Niosomal Delivery of Celecoxib and Metformin for Targeted Breast Cancer Treatment.

Breast cancer continues to be a prominent worldwide health concern and requires continued investigation into innovative therapeutic approaches. Here, we report the first investigation into the therapeutic efficacy of combining Metformin (MET) and Celecoxib (CXB), both in free and niosomal form, for the treatment of breast cancer. Our investigation encompassed the characterization of these niosomal drug carriers, their stability assessment, and their effect on breast cancer cell models. The thin-film hydration technique was employed to prepare niosomes with spherical, uniform-size distributions and high encapsulation efficiencies. The niosomes were characterized by TEM, particle size analyzer, and ATR-FTIR. The niosomes with an average size of 110.6 ± 0.6 and 96.7 ± 0.7, respectively, for MET and CXB were stable when stored at 4 °C for three months with minimal drug leakage, minor changes in encapsulation efficiency and size, and unchanged physicochemical parameters. Evaluation in two-dimensional (2D) and three-dimensional (3D) viability assays demonstrated an increased cytotoxicity of encapsulated drugs when compared to their free-drug counterparts. Additionally, the combination of Metformin Niosomal Particles (MET NPs) and Celecoxib Niosomal Particles (CXB NPs) led to decreased cell viability in both 2D and 3D models compared to each drug administered individually. When comparing the effect of the niosomal versus the free combination of the drugs on cell migration, we found that both interventions effectively prevented cell migration. However, the efficacy of the niosomes' combination was not superior to that of the free drug combination (p < 0.05). In conclusion, the results of this study provide valuable insights into the potential application of combining MET and CXB nanoparticle delivery systems to breast cancer treatment. Exploring the in vivo application of this drug delivery system could open new avenues for more effective and targeted therapeutic approaches for breast cancer patients.

Investigating Carvedilol's Repurposing for the Treatment of Non-Small Cell Lung Cancer via Aldehyde Dehydrogenase Activity Modulation in the Presence of ß-Adrenergic Agonists.

Repurposing existing drugs appears to be a potential solution for addressing the challenges in the treatment of non-small cell lung cancer (NSCLC). ß-adrenoceptor antagonist drugs (ß-blockers) have tumor-inhibiting effects, making them promising candidates for potential NSCLC treatment. This study investigates the anticancer potential of a subset of ß-blockers in NSCLC cell lines; A549 and H1299. Additionally, it investigates the underlying mechanism behind ß-blockers' anticancer effect by influencing a potential novel target named aldehyde dehydrogenase (ALDH). The MTT assay assessed ß-blockers' cytotoxicity on both cell lines, while Western blot and NADH fluorescence assays evaluated their influence on ALDH protein expression and activity. Carvedilol (CAR) was the most effective blocker in reducing cell survival of A549 and H1299 with IC50 of 18 µM and 13.7 µM, respectively. Significantly, CAR led to a 50% reduction in ALDH expression and 80% decrease in ALDH activity in A549 cells, especially when combined with ß-agonists, in comparison to the control. This effect might be attributed to ß-agonist blockade or an alternative pathway. This novel finding adds to our understanding of CAR's multifaceted anticancer properties, implying that combining CAR with ß-agonists could be a useful strategy for lung cancer treatment.

Serum Leptin Receptor and the rs1137101 Variant of the LEPR Gene Are Associated with Bladder Cancer.

