.

BACKGROUND: Today, the cell phone is the most widespread technology globally. However, the outcome of cell-phone radiofrequency on head and neck cancer progression has not yet been explored. METHODS: The chorioallantoic membrane (CAM) and human head and neck cancer cell lines, FaDu and SCC25, were used to explore the outcome of cell-phone radiofrequency on angiogenesis, cell invasion, and colony formation of head and neck cancer cells, respectively. Western blot analysis was used to investigate the impact of the cell phone on the regulation of E-cadherin and Erk1/Erk2 genes. RESULTS: Our data revealed that cell-phone radiofrequency promotes angiogenesis of the CAM. In addition, the cell phone enhances cell invasion and colony formation of human head and neck cancer cells; this is accompanied by a downregulation of E-cadherin expression. More significantly, we found that the cell phone can activate Erk1/Erk2 in our experimental models. CONCLUSION: Our investigation reveals that cell-phone radiofrequency could enhance head and neck cancer by stimulating angiogenesis and cell invasion via Erk1/Erk2 activation.