Advances in nanotechnology-enabled drug delivery for combining PARP inhibitors and immunotherapy in advanced ovarian cancer.

Advanced ovarian cancer is a malignancy that spreads beyond the ovaries to the pelvis, abdomen, lungs, or lymph nodes. Effective treatment options are available to improve survival rates in patients with advanced ovarian cancer. These include radiation, surgery, chemotherapy, immunotherapy, and targeted therapy. Drug resistance, however, remains a significant challenge in pharmacotherapeutic interventions, leading to reduced efficacy and unfavorable patient outcomes. Combination therapy, which involves using multiple drugs with different mechanisms of action at their optimal dose, is a promising approach to circumvent this challenge and it involves using multiple drugs with different mechanisms of action at their optimal dose. In recent years, nanotechnology has emerged as a valuable alternative for enhancing drug delivery precision and minimize toxicity. Nanoparticles can deliver drugs to specific cancer cells, resulting in higher drug concentrations at the tumor site, and reducing overall drug toxicity. Nanotechnology-based drug delivery systems have the potential to improve the therapeutic effects of anti-cancer drugs, reduce drug resistance, and improve outcomes for patients with advanced ovarian cancer. This literature review aims to examine the current understanding of combining poly (ADP-ribose) polymerase (PARP) inhibitors and immunotherapy in treating advanced ovarian cancer and the potential impact of nanotechnology on drug delivery.

Effects of neratinib on angiogenesis and the early stage of the embryo using chicken embryo as a model.

Angiogenesis is the process of forming new blood capillaries from pre-existing vessels. Even though it is essential during normal development, it plays a major role in cancer progression. Neratinib is a pan-human epidermal growth factor receptor (HER) inhibitor that has recently been approved for the treatment of HER2-positive breast cancer. However, its effects on angiogenesis and embryogenesis remain unknown. This study examined the antiangiogenic effects of neratinib using the chorioallantoic membrane (CAM) of chicken embryos. We also evaluated neratinib's toxicity during the early stages of normal development using the chicken embryos, primary embryonic fibroblasts (EFBs), and human umbilical vein endothelial cells (HUVEC). Our findings revealed that neratinib significantly inhibited the CAM angiogenesis compared to controls by reducing vessel percentage area and the average vessel length. Furthermore, neratinib downregulated vascular endothelial growth factor (VEGF), a key mediator of angiogenesis. At lower concentrations, neratinib was well-tolerated during early stages of normal development. Additionally, EFBs treated with neratinib showed no morphological or viability changes when compared to controls. However, at the highest concentration tested, neratinib treatment reduced HUVEC cell viability. This effect may be associated with the dysregulation of key apoptotic genes, including caspase-3, caspase-8, caspase-9, and the B-cell lymphoma 2 (Bcl2) gene. Our findings indicate a novel potential application of neratinib as an antiangiogenic agent, exhibiting tolerable toxicity in the early stages of embryogenesis.

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.

Coinfection of HPVs Is Associated with Advanced Stage in Colorectal Cancer Patients from Qatar.

High-risk human papillomaviruses (HPVs) are considered risk factors in the origin of several human malignancies, such as breast, cervical, head and neck, as well as colorectal cancers. However, there are no data reported on the HPV status in colorectal cancer in the State of Qatar. Therefore, we herein examined the presence of high-risk HPVs (16, 18, 31, 33, 35, 45, 51, 52, and 59), using polymerase chain reaction (PCR) in a cohort of 100 Qatari colorectal cancer patients, and their association with tumor phenotype. We found that high-risk HPV types 16, 18, 31, 35, 45, 51, 52, and 59 were present in 4, 36, 14, 5, 14, 6, 41, and 17% of our samples, respectively. Overall, 69 (69%) of the 100 samples were HPV positive; among these, 34/100 (34%) were positive for single HPV subtypes, while 35/100 (35%) of the samples were positive for two or more HPV subtypes. No significant association was noted between the presence of HPV and tumor grade, stage, or location. However, the presence of coinfection of HPV subtypes strongly correlated with advanced stage (stage 3 and 4) colorectal cancer, indicating that the copresence of more than one HPV subtype can significantly worsen the prognosis of colorectal cancer. The results from this study imply that coinfection with high-risk HPV subtypes is associated with the development of colorectal cancer in the Qatari population.

Human Papillomaviruses-Related Cancers: An Update on the Presence and Prevention Strategies in the Middle East and North African Regions.

The human papillomavirus (HPV) is a non-enveloped double-stranded DNA virus capable of infecting skin and mucosa epithelial cells. Commonly, HPV infection is associated with sexually transmitted diseases and is considered the leading cause of cervical cancer and other carcinomas of the anogenital tract. However, several studies reported their involvement in cancers of non-sexual regions, including colorectal, head and neck, and breast cancers. There are several studies from the Middle East and North Africa (MENA) regions on the potential association between high-risk HPVs and cancer; nevertheless, there are limited studies that address the significance of HPV vaccination as a potential guard against these cancers. In the current review, we present a comprehensive description of the current HPV-associated cancers prevalence rates in the MENA region, demonstrating their steady increase with time, especially in African regions. Moreover, we discuss the potential impact of vaccination against HPV infections and its outcome on human health in this region.

Incidence of HPVs, EBV, and MMTV-Like Virus in Breast Cancer in Qatar.

INTRODUCTION: Human papillomaviruses (HPVs), Epstein-Barr virus (EBV), and mouse mammary tumor virus-like virus (MMTV-like virus) can be present and contribute to breast cancer development and progression. However, the role of these oncoviruses and their crosstalk in breast cancer is still unclear. METHODS: We explored the co-presence of high-risk HPVs, EBV, and MMTV-like virus in 74 breast cancer samples from Qatar using PCR. RESULTS: We found the presence of HPV and EBV in 65% and 49% of our cancer sample cohorts; 47% of the samples are positive for both oncoviruses. The MMTV-like virus alone was detected in 15% of the samples with no significant association with clinicopathological features. The three oncoviruses were co-present in 14% of the cases; no significant association was noted between the co-presence of these viruses and the clinicopathological features. CONCLUSION: Despite the presence of the oncoviruses, additional studies are necessary to understand their interactions in human breast carcinogenesis.

HPV and Recurrent Respiratory Papillomatosis: A Brief Review.

Recurrent Respiratory Papillomatosis (RRP) is a rare but severe manifestation of human papillomavirus (HPV). As our knowledge about HPV infections has expanded, it has become possible to understand the course of RRP disease and unravel plausible efficient methods to manage the disease. However, the surge in reports on HPV has not been accompanied by a similar increase in research about RRP specifically. In this paper, we review the clinical manifestation and typical presentation of the illness. In addition, the pathogenesis and progression of the disease are described. On the other hand, we discuss the types of treatments currently available and future treatment strategies. The role of vaccination in both the prevention and treatment of RRP will also be reviewed. We believe this review is essential to update the general knowledge on RRP with the latest information available to date to enhance our understanding of RRP and its management.

Fascin in Gynecological Cancers: An Update of the Literature.

Fascin is an actin-binding protein that is encoded by the FSCN1 gene (located on chromosome 7). It triggers membrane projections and stimulates cell motility in cancer cells. Fascin overexpression has been described in different types of human cancers in which its expression correlated with tumor growth, migration, invasion, and metastasis. Moreover, overexpression of fascin was found in oncovirus-infected cells, such as human papillomaviruses (HPVs) and Epstein-Barr virus (EBV), disrupting the cell-cell adhesion and enhancing cancer progression. Based on these findings, several studies reported fascin as a potential biomarker and a therapeutic target in various cancers. This review provides a brief overview of the FSCN1 role in various cancers with emphasis on gynecological malignancies. We also discuss fascin interactions with other genes and oncoviruses through which it might induce cancer development and progression.

Oncoproteins of High-Risk HPV and EBV Cooperate to Enhance Cell Motility and Invasion of Human Breast Cancer Cells via Erk1/Erk2 and ß-Catenin Signaling Pathways.

Breast cancer is a leading cause of death in women around the world. Most breast cancer-related deaths are a result of complications from the metastatic spread. Several recent studies reported that high-risk human papillomaviruses (HPVs) and Epstein-Barr virus (EBV) are co-presented in different types of human carcinomas including breast; however, the cooperative effects between high-risk HPVs and EBV oncoproteins in human breast cancer have not been investigated yet. Thus, we herein explored the cooperation outcome between E6/E7 and latent membrane protein 1 (LMP1) oncoproteins of high-risk HPV type 16 and EBV, respectively, in two human breast cancer cell lines, MCF7 and MDA-MB-231. Our data revealed that the cooperation of E6/E7 and LMP1 oncoproteins stimulates cell proliferation and deregulates cell cycle progression of human breast cancer and normal mammary cells; in parallel, we noted that E6/E7/LMP1 incite colony formation of both breast cancer cell lines but not normal cells. More significantly, our results point out that the co-expression of E6/E7 and LMP1 oncoproteins enhances cell motility and invasion of MCF7 and MDA-MB-231 cell lines; this is accompanied by deregulation of epithelial-mesenchymal transition biomarkers including E-cadherin, ß-catenin, fascin, and vimentin. The molecular pathway analysis of HPV and EBV oncoproteins cooperation shows that it can enhance the phosphorylation of extracellular signal-regulated kinases (Erk1/Erk2) in addition to ß-catenin, which could be behind the effect of this cooperation in our cell models. The study clearly suggests that high-risk HPV and EBV coinfection can play an important role in breast cancer progression via Erk1/Erk2 and ß-catenin signaling pathways.

The co-presence of high-risk human papillomaviruses and Epstein-Barr virus is linked with tumor grade and stage in Qatari women with breast cancer.

High-risk human papillomaviruses (HPV) can be present and cooperate with Epstein-Barr virus (EBV) to promote the onset and/or progression of various cancers including cervical, breast, head and neck as well as colorectal. In this investigation, we explored the co-prevalence of high-risk HPV and EBV in 74 breast cancer tissues from Qatari women using polymerase chain reaction. We found that high-risk HPV and EBV are present in 48/74 (65%) and 36/74 (49%) of the cases, respectively. While we noted that the presence of HPV presence is associated with triple-negative breast cancer (TNBC) (p = .008), however, the presence of EBV did not correlate with any breast cancer subgroup. Moreover, our data revealed that high-risk HPV and EBV are co-present in 35/74 (47%) of the samples and their co-presence is significantly associated with tumor grade (p = .04) and tumor stage (p = .04). These data indicate that HPV and EBV are commonly co-present in breast cancer and their association could be linked with a more aggressive tumor phenotype. Thus, further investigations are essential to understand the underlying mechanisms of HPV and EBV cooperation in breast carcinogenesis.

Co-incidence of Human Papillomaviruses and Epstein-Barr Virus Is Associated With High to Intermediate Tumor Grade in Human Head and Neck Cancer in Syria.

High-risk human papillomaviruses (high-risk HPVs) have been recently reported to be co-present with Epstein-Barr virus (EBV) in different types of human cancers including head and neck (HN), where they can cooperate in the initiation and/or progression of this cancer. Accordingly, we herein explored the prevalence of high-risk HPVs and EBV in 80 HN cancer tissues from the Syrian population using polymerase chain reaction, immunohistochemistry, and tissue microarray methodologies. We report that high-risk HPVs and EBV are present in 35/80 (43.7%) and 41/80 (51.2%) of our samples, respectively, and the most frequent HPV types are 33, 16, 18, 45, 52, 58, 35, 51, and 31, in this order. More significantly, our data reveal that 25/80 (31.2%) of cancer cases are positive for high-risk HPVs as well as EBV, and their co-presence is associated with high/intermediate-grade squamous cell carcinomas. These data confirm the co-presence of high-risk HPVs and EBV in HN cancers in the Syrian population of the Middle East and demonstrate that their co-incidence is linked to a more aggressive cancer phenotype. Thus, future studies are required to confirm these data and elucidate the exact role of high-risk and EBV cooperation in human HN carcinogenesis.

Co-presence of human papillomaviruses and Epstein-Barr virus is linked with advanced tumor stage: a tissue microarray study in head and neck cancer patients.

BACKGROUND: Human papillomaviruses (HPVs) and Epstein-Barr virus (EBV), known oncoviruses, can be co-present and cooperate in the initiation and/or progression of human carcinomas, including head and neck. Based on this fact, we recently reported the prevalence of both HPVs and EBV in cervical and breast cancers. METHODS: We herein explore for the first time the co-prevalence of high-risk HPVs and EBV in 98 head and neck (HN) squamous cell carcinoma (SCC) tissues from Bosnian patients using polymerase chain reaction (PCR) and immunohistochemistry (IHC) analysis, as well as tissue microarray methodology. RESULTS: The majority of these cancer tissue cases were from the oral cavity (68%). We found that high-risk HPVs and EBV are co-present in 34.7% of the SCC samples; with a significant correlation between the various HPV types and EBV co-incidence (p = 0.03). Our data showed that 30.8% of oral SCCs are positive for E6 oncoprotein of high-risk HPVs and 44.6% are positive for LMP1 of EBV. The most commonly expressed HPVs in our HNSCC samples include HPV types 16, 18, 45 and 58. Additionally, 37.5% of oral SCCs are positive for both HPVs and EBV, with statistically significant association between high-risk HPV types and EBV (p < 0.05). More importantly, our data revealed that the co-presence of HPV and EBV is strongly correlated with advanced tumor stage (p = 0.035). CONCLUSION: In this study we show that HPV and EBV oncoviruses are co-present in HNSCC, particularly in oral cancer, where they can cooperate in the initiation and/or progression of this cancer. Thus, further studies are necessary to elucidate the mechanism of this cooperation.

High-Risk Human Papillomaviruses and Epstein-Barr Virus in Colorectal Cancer and Their Association with Clinicopathological Status.

Colorectal cancer (CRC) is a common malignancy with a high mortality rate worldwide. It is a complex, multifactorial disease that is strongly impacted by both hereditary and environmental factors. The role of microbes (e.g., viruses) in the pathogenesis of CRC is poorly understood. In the current study, we explored the status of high-risk human papillomaviruses (HPV) and Epstein-Barr virus (EBV) in a well-defined CRC cohort using immunohistochemistry and polymerase chain reaction assays. Our data showed that high-risk HPVs were common (~80%) and EBV had a low presence (14-25%) in the CRC samples. The most common high-risk HPVs are HPV16, 31, 18, 51, 52 and 45 genotypes. The co-presence of high-risk HPV and EBV was observed in ~16% of the sample population without any significant association with the clinicopathological variables. We conclude that high-risk HPVs are very prevalent in CRC samples while EBV positivity is relatively low. The co-expression of the two viruses was observed in a minority of cases and without any correlation with the studied parameters. Further studies are necessary to confirm the clinical relevance and potential therapeutic (preventive) effects of the observations reported herein.

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.

Co-presence of Epstein-Barr virus and high-risk human papillomaviruses in Syrian colorectal cancer samples.

We recently performed two studies exploring the presence of Epstein-Barr virus (EBV) and high-risk human papillomaviruses (HPVs) types 16, 18, 31, 33 and 35 in human colorectal cancers from the Syrian population. Herein, we report that EBV and high-risk HPVs are co-present in colorectal cancers from Syria. We reveal that 17 (~17%) of 102 cancer samples are positive for both EBV and high-risk HPVs and their co-presence is associated with high/intermediate grade invasive carcinomas. These data suggest that EBV and high-risk HPVs are co-present in human colorectal cancers where they might cooperate on the initiation and/or progression of these cancers. Thus, we believe that future studies are necessary to confirm the co-presence of these oncoviruses and their cooperative role in human colorectal carcinogenesis.

Gene Expression and miRNAs Profiling: Function and Regulation in Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Breast Cancer.

Breast cancer is the second most common cause of cancer-related deaths among women worldwide. It is a heterogeneous disease with four major molecular subtypes. One of the subtypes, human epidermal growth factor receptor 2 (HER2)-enriched (HER2-positive) is characterized by the absence of estrogen and progesterone receptors and overexpression of HER2 receptor, and accounts for 15-20% of all breast cancers. Despite the anti-HER2 and cytotoxic chemotherapy, HER2 subtype is an aggressive disease with significant mortality. Recent advances in molecular biology techniques, including gene expression profiling, proteomics, and microRNA analysis, have been extensively used to explore the underlying mechanisms behind human breast carcinogenesis and metastasis including HER2-positive breast cancer, paving the way for developing new targeted therapies. This review focuses on recent advances on gene expression and miRNA status in HER2-positive breast cancer.

Triple Negative Breast Cancer Profile, from Gene to microRNA, in Relation to Ethnicity.

Breast cancer is the most frequent cause of cancer-related deaths among women worldwide. It is classified into four major molecular subtypes. Triple-negative breast cancers (TNBCs), a subgroup of breast cancer, are defined by the absence of estrogen and progesterone receptors and the lack of HER-2 expression; this subgroup accounts for ~15% of all breast cancers and exhibits the most aggressive metastatic behavior. Currently, very limited targeted therapies exist for the treatment of patients with TNBCs. On the other hand, it is important to highlight that knowledge of the molecular biology of breast cancer has recently changed the decision-making process regarding the course of cancer therapies. Thus, a number of new techniques, such as gene profiling and sequencing, proteomics, and microRNA analysis have been used to explore human breast carcinogenesis and metastasis including TNBC, which consequently could lead to new therapies. Nevertheless, based on evidence thus far, genomics profiles (gene and miRNA) can differ from one geographic location to another as well as in different ethnic groups. This review provides a comprehensive and updated information on the genomics profile alterations associated with TNBC pathogenesis associated with different ethnic backgrounds.

Co-Incidence of Epstein-Barr Virus and High-Risk Human Papillomaviruses in Cervical Cancer of Syrian Women.

Epstein-Barr virus (EBV) has been recently shown to be co-present with high-risk human papillomaviruses (HPVs) in human cervical cancer; thus, these oncoviruses play an important role in the initiation and/or progression of this cancer. Accordingly, our group has recently viewed the presence and genotyping distribution of high-risk HPVs in cervical cancer in Syrian women; our data pointed out that HPVs are present in 42/44 samples (95%). Herein, we aim to explore the co-prevalence of EBV and high-risk HPVs in 44 cervical cancer tissues from Syrian women using polymerase chain reaction, immunohistochemistry, and tissue microarray analyses. We found that EBV and high-risk HPVs are co-present in 15/44 (34%) of the samples. However, none of the samples was exclusively EBV-positive. Additionally, we report that the co-expression of LMP1 and E6 genes of EBV and high-risk HPVs, respectively, is associated with poorly differentiated squamous cell carcinomas phenotype; this is accompanied by a strong and diffuse overexpression of Id-1 (93% positivity), which is an important regulator of cell invasion and metastasis. These data imply that EBV and HPVs are co-present in cervical cancer samples in the Middle East area including Syria and their co-presence is associated with a more aggressive cancer phenotype. Future investigations are needed to elucidate the exact role of EBV and HPVs cooperation in cervical carcinogenesis.

VE-cadherin cleavage by ovarian cancer microparticles induces ß-catenin phosphorylation in endothelial cells.

Microparticles (MPs) are increasingly recognized as important mediators of cell-cell communication in tumour growth and metastasis by facilitating angiogenesis-related processes. While the effects of the MPs on recipient cells are usually well described in the literature, the leading process remains unclear. Here we isolated MPs from ovarian cancer cells and investigated their effect on endothelial cells. First, we demonstrated that ovarian cancer MPs trigger ß-catenin activation in endothelial cells, inducing the upregulation of Wnt/ß-catenin target genes and an increase of angiogenic properties. We showed that this MPs mediated activation of ß-catenin in ECs was Wnt/Frizzled independent; but dependent on VE-cadherin localization disruption, αVß3 integrin activation and MMP activity. Finally, we revealed that Rac1 and AKT were responsible for ß-catenin phosphorylation and translocation to the nucleus. Overall, our results indicate that MPs released from cancer cells could play a major role in neo-angiogenesis through activation of beta catenin pathway in endothelial cells.