Globally, bladder cancer (BC) is one of the ten most common tumors. Obesity is a worldwide problem associated with an increased BC risk. Considering that levels of leptin and/or its receptor are often deregulated in obese individuals, we hypothesized that they could contribute to BC. To test this hypothesis, we utilized a case-control study in which 116 patients with a confirmed diagnosis of BC and 116 controls were recruited. The serum levels of leptin and leptin receptor were measured. Patients and controls were also genotyped for SNPs in the LEP (rs7799039, rs791620, and rs2167270) and LEPR genes (rs1137100, rs1137101, and rs1805094). The univariate analysis indicated that BC patients had significantly higher levels of leptin and lower levels of leptin receptor (p < 0.05). Moreover, rs7799039 of LEP and rs1137101 of LEPR were associated with BC (p < 0.05). In the multivariate analysis, leptin receptor levels were protective (OR: 0.98, 95% CI = 0.97-0.99, p = 0.002) while the GG genotype of rs1137101 of LEPR increased BC risk (OR: 3.42, 95% CI = 1.27-9.20, p = 0.02). These findings highlight that lifestyle changes could be useful in preventing BC and that disturbances in energy metabolism could play a role in the pathobiology of BC.

Discovery of a novel genetic variant in the N-acetyltransferase2 (NAT2) gene that is associated with bladder cancer risk.

Smoking is a main risk factor for bladder cancer (BC). NAT2 is a drug-metabolizing enzyme that catalyses the detoxification of many xenobiotics and carcinogens. Single nucleotide polymorphism (SNP) in NAT2 results in different acetylation phenotypes (fast, intermediate or slow). Certain NAT2 SNPs were associated with BC and/or modified the association of BC with smoking. However, limited evidence is available among BC patients or smokers from Jordan. This study aimed to discover novel SNPs in NAT2 and to assess the association with BC. This was a case-control study among 120 BC patients and 120 controls. Amplification of a 446 bp fragment of NAT2 encoding the N-catalytic domain was conducted using a polymerase chain reaction. Gene sequencing was done using Sanger-based technology. A total of 40 SNPs were detected. Two variants were significantly associated with BC (p<0.05); namely a novel c.87G>A and the reported c.341T>C. Regarding c.87G>A, genotype distribution was significantly associated with BC and subgroup analysis confirmed that this was significant in both smokers (p=0.007) and non-smokers (p=0.001). Regression subgroup analysis suggested GA as a risk factor among smokers (AOR= 2.356). The frequencies of TC and CC genotypes of c.341T>C were significantly higher in BC (p<0.05). This was statistically significant among smokers only (p=0.044), upon subgroup analysis. Multivariate analysis showed that subjects with TC genotype are 6.15 more likely to develop BC and regression subgroup analysis revealed TC as a risk factor among smokers (AOR=5.47). This is the first study from Jordan to report the association of smoking and two NAT2 variants with BC. The data supports the use of GA and TC genotypes of the novel c.87G>A and the reported c.341T>C SNPs, respectively as potential biomarkers of BC, particularly among smokers. Future investigations with a larger population are required to support our findings.

Genetic variation in the ADIPOQ gene and serum adiponectin increase the risk of bladder cancer.

Bladder cancer (BC) is the 10th most common cancer worldwide. Genetic studies estimated 30% heritability in BC risk. Adiponectin is an adipocytokine that has important roles in the regulation of energy metabolism. Recent evidence suggests dysregulation of adiponectin levels in BC tissues. Serum level of adiponectin is influenced by single nucleotide polymorphisms (SNPs) in the ADIPOQ gene. However, limited evidence is available regarding the association between adiponectin serum levels or SNPs in ADIPOQ and BC risk. This study aimed to assess whether adiponectin serum levels or SNPs in ADIPOQ may modify BC risk. In this case-control study, 114 BC patients were recruited along with 114 controls. Study subjects were genotyped for variations in ADIPOQ SNPs, namely rs17300539, rs266729, rs2241766, and rs1501299. Adiponectin levels were measured from the serum of study subjects. Our analysis showed that the G allele and the GG genotype of rs1501299 were significantly more frequent in BC patients compared to those in the control group (p-value < 0.05). Moreover, two ADIPOQ haplotypes containing the above G allele were associated with increased BC risk (p-value < 0.05). Multivariate analysis showed that increased serum adiponectin, smoking or age were all significant predictors of BC (p-value < 0.05). The data supports use of serum adiponectin and the G allele of rs1501299 SNP in ADIPOQ as potential biomarkers and/or targets in BC. To further validate findings in this study, larger populations of various ethnicities and/or genetic backgrounds are required. More investigations on the functional role of adiponectin in BC will also provide better understanding of potential targeting adiponectin for BC treatment.

