BRAFV600E mutational status assessment in cutaneous melanocytic neoplasms in a group of the Egyptian population.

BACKGROUND: Melanocytic neoplasms range from banal nevi to malignant melanomas. The genetic background has been extensively studied in the Caucasian population. BRAF mutations were reported among the early driver mutations in nevogenesis. Nevertheless, the pathogenesis in the Egyptian population has not been elucidated. AIM AND METHODS: The present study was carried out to assess the sensitivity and specificity of immunohistochemistry (IHC) using the RM-08 clone in reference to allele-specific real-time PCR (CAST-PCR) for the detection of the BRAF V600E mutation in 50 formalin-fixed paraffin-embedded blocks of melanocytic neoplasms with prior bleaching using hydrogen peroxide in Tris-HCL and Bovine Serum Albumin respectively. RESULTS: IHC staining was interpreted using staining reaction (positive versus negative) and staining pattern (negative and heterogeneous versus homogenous). Using the staining pattern, the specificity increased from 73.3 to 88.2%, the negative predictive value increased from 73.3 to 100%, the diagnostic accuracy increased from 71.4 to 90.48% and the overall accuracy increased from 69.9 to 77.3%. The sensitivity and positive predictive value remained unchanged. The K-agreement coefficient increased from 0.364 (fair agreement) to 0.741 (good agreement) and was statistically significant (p = 0.00). Next-generation sequencing was performed in 11 cases, 8 cases with IHC-positive and BRAF wild type in addition to 3 cases that failed PCR analysis and revealed no BRAF V600E. No statistically significant difference was found in the clinicopathological parameters between BRAF V600E and BRAF wild-type melanomas. CONCLUSIONS: These findings suggest that IHC staining homogeneity may be more accurate in predicting BRAF V600E mutational status. However, IHC cannot replace molecular methods.

The Role of ATP-Binding Cassette Subfamily A in Colorectal Cancer Progression and Resistance.

Colorectal cancer (CRC) is one of the most common malignancies worldwide; it is the fourth leading cause of cancer-related deaths. CRC arises due to mutations that can affect oncogenes, tumour suppressor genes and DNA repair genes. The lack of novel diagnostic and therapeutic targets and the development of chemoresistance are some of the major issues when dealing with CRC. The overexpression of ATP-binding cassette (ABC) transporters is considered one facilitating mechanism for chemoresistance. Furthermore, ABC transporters have additional roles in cancer development beyond multidrug resistance. In CRC, lipid dysregulation has a key role in tumour development and progression, as cancer cells rely on lipids for energy and rapid cell proliferation. ABC subfamily A (ABCA) contains the largest members of ABC proteins, mainly known for their role in lipid transport, mostly membrane lipids such as cholesterol and phospholipids. Although the exact mechanism of action of these members is not confirmed, their expression is usually correlated with tumour progression and therapy resistance, probably due to their role in lipid homeostasis. CRC shows alteration in the expression of ABCA transporters, which is usually linked to poor prognosis and overall survival. Therefore, as lipid transporters, their role in CRC is investigated, and their diagnostic and prognostic potential is evaluated. This minireview presents evidence from various studies suggesting that ABCA transporters might have an active role in CRC and can be utilized as potential diagnostic and therapeutic targets.

Immunohistochemical Expression Analysis of Caldesmon Isoforms in Colorectal Carcinoma Reveals Interesting Correlations with Tumor Characteristics.

