Contraceptives Knowledge and Perception: A Cross-Sectional Study Among Future Pharmacists in Jordan.

Background: Unintended pregnancy has huge burdens on healthcare resources and society. Contraception is essential to reduce it, and pharmacists are usually the first healthcare providers who are asked for advice about contraceptives. Therefore, the study aimed to evaluate future pharmacists' knowledge, awareness, and perceptions of contraceptive methods and assess the factors influencing their knowledge, awareness, and perceptions. Methods: This cross-sectional study was conducted among senior pharmacy students at four universities. Data was collected over three months using a structured and validated questionnaire. Both inferential (Mann-Whitney U-test and Kruskal-Wallis test) and descriptive analyses were employed. Results: A total of 310 eligible participants completed the questionnaire, and more than half of them (N=172; 55.5%) were final-year students. The Mann-Whitney U-test revealed that final-year students had significantly better knowledge (U= 14,261.5, p<0.002) and a higher level of awareness (U= 13,971.5, p<0.007) than fourth-year students. Interestingly, the Kruskal-Wallis test showed that the type of training (hospital, community, none) had a statistically significant impact on awareness scores (p<0.001). Conclusion: Final-year students had higher knowledge and were more aware of contraception than fourth-year students. Also, community pharmacy training was associated with better awareness about contraceptives . Therefore, future studies should explore the impact of incorporating more targeted contraceptive education into earlier years of pharmacy education to bridge the knowledge gap observed between final-year and fourth-year students. Additionally, research should also investigate the effectiveness of specific community pharmacy training modules on contraceptive awareness.

USP28 controls SREBP2 and the mevalonate pathway to drive tumour growth in squamous cancer.

SREBP2 is a master regulator of the mevalonate pathway (MVP), a biosynthetic process that drives the synthesis of dolichol, heme A, ubiquinone and cholesterol and also provides substrates for protein prenylation. Here, we identify SREBP2 as a novel substrate for USP28, a deubiquitinating enzyme that is frequently upregulated in squamous cancers. Our results show that silencing of USP28 reduces expression of MVP enzymes and lowers metabolic flux into this pathway. We also show that USP28 binds to mature SREBP2, leading to its deubiquitination and stabilisation. USP28 depletion rendered cancer cells highly sensitive to MVP inhibition by statins, which was rescued by the addition of geranyl-geranyl pyrophosphate. Analysis of human tissue microarrays revealed elevated expression of USP28, SREBP2 and MVP enzymes in lung squamous cell carcinoma (LSCC) compared to lung adenocarcinoma (LADC). Moreover, CRISPR/Cas-mediated deletion of SREBP2 selectively attenuated tumour growth in a KRas/p53/LKB1 mutant mouse model of lung cancer. Finally, we demonstrate that statins synergise with a dual USP28/25 inhibitor to reduce viability of SCC cells. Our findings suggest that combinatorial targeting of MVP and USP28 could be a therapeutic strategy for the treatment of squamous cell carcinomas.

Attitudes Toward Providing Open Access for Use of Biospecimens and Health Records: A Cross-Sectional Study from Jordan.

Purpose: Biospecimen repositories and big data generated from clinical research are critically important in advancing patient-centered healthcare. However, ethical considerations arising from reusing clinical samples and health records for subsequent research pose a hurdle for big-data health research. This study aims to assess the public's opinions in Jordan toward providing blanket consent for using biospecimens and health records in research. Participants and Methods: A cross-sectional study utilizing a self-reported questionnaire was carried out in different cities in Jordan, targeting adult participants. Outcome variables included awareness of clinical research, participation in clinical research, and opinions toward providing open access to clinical samples and records for research purposes. Descriptive analysis was utilized for reporting the outcome as frequency (percentages) out of the total responses. Univariate and multivariate logistic regression were used to investigate the association between independent variables and the outcome of interest. Results: A total of 1033 eligible participants completed the questionnaire. Although the majority (90%) were aware of clinical research, only 24% have ever participated in this type of research. About half (51%) agreed on providing blanket consent for the use of clinical samples, while a lower percentage (43%) agreed on providing open access to their health records. Privacy concerns and lack of trust in the researcher were cited as major barriers to providing blanket consent. Participation in clinical research and having health insurance were predictors for providing open access to clinical samples and records. Conclusion: The lack of public trust in Jordan toward data privacy is evident from this study. Therefore, a governance framework is needed to raise and maintain the public's trust in big-data research that warrants the future reuse of clinical samples and records. As such, the current study provides valuable insights that will inform the design of effective consent protocols required in data-intensive health research.

Comparison of Oleocanthal-Low EVOO and Oleocanthal against Amyloid-ß and Related Pathology in a Mouse Model of Alzheimer's Disease.

Alzheimer's disease (AD) is characterized by several pathological hallmarks, including the deposition of amyloid-ß (Aß) plaques, neurofibrillary tangles, blood-brain barrier (BBB) dysfunction, and neuroinflammation. Growing evidence support the neuroprotective effects of extra-virgin olive oil (EVOO) and oleocanthal (OC). In this work, we aimed to evaluate and compare the beneficial effects of equivalent doses of OC-low EVOO (0.5 mg total phenolic content/kg) and OC (0.5 mg OC/kg) on Aß and related pathology and to assess their effect on neuroinflammation in a 5xFAD mouse model with advanced pathology. Homozygous 5xFAD mice were fed with refined olive oil (ROO), OC-low EVOO, or OC for 3 months starting at the age of 3 months. Our findings demonstrated that a low dose of 0.5 mg/kg EVOO-phenols and OC reduced brain Aß levels and neuroinflammation by suppressing the nuclear factor-κB (NF-κB) pathway and reducing the activation of NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasomes. On the other hand, only OC suppressed the receptor for advanced glycation endproducts/