In vitro radiosensitization of breast cancer with hypoxia-activated prodrugs.

KP167 is a novel hypoxia-activated prodrug (HAP), targeting cancer cells via DNA intercalating and alkylating properties. The single agent and radiosensitizing efficacy of KP167 and its parental comparator, AQ4N, were evaluated in 2D and 3D cultures of luminal and triple negative breast cancer (TNBC) cell lines and compared against DNA damage repair inhibitors. 2D normoxic treatment with the DNA repair inhibitors, Olaparib or KU-55933 caused, as expected, substantial radiosensitization (sensitiser enhancement ratio, SER0.01 of 1.60-3.42). KP167 induced greater radiosensitization in TNBC (SER0.01 2.53 in MDAMB-231, 2.28 in MDAMB-468, 4.55 in MDAMB-436) and luminal spheroids (SER0.01 1.46 in MCF-7 and 1.76 in T47D cells) compared with AQ4N. Significant radiosensitization was also obtained using KP167 and AQ4N in 2D normoxia. Although hypoxia induced radioresistance, radiosensitization by KP167 was still greater under 2D hypoxia, yielding SER0.01 of 1.56-2.37 compared with AQ4N SER0.01 of 1.13-1.94. Such data show KP167 as a promising single agent and potent radiosensitiser of both normoxic and hypoxic breast cancer cells, with greater efficacy in TNBCs.

Clinical and biological indicators of periodontal disease in obese and non-obese adults with and without bronchial asthma.

OBJECTIVE: The present study aims to assess clinical and inflammatory parameters as indicators for periodontal disease in obese and non-obese adults with and without bronchial asthma (BA). METHODS: 168 patients visiting the outpatient pulmonary clinics were divided into four groups according to BA and obesity. Obesity was defined by body mass index (BMI) and BA was diagnosed by a pulmonary consultant and being on inhaled asthma medication for at least 12 months. Participants were examined for clinical periodontal parameters and samples of gingival crevicular fluid (GCF) were taken and analyzed for the levels of 5 different inflammatory cytokines. RESULTS: Compared with controls, obese asthmatic group had significant higher mean clinical attachment loss (CAL) (2.64 vs. 1.00, p < .001). Also, the occurrence of periodontitis was significantly higher among obese patients compared to non-obese patients (p = 0.003). Multivariate logistic regression model showed that age was the strongest predictor of periodontitis (aOR = 1.23). The levels of IL-1ß and IL-8 were significantly higher in the non-obese asthmatic group compared to the control group (p < 0.05). The level of IL-6 was significantly lower in the control group compared to the other groups (p < 0.001). Obese patients had significantly higher concentration of hsCRP compared to non-obese patients (p < 0.001). There was no significant difference in the level of TNF- α between groups. CONCLUSIONS: BA and obesity combined did not seem to be associated with a significant increased risk of having periodontitis. BA and obesity are associated with increased levels of some local proinflammatory cytokines which adds to the local and systemic inflammatory burden.

The Expression of Glutaminases and their Association with Clinicopathological Parameters in the Head and Neck Cancers.

BACKGROUND: The increased glutamine metabolism is a characteristic feature of cancer cells. The interconversion between glutamine and glutamate is catalyzed by two glutaminase isoforms, GLS1 and GLS2, which appear to have different roles in different types of cancer. We investigated for the first time the protein expression of GLS1 and GLS2, and their correlation with advanced clinicopathological parameters in head and neck cancers. METHODS: Consecutive slides from a tissue microarray comprised of 80 samples ranging from normal to metastatic were stained immunohistochemically for GLS1, GLS2, HIF-1α or CD147. Following analysis by two expert pathologists, we carried out a statistical analysis of the scores. RESULTS: GLS1 and GLS2 were found to be upregulated at the protein level in head and neck tumours compared to normal tissues, and this increased expression correlated positively (GLS1) and negatively (GLS2) with tumor grade, indicating a shift of expression between GLS enzyme isoforms based on tumor differentiation. Increased expression of GLS1 was associated with high CD147 expression, and elevated GLS2 expression was associated with both high CD147 and high HIF-1α expressions. The correlation of the GLS1 and GLS2 with HIF-1α or CD147 was strongly associated with more advanced clinicopathological parameters. CONCLUSION: The increased expression of GLS1 and GLS2 may be explored as a new treatment for head and neck cancers.

Remote E-exams during Covid-19 pandemic: A cross-sectional study of students' preferences and academic dishonesty in faculties of medical sciences.

BACKGROUND: Since the emergence of coronavirus disease 2019 (Covid-19), distance education has been extensively implemented in all educational institutes and remote electronic exams (E-exams) have been adopted as a primary mode of assessment. OBJECTIVES: This cross-sectional study aimed to evaluate the experience of students at faculties of Medicine, Dentistry, Pharmacy, Nursing and Applied Medical Sciences at Jordan University of Science and Technology regarding remote E-exams preferences and academic dishonesty during the pandemic. MATERIALS AND METHODS: The survey composed of 16 questions, prepared using Google forms and distributed through students' E-learning platforms. The survey explored factors affecting students' preference for remote E-exams, methods for course assessment/evaluation, factors related to students' exam dishonesty/misconduct during remote E-exams and measures that can be considered to reduce this behavior. Data were analyzed using descriptive, cross tabulation and Chi-square tests. RESULTS: Among 730 students, approximately only one third preferred remote E-exams. This was significantly (P < 0.05) associated with academic major, efforts/time for remote E-exam preparation, questions appropriateness with study material, and academic achievements (students Grade Point Average (GPA), curriculum objectives). Combining both exams and quizzes was the most preferred method of assessment (30%), while submission of reports or short written assignments were the least preferred ones. Exam dishonesty/misconduct appears as one of the major challenges with remote E-exams. The main measures considered by students to reduce exam dishonesty included substituting the exam with other forms of assessment, using different exam forms, the use of online proctoring solutions and considering compulsory pass/fail grades. CONCLUSION: Results suggested less preference of remote E-exams among students at medical faculties. Findings from this study are highly valuable to plan for academic strategies to overcome difficulties and challenges of remote E-exams. These might include improvement for the distance teaching methodologies, rearrangement of assessment options, modification of the academic curriculum to fit the current situation, and adopting certain measures to prevent exam dishonesty and maintain academic integrity.

Hypertension prevalence and associated factors among patients with diabetes: A retrospective cross-sectional study from Jordan.

BACKGROUND: Hypertension (HTN) is a common comorbidity among diabetic patients. Studies reported that HTN prevalence in patients with diabetes mellitus (DM) depends on many risk factors related to the disease (the type and duration of DM), patients (age, sex, race/ethnicity, BMI), and medical history (glycemic control, renal problems). Best to our knowledge, limited evidence is available in this regard among Jordanian population. OBJECTIVES: This retrospective cross-sectional study aimed to determine the prevalence of HTN among patients with DM in Jordan and factors that might be associated with the concurrence of both diseases. MATERIALS AND METHODS: A cross-sectional study was conducted to determine HTN prevalence and risk factors among diabetic outpatients in Jordan. Patients were asked about their sociodemographic information and medical history. A descriptive analysis was used to determine HTN prevalence and a fit bivariate logistic regression model was used to identify the significant risk factors of HTN in patients with type 2 DM (T2DM). RESULTS: HTN was found to be concurrently occurring in approximately 80% of T2DM patients. This was found to increase with age. In addition, dyslipidemia, gout disease, ischemic heart disease, renal impairment, or a family history of HTN were found to be associated with the concurrence of HTN among T2DM patients. CONCLUSION: Findings from this study highlight the need for proper monitoring of DM patients to reduce the co-occurrence of HTN. Specific attention should be directed to control the patients' glycemic and lipid profiles as well as the cardiac and renal health using non-pharmacological and pharmacological measures. This is of particular importance in T2DM patients at old age and with family history of HTN, to reduce patients' deterioration. Results from this study will also be informative for the development of public health strategies to increase the awareness of the general population regarding T2DM and HTN since both diseases are very common among Jordanian population.

Stress and behavioral changes with remote E-exams during the Covid-19 pandemic: A cross-sectional study among undergraduates of medical sciences.

Emergence of coronavirus disease 2019 (COVID-19) forced the worldwide higher educational institutes to adopt distance learning mode. Further, remote electronic exams (E-exams) were considered as mode of assessment. Objectives: This cross-sectional study evaluated the students' experience of remote E-exams during the COVID-19 pandemic among Medical Sciences students in Jordan. Materials and Methods: A survey of 29 questions was prepared on Google forms and distributed among students at Faculties of Medical Sciences (Medicine, Dentistry, Pharmacy, Nursing and Applied Medical Sciences) at Jordan University of Science and Technology. The questions include students' demographics, stress experience, and factors contributing to stress as well as behavioral changes related to remote E-exams. Responses were analyzed using descriptive, cross tabulation and Chi-square tests. Results: Among 1019 respondents, 32% reported more stress with remote E-exams. This was associated with academic major and gender. Among students with more stress during remote E-exams, the exam duration, mode of questions navigation and technical problems (exam platform and internet connectivity) appeared as the main factors related to stress in 78%, 76% and >60%, respectively. Other factors include concern regarding the teaching methods, exam environment and students' dishonesty. Remote E-exams had negative impact on students' dietary habits (increase consumption of caffeine and high energy drinks, high sugar food, fast food), sleep (reduction in sleeping hours, more consumption of insomnia medications), physical activity (less exercises) and smoking habits (increase). Conclusion: Results suggested a negative impact of E-exams on students within Medical Faculties. Robust exam platform and remote mock E-exams are recommended to reduce students' potential stress. A stress-free environment is very essential to encourage students to adopt remote E-exams, particularly if the pandemic will take longer. Various awareness programs about students' habits related to dietary, sleep quality, physical activity and smoking are highly valuable for students' health benefits. This is of particular importance since the current students at Faculties of Medical Sciences are the future health care providers.

Distance education during the COVID-19 outbreak: A cross-sectional study among medical students in North of Jordan.

INTRODUCTION: In the spot of the new emerging COVID-19 pandemic and its major impact worldwide on day-to-day activities many rules had to be changed in order to fight this pandemic. Lockdown started in Jordan and around the globe affecting several aspects of life including economy, education, entertainment, and government policies. Regarding education, the priority was to ensure the safety and progress of the educational process. Thus, new methods of teaching had to be applied using the online learning at Jordan University of Science and Technology (JUST), Faculty of Medicine. This study was done to assess (1) Class Experience (2) Students and Lecturers' Interaction (3) Online Learning Advantages & Disadvantages (4) Students' Preference. METHODS: A cross sectional study was conducted Convenience sampling technique was used to collect the data from the participants using a survey composed of 18 questions on Google Forms platform. A link was sent to the undergraduate medical students at the Jordan University of Science & Technology via their e-learning accounts (n = 3700). The form was available from May 22nd, 2020 to May 30th, 2020 for 8 days long. Data analysis was done using SPSS V 23. RESULTS: 2212 out of 3700 students responded, (55.8%) of them were in the basic years and (44.2%) of them were in the clinical years. (55.8%) of students started to take online lectures after 3 weeks. (45.7%) used the hybrid teaching method (asynchronous and synchronous), (31.4%) used live classes, and 22.8% recorded classes. Zoom was the most used platform. (48.7%) and (57%) of clinical students and basic students express their interaction as bad, while the others had good and excellent interaction. Maintaining social distance was the most advantage of online teaching, while poor technical setup and no direct contact were the most disadvantage, furthermore inability to have real clinical access was a significant problem for clinical students (p < .001). With reference to students' preferences 75% of students were not pleased with their experience and 42% of students prefer to integrate online learning with traditional learning. CONCLUSION: Most medical students at JUST preferred the traditional face-to-face teaching method over the solo online teaching methods with recommendations to convert to a more integrated educational system. Also, a well-established infrastructure should be done in involving online teaching.

Leukotriene D4 role in allergic asthma pathogenesis from cellular and therapeutic perspectives.

Asthma is a chronic inflammatory and allergic disease that is mainly characterized by reversible airway obstruction and bronchial hyperresponsiveness. The incidence of asthma is increasing with more than 350 million people worldwide are affected. Up to now, there is no therapeutic option for asthma and most of the prescribed drugs aim to ameliorate the symptoms of the disease especially during the acute exacerbations after trigger exposure. Asthma is a heterogonous disease that involves interactions between inflammatory mediators and cellular components within the disease microenvironment including inflammatory and structural cells. Cysteinyl leukotrienes (cys-LTs) are inflammatory lipid mediators that have potent roles in asthma pathogenesis. CysLTs consisting of LTC4, LTD4, and LTE4 are mainly secreted by leukocytes and act through three main G-protein coupled receptors (CysLT1R, CysLT2R, and CysLT3R). LTD4 is the most potent bronchoconstrictor which gives it the priority to be discussed in detail in this review. LTD4 binds with high affinity to CysLT1R and many studies showed that using CysLT1R antagonists such as montelukast has a beneficial effect for asthmatics especially in corticosteroid refractory cases. Since asthma is a heterogeneous inflammatory disease of many cell types involved in the disease pathogenies and LTD4 has a special role in inflammation and bronchoconstriction, this review highlights the role of LTD4 on each cellular component in asthma and the benefits of using CysLT1R antagonists in ameliorating LTD4-induced effects.

The Bacterial Microbiota of Gastrointestinal Cancers: Role in Cancer Pathogenesis and Therapeutic Perspectives.

The microbiota has an essential role in the pathogenesis of many gastrointestinal diseases including cancer. This effect is mediated through different mechanisms such as damaging DNA, activation of oncogenic pathways, production of carcinogenic metabolites, stimulation of chronic inflammation, and inhibition of antitumor immunity. Recently, the concept of "pharmacomicrobiomics" has emerged as a new field concerned with exploring the interplay between drugs and microbes. Mounting evidence indicates that the microbiota and their metabolites have a major impact on the pharmacodynamics and therapeutic responses toward anticancer drugs including conventional chemotherapy and molecular-targeted therapeutics. In addition, microbiota appears as an attractive target for cancer prevention and treatment. In this review, we discuss the role of bacterial microbiota in the pathogenesis of different cancer types affecting the gastrointestinal tract system. We also scrutinize the evidence regarding the role of microbiota in anticancer drug responses. Further, we discuss the use of probiotics, fecal microbiota transplantation, and antibiotics, either alone or in combination with anticancer drugs for prevention and treatment of gastrointestinal tract cancers.

Re-engineering of the duocarmycin structural architecture enables bioprecursor development targeting CYP1A1 and CYP2W1 for biological activity.

A library of duocarmycin bioprecursors based on the CPI and CBI scaffolds was synthesized and used to probe selective activation by cells expressing CYP1A1 and 2W1, CYPs known to be expressed in high frequency in some tumors. Several CPI-based compounds were pM-nM potent in CYP1A1 expressing cells. CYP2W1 was also shown to sensitize proliferating cells to several compounds, demonstrating its potential as a target for tumor selective activation of duocarmycin bioprecursors.