Colorectal cancer is a notorious disease, with almost half of the patients succumbing to the disease. The prevalence and incidence rates of colorectal cancer are increasing in many parts of the world, highlighting the need to discover new biomarkers for diagnosis and therapy. Caldesmon (CaD), an actin-binding protein that plays a significant role in controlling cell motility, has emerged as a promising biomarker. The CALD1 gene encodes CaD as multiple transcripts that mainly encode two protein isoforms: High-molecular-weight (h-CaD), expressed in smooth muscle, and low-molecular-weight (l-CaD), expressed in nonsmooth muscle cells. Most studies have suggested an oncogenic role of CaD in colorectal cancer, but the exact subcellular localization of the two CaD isoforms in tumor cells and stroma have not been clarified yet. Here, we analyzed tissue samples from 262 colorectal cancer patients by immunohistochemistry analysis using specific antibodies for l-CaD and h-CaD. The results showed elevated cytoplasmic expression levels of l-Cad in 187/262 (71.4%) cases. l-Cad was expressed at low levels in the normal colon mucosa and was also consistently expressed in the cancer-associated stroma of all cases, suggesting that it could play a role in modulating the tumor microenvironment. l-CaD expression in cancer cells was associated with preinvasive stages of cancer. Survival analysis indicated that patients with high l-CaD expression in tumor cells could respond poorly to selective chemotherapeutic 5FU, but not combination chemotherapy. h-CaD was expressed in colonic and vascular smooth muscle cells as expected and to a lesser extent in the tumor-associated stroma, but it was not expressed in the cancer cells or normal colon mucosal epithelial cells. Collectively, these data clarify how the expression patterns of CaD isoforms in colorectal cancer can have applications in the management of colorectal cancer patients.

Titanium Particles Modulate Lymphocyte and Macrophage Polarization in Peri-Implant Gingival Tissues.

Titanium dental implants are one of the modalities to replace missing teeth. The release of titanium particles from the implant's surface may modulate the immune cells, resulting in implant failure. However, little is known about the immune microenvironment that plays a role in peri-implant inflammation as a consequence of titanium particles. In this study, the peri-implant gingival tissues were collected from patients with failed implants, successful implants and no implants, and then a whole transcriptome analysis was performed. The gene set enrichment analysis confirmed that macrophage M1/M2 polarization and lymphocyte proliferation were differentially expressed between the study groups. The functional clustering and pathway analysis of the differentially expressed genes between the failed implants and successful implants versus no implants revealed that the immune response pathways were the most common in both comparisons, implying the critical role of infiltrating immune cells in the peri-implant tissues. The H&E and IHC staining confirmed the presence of titanium particles and immune cells in the tissue samples, with an increase in the infiltration of lymphocytes and macrophages in the failed implant samples. The in vitro validation showed a significant increase in the level of IL-1ß, IL-8 and IL-18 expression by macrophages. Our findings showed evidence that titanium particles modulate lymphocyte and macrophage polarization in peri-implant gingival tissues, which can help in the understanding of the imbalance in osteoblast-osteoclast activity and failure of dental implant osseointegration.

Assessment of risk factors and molecular biomarkers in children with supernumerary teeth: a single-center study.

BACKGROUND: Supernumerary teeth are considered one of the commonly observed dental anomalies in children. Several theories have been proposed to explain the presence of supernumerary teeth, including environmental and genetic factors. This study aimed to identify the different risk factors and molecular biomarkers in patients presented with supernumerary teeth. METHODS: This case-control study included 240 children, 6 to 12-year-old. They were divided into a test group (n = 120 children presented with supernumerary teeth) and a control group (n = 120 children with no supernumerary teeth). Questionnaires were distributed to assess demographics and exposure to several environmental factors. Ten extracted supernumerary teeth from the test group were processed for histopathological analysis. RESULTS: Male gender, dental history of severe oral infection or medical history of chemotherapy treatment, previous history of taking medication or illness during pregnancy, family history of neoplastic disorders, use of electronic devices, and living beside agricultural fields or industrial areas were found to be statistically significant associated with the risk of supernumerary teeth development. Immunohistochemistry panel revealed that supernumerary teeth showed enhanced expression of wingless (Wnt) and sonic hedgehog (SHH) proteins as well as a reduced expression of adenomatous polyposis coli (APC) protein, denoting molecular derangement in a group of pathways classically believed to be involved in its pathogenesis. CONCLUSIONS: Males were more frequently affected by supernumerary teeth than females. Several risk factors were notably correlated with the existence of supernumerary teeth. Additionally, molecular biomarkers assessment demonstrated a high expression level of pro-tumorigenic proteins such as Wnt and SHH in patients with supernumerary teeth.

Function of gold nanoparticles in oral cancer beyond drug delivery: Implications in cell apoptosis.

OBJECTIVES: Gold nanoparticles (AuNPs) are used to deliver drugs and therapeutic small molecule inhibitors to cancer cells. Evidence shows that AuNPs coated with nuclear localization sequence can cross the nuclear membrane and induce cellular apoptosis. To determine the therapeutic role of AuNPs, we compared two nanoconstructs conjugated to doxorubicin (DOX) through pH-sensitive and pH-resistant linkers. MATERIALS AND METHODS: We tested DOX nanoconjugates' cytotoxicity, cellular and nuclear uptake in oral squamous cell carcinoma cell line. Furthermore, we evaluated the therapeutic effect of pH-sensitive and pH-resistant DOX bioconjugates in hamster buccal pouch carcinoma model. RESULTS: Our data indicate that pH-resistant and pH-sensitive DOX-nanoconjugates were equally localized in cancer cells, but the pH-resistant DOX nanoparticles were more localized in the nuclei inducing a 2-fold increase in the apoptotic effect compared with the pH-sensitive DOX nanoparticles. Our in vivo results show significantly higher tumor shrinkage and survival rates in animals treated with DOX pH-resistant AuNPs compared with pH-sensitive ones. CONCLUSION: Our findings suggest that AuNPs enhance the cytotoxic effect against cancer cells in addition to acting as drug carriers. DOX pH-resistant AuNPs enhanced accumulation of AuNPs in cancer cells' nuclei inducing a significant cellular apoptosis which was confirmed using in vitro and in vivo experiments without deleterious effects on blood cell count.

Role of free style Libre-Flash Glucose Monitoring: Glycemic control of Type-1 Diabetes.

BACKGROUND & OBJECTIVE: Type-1 diabetics (T1D) usually do not meet guidelines for glycaemic control. This study aimed to determine the benefit of free style libre-flash glucose monitoring system (FSL-FGM) in lowering glycated hemoglobin (HbA1c) in poorly controlled T1D patients. METHODS: This prospective two single arm clinical study included 273 T1D patients, and data collected at one, six and 18 months with concomitant extraction of samples for HbA1c basal and at six and 18 months. The study was conducted in Prince Mansour Military Hospital at Taif, Saudi Arabia from June 2017 to November 2018. RESULTS: HbA1c % was significantly diminished in patients used FSL-FGM at 6 and 18 months. The median percentage difference in HbA1c at 6 and 18 months versus basal was significantly decreased in those using FSL-FGM. Within diabetics using FSL-FGM, the median difference in HbA1c after 18 months was significantly decreased in patients with HbA1c >10% compared to those with HbA1c <10%. Estimated HbA1c by FSL showed a significant correlation with HbA1C assayed in the blood. The snapshot information showed a highly significant difference in average glucose with low significant difference in hypoglycemia parameters. The FSL-FGM provides significant changes in HbA1c in diabetic patients without observed risk for hypoglycemia. CONCLUSIONS: The dynamic way of blood glucose monitoring using FSL-FGM provides improvement in HbA1c in diabetic patients without observed risk for hypoglycemia.

Potential Therapeutic Strategies for Lung and Breast Cancers through Understanding the Anti-Angiogenesis Resistance Mechanisms.

Breast and lung cancers are among the top cancer types in terms of incidence and mortality burden worldwide. One of the challenges in the treatment of breast and lung cancers is their resistance to administered drugs, as observed with angiogenesis inhibitors. Based on clinical and pre-clinical findings, these two types of cancers have gained the ability to resist angiogenesis inhibitors through several mechanisms that rely on cellular and extracellular factors. This resistance is mediated through angiogenesis-independent vascularization, and it is related to cancer cells and their microenvironment. The mechanisms that cancer cells utilize include metabolic symbiosis and invasion, and they also take advantage of neighboring cells like macrophages, endothelial cells, myeloid and adipose cells. Overcoming resistance is of great interest, and researchers are investigating possible strategies to enhance sensitivity towards angiogenesis inhibitors. These strategies involved targeting multiple players in angiogenesis, epigenetics, hypoxia, cellular metabolism and the immune system. This review aims to discuss the mechanisms of resistance to angiogenesis inhibitors and to highlight recently developed approaches to overcome this resistance.

Association between cytokine genes polymorphisms and type 1 diabetes: a case-control study on Saudi population.

BACKGROUND: Association studies of genes encoding cytokines that play an important role in inflammatory response represent one approach to finding type 1 diabetes (T1D) disease genes. The aim of this study was to investigate the association of single nucleotide polymorphisms (SNPs) within cytokine genes with T1D in a cohort of Saudi subjects. METHODS: A total of 300 well-characterized type 1 diabetic patients and 300 T1D-free control subjects were enrolled in this investigation. Cytokine SNPs were genotyped by using Polymerase chain reaction (PCR) with sequence-specific primers. RESULTS: Our data revealed that IFN-γ +874T allele carriers [odds ratio (OR) = 1.87, p < 0.001] and TT homozygotes (OR = 1.28, p < 0.001) were significantly more susceptible to developing T1D than the A allele carriers. In addition, TNF-α -308A allele carriers (OR = 1.73, p < 0.001) and AA homozygotes (OR = 1.74, p < 0.001) were also overrepresented among the diabetics than G allele carriers. IL-4 -590C/T TT homozygotes (OR = 2.23, p < 0.001) were significantly more susceptible to develop T1D than CC genotypes, whereas CT heterozygotes were not significantly associated (OR = 1.43, p = 0.78) with T1D. Furthermore, IL-4 T allele was statistically associated with T1D patients compared to control group (OR = 2.24, p < 0.001). Similarly, IL-1ß -511C/T TT homozygotes (OR = 1.85, p = 0.012) and the T allele (OR = 1.85, p < 0.001) were significantly more susceptible to T1D than CC genotypes, whereas TC heterozygotes (OR = 1.04, p = 0.86) were not significantly associated with T1D. CONCLUSION: Our data concluded that IFN-γ +874T allele, TNF-α -308A allele, IL-1ß -511T allele, and IL-4 -590T allele could be considered risk factors for T1D development in Saudi subjects.

The Potential Role of PTPN-22 C1858T Gene Polymorphism in the Pathogenesis of Type 1 Diabetes in Saudi Population.

BACKGROUND: Recent investigations have reported an association between protein tyrosine phosphatase non-receptor type-22 (PTPN-22) gene polymorphism and susceptibility to the development of type 1 diabetes (T1D) in some populations and not in others. In this study, we aimed to investigate the association of PTPN-22 C1858T polymorphism with T1D in Saudi children. METHODS: A cohort of 372 type 1 diabetic children and 372 diabetes-free subjects was enrolled in the current investigation. The PTPN-22 C1858T polymorphism was identified using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. RESULTS: Our data showed that the frequency of CT and TT genotypes of PTPN-22 C1858T was higher in T1D children (17.7% and 4.3%, respectively) compared to healthy controls (4.8% and 1.6%, respectively), and both genotypes were statistically associated with T1D patients (OR = 4.4, 95% CI: 2.55-7.58, p < 0.001; and OR = 3.2, 95% CI: 1.23-8.28, p = 0.017, respectively). Moreover, the 1858T allele was significantly associated with T1D patients compared to the C allele (OR = 3.2, 95% CI: 1.59-6.88, p < 0.001). In addition, the T allele was significantly associated with elevated levels of HbA1c, anti-GAD, and anti-insulin antibodies (p < 0.001) and a lower concentration of C-peptide (p < 0.001) in T1D children. CONCLUSION: The data presented here suggests that the T allele of PTPN-22 C1858T polymorphism might be a risk factor for T1D development in Saudi children.

Orthodontically induced osteocyte apoptosis under different force magnitudes in rats: an immunohistochemical study.

We investigated the effect of different force magnitudes on osteocyte apoptosis in a model of orthodontic tooth movement. Forty-nine male Sprague Dawley rats (7-9 wk of age) were divided into light- and heavy-force groups (n = 21 each group) and a control group (n = 7). A coil spring delivered pressure (either 10-15 g or 20-25 g) to the left maxillary first molar. The rats were sacrificed 1, 3, or 5 d after placement of the appliance. Sections of the maxillary first molars were immunostained for caspase-3. Upon force application, the number of apoptotic osteocytes significantly increased in the pressure side at 1 d and remained the same at 3 d and 5 d. However, there was no significant difference in the number of apoptotic osteocytes between the two force groups. We conclude that osteocyte apoptosis appears to increase under orthodontic loading, reaching a plateau after 1 d. However, osteocyte apoptosis seems to be independent of the magnitude of orthodontic forces tested.

The role of RNA-modifying proteins in renal cell carcinoma.

Gene expression is one of the most critical cellular processes. It is controlled by complex mechanisms at the genomic, epigenomic, transcriptomic, and proteomic levels. Any aberration in these mechanisms can lead to dysregulated gene expression. One recently discovered process that controls gene expression includes chemical modifications of RNA molecules by RNA-modifying proteins, a field known as epitranscriptomics. Epitranscriptomics can regulate mRNA splicing, nuclear export, stabilization, translation, or induce degradation of target RNA molecules. Dysregulation in RNA-modifying proteins has been found to contribute to many pathological conditions, such as cancer, diabetes, obesity, cardiovascular diseases, and neurological diseases, among others. This article reviews the role of epitranscriptomics in the pathogenesis and progression of renal cell carcinoma. It summarizes the molecular function of RNA-modifying proteins in the pathogenesis of renal cell carcinoma.

Insulin-like growth factor family and prostate cancer: new insights and emerging opportunities.

Prostate cancer is the second most commonly diagnosed cancer in men. The mammalian insulin-like growth factor (IGF) family is made up of three ligands (IGF-I, IGF-II, and insulin), three receptors (IGF-I receptor (IGF-1R), insulin receptor (IR), and IGF-II receptor (IGF-2R)), and six IGF-binding proteins (IGFBPs). IGF-I and IGF-II were identified as potent mitogens and were previously associated with an increased risk of cancer development including prostate cancer. Several reports showed controversy about the expression of the IGF family and their connection to prostate cancer risk due to the high degree of heterogeneity among prostate tumors, sampling bias, and evaluation techniques. Despite that, it is clear that several IGF family members play a role in prostate cancer development, metastasis, and androgen-independent progression. In this review, we aim to expand our understanding of prostate tumorigenesis and regulation through the IGF system. Further understanding of the role of IGF signaling in PCa shows promise and needs to be considered in the context of a comprehensive treatment strategy.

The prognostic value of Dickkopf-3 (Dkk3), TGFB1 and ECM-1 in prostate cancer.

Prostate cancer (PCa) is considered one of the most common cancers worldwide. Despite advances in patient diagnosis, management, and risk stratification, 10%-20% of patients progress to castration-resistant disease. Our previous report highlighted a protective role of Dickkopf-3 (DKK3) in PCa stroma. This role was proposed to be mediated through opposing extracellular matrix protein 1 (ECM-1) and TGF-ß signalling activity. However, a detailed analysis of the prognostic value of DKK3, ECM-1 and members of the TGF-ß signalling pathway in PCa was not thoroughly investigated. In this study, we explored the prognostic value of DKK3, ECM-1 and TGFB1 using a bioinformatical approach through analysis of large publicly available datasets from The Cancer Genome Atlas Program (TGCA) and Pan-Cancer Atlas databases. Our results showed a significant gradual loss of DKK3 expression with PCa progression (p < 0.0001) associated with increased DNA methylation in its promoter region (p < 1.63E-12). In contrast, patients with metastatic lesions showed significantly higher levels of TGFB1 expression compared to primary tumours (p < 0.00001). Our results also showed a marginal association between more advanced tumour stage presented as positive lymph node involvement and low DKK3 mRNA expression (p = 0.082). However, while ECM1 showed no association with tumour stage (p = 0.773), high TGFB1 expression showed a significant association with more advanced stage presented as advanced T3 stage compared to patients with low TGFB1 mRNA expression (p < 0.001). Interestingly, while ECM1 showed no significant association with patient outcome, patients with high DKK3 mRNA expression showed a significant association with favourable outcomes presented as prolonged disease-specific (p = 0.0266), progression-free survival (p = 0.047) and disease-free (p = 0.05). In contrast, high TGFB1 mRNA expression showed a significant association with poor patient outcomes presented as shortened progression-free (p = 0.00032) and disease-free survival (p = 0.0433). Moreover, DKK3, TGFB1 and ECM1 have acted as immune-associated genes in the PCa tumour microenvironment. In conclusion, our findings showed a distinct prognostic value for this three-gene signature in PCa. While both DKK3 and TGFB1 showed a potential role as a clinical marker for PCa stratification, ECM1 showed no significant association with the majority of clinicopathological parameters, which reduce its clinical significance as a reliable prognostic marker.

Are embryonic stem cell markers and ALDH1A1 relevant in the context of breast cancer estrogen positivity?

BACKGROUND: Embryonic pluripotency markers are recognized for their role in ER- BC aggressiveness, but their significance in ER+ BC remains unclear. This study aims to investigate the prevalence of expression of pluripotency markers in ER+ BC and their effect on survival and prognostic indicators. METHODS: We analyzed data of ER+ BC patients from three large cancer datasets to assess the expression of three pluripotency markers (NANOG, SOX-2, and OCT4), and the stem cell marker ALDH1A1. Additionally, we investigated associations between gene expression, through mRNA-Seq analysis, and overall survival (OS). The prevalence of mutational variants within these genes was explored. Using immunohistochemistry (IHC), we examined the expression and associations with clinicopathologic prognostic indicators of the four markers in 81 ER+ BC patients. RESULTS: Through computational analysis, NANOG and ALDH1A1 genes were significantly upregulated in ER+ BC compared to ER- BC patients (p < 0.001), while POU5F1 (OCT4) was downregulated (p < 0.001). NANOG showed an adverse impact on OS whereas ALDH1A1 was associated with a highly significant improved survival in ER+ BC (p = 4.7e-6), except for the PR- and HER2+ subgroups. Copy number alterations (CNAs) ranged from 0.4% to 1.6% in these genes, with the highest rate detected in SOX2. In the IHC study, approximately one-third of tumors showed moderate to strong expression of each of the four markers, with 2-4 markers strongly co-expressed in 56.8% of cases. OCT-4 and ALDH1A1 showed a significant association with a high KI-67 index (p = 0.009 and 0.008, respectively), while SOX2 showed a significant association with perinodal fat invasion (p = 0.017). CONCLUSION: Pluripotency markers and ALDH1A1 are substantially expressed in ER+ BC tumors with different, yet significant, associations with prognostic and survival outcomes. This study suggests these markers as targets for prospective clinical validation studies of their prognostic value and their possible therapeutic roles.

Seedless black Vitis vinifera polyphenols suppress hepatocellular carcinoma in vitro and in vivo by targeting apoptosis, cancer stem cells, and proliferation.

Hepatocellular carcinoma (HCC) is an aggressive tumor and one of the most challenging cancers to treat. Here, we evaluated the in vitro and in vivo ameliorating impacts of seedless black Vitis vinifera (VV) polyphenols on HCC. Following the preparation of the VV crude extract (VVCE) from seedless VV (pulp and skin), three fractions (VVF1, VVF2, and VVF3) were prepared. The anticancer potencies of the prepared fractions, compared to 5-FU, were assessed against HepG2 and Huh7 cells. In addition, the effects of these fractions on p-dimethylaminoazobenzene-induced HCC in mice were evaluated. The predicted impacts of selected phenolic constituents of VV fractions on the activity of essential HCC-associated enzymes (NADPH oxidase "NADPH-NOX2", histone deacetylase 1 "HDAC1", and sepiapterin reductase "SepR") were analyzed using molecular docking. The results showed that VVCE and its fractions induced apoptosis and collapsed CD133+ stem cells in the studied cancer cell lines with an efficiency greater than 5-FU. VVF1 and VVF2 exhibited the most effective anticancer fractions in vitro; therefore, we evaluated their influences in mice. VVF1 and VVF2 improved liver morphology and function, induced apoptosis, and lowered the fold expression of various crucial genes that regulate cancer stem cells and other vital pathways for HCC progression. For most of the examined parameters, VVF1 and VVF2 had higher potency than 5-FU, and VVF1 showed more efficiency than VVF2. The selected phenolic compounds displayed competitive inhibitory action on NADPH-NOX2, HDAC1, and SepR. In conclusion, these findings declare that VV polyphenolic fractions, particularly VVF1, could be promising safe anti-HCC agents.

Association of specific ACE2 and TMPRSS2 variants with circulatory cytokines of COVID-19 Emirati patients.

Introduction: The COVID-19 pandemic represented one of the most significant challenges to researchers and healthcare providers. Several factors determine the disease severity, whereas none alone can explain the tremendous variability. The Single nucleotide variants (SNVs) in angiotensin-converting enzyme-2 (ACE2) and transmembrane serine protease type-2 (TMPRSS2) genes affect the virus entry and are considered possible risk factors for COVID-19. Methods: We compiled a panel of gene variants from both genes and used in-silico analysis to predict their significance. We performed biological validation to assess their capacity to alter the ACE2 interaction with the virus spike protein. Subsequently, we conducted a retrospective comparative genome analysis on those variants in the Emirati patients with different disease severity (total of 96) along with 69 healthy control subjects. Results: Our results showed that the Emirati population lacks the variants that were previously reported as associated with disease severity, whereas a new variant in ACE2 "Chr X:g.15584534" was associated with disease severity specifically among female patients. In-silico analysis revealed that the new variant can determine the ACE2 gene transcription. Several cytokines (GM-CSF and IL-6) and chemokines (MCP-1/CCL2, IL-8/CXCL8, and IP-10/CXCL10) were markedly increased in COVID-19 patients with a significant correlation with disease severity. The newly reported genetic variant of ACE2 showed a positive correlation with CD40L, IL-1ß, IL-2, IL-15, and IL-17A in COVID-19 patients. Conclusion: Whereas COVID-19 represents now a past pandemic, our study underscores the importance of genetic factors specific to a population, which can influence both the susceptibility to viral infections and the level of severity; subsequently expected required preparedness in different areas of the world.

Ozone Therapy in Medicine and Dentistry: A Review of the Literature.

Ozone has been successfully used in medicine for over 100 years due to its microbiological qualities. Its powerful oxidation impact, which results in the production of free radicals, and its ability to cause the direct death of nearly all microorganisms is the basis for its bactericide, virucide, and fungicide properties. Ozone also has a medicinal impact that speeds up blood flow and aids wound healing. Ozone may be applied as a gas or dissolved in water for medical purposes. Despite the benefits of using ozone therapeutically, concerns about its use in dentistry still exist. We aimed to provide a summary of the current uses of ozone in medicine and dentistry. An electronic search was performed for all English scientific papers published between 2012 and 2023 using PubMed, Cochrane, and Google Scholar search engines. Ozone, clinical applications, medicine, and dentistry were the search terms used. Seventy full-text articles describing the use of ozone therapy in medicine and dentistry were included in the present review. Ozone has shown several beneficial effects in the medical field. However, despite the encouraging in vitro evidence, the clinical use of ozone in dentistry has not yet been demonstrated as highly effective.

Liver Injury Associated with COVID-19 Infection: Pathogenesis, Histopathology, Prognosis, and Treatment.

Liver injury occurs frequently as a consequence of SARS-CoV-2 infection. Direct infection of the liver leads to hepatic impairment with elevated transaminases. In addition, severe COVID-19 is characterized by cytokine release syndrome, which may initiate or exacerbate liver injury. In patients with cirrhosis, SARS-CoV-2 infection is associated with acute-on-chronic liver failure. The Middle East and North Africa (MENA) region is one of the world's regions characterized by a high prevalence of chronic liver diseases. Both parenchymal and vascular types of injury contribute to liver failure in COVID-19, with a myriad of pro-inflammatory cytokines playing a major role in perpetuating liver injury. Additionally, hypoxia and coagulopathy complicate such a condition. This review discusses the risk factors, and the underlying causes of impaired liver functions in COVID-19, with a focus on key players in the pathogenesis of liver injury. It also highlights the histopathological changes encountered in postmortem liver tissues as well as potential predictors and prognostic factors of such injury, in addition to the management strategies to ameliorate liver damage.

Anticancer role of mango (Mangifera indica L.) peel and seed kernel extracts against 7,12- dimethylbenz[a]anthracene-induced mammary carcinogenesis in female rats.

Breast cancer is the second leading cause of cancer death among women. The present study is an effort to reveal the antiproliferative and antioxidant actions of mango seed kernel extract (KE), peel extract (PE), and their combination (KEPE) on mammary tumors induced by 7,12 dimethylbenz[a]anthracene (DMBA). Seven groups of adult female Sprague-Dawley rats were prepared, including C: (control), DMBA: (rats were administered with DMBA), (DMBA-KE), (DMBA-PE), and (DMBA-KEPE): rats were administered with DMBA and then treated with KE, PE, and (both KE and PE), respectively, (KE) and (PE): rats were administered with KE and PE, separately. The study focused on the assessment of markers of endocrine derangement [serum 17-ß estradiol (E2)], apoptosis [caspase-3 and deoxyribonucleic acid fragmentation (DNAF)], and oxidative stress [lipid peroxidation and antioxidants (glutathione, glutathione-S-transferase, glutathione reductase, glutathione peroxidase, and superoxide dismutase)]. Histopathological examination and immunohistochemical expression of caspase-3 and estrogen receptor-α (ER-α) in mammary gland tissues (MGTs) were determined, as well as the characterization of mango extracts. The results showed that DMBA administration induced mammary tumors by increasing cell proliferation and evading apoptosis. In addition, DMBA administration caused oxidative stress by the production of reactive oxygen species, which increased lipid peroxidation and decreased cellular antioxidants, allowing cancer to progress. In contrast, treatment with DMBA-KE, DMBA-PE, or DMBA-KEPE diminished mammary tumors induced by DMBA, where they reduced oxidative stress via increased antioxidant parameters including reduced glutathione, superoxide dismutase, total glutathione peroxidase, glutathione reductase, and glutathione S-transferase. Also, different treatments decreased proliferation through the reduction of E2, and ER-α expression levels. However, these treatments increased the apoptosis of unwanted cells as they increased caspase-3 activity and DNAF. All these changes led to the prevention of breast injuries and the reduction of mammary tumors. This demonstrates that the contents of mango extracts, especially phenolics and flavonoids, have an important role in mammary tumor treatment through their potential antioxidant, antiproliferative, proapoptotic, and anti-estrogenic effects. KE and PE administration for 4 weeks had no adverse effects. Conclusion: Each of KE, PE, and KEPE has a therapeutic effect against DMBA-induced mammary tumors via induction of apoptosis and reduction of each of the OS, proliferation, and estrogenic effects. So, they can play an important role in the pharmacological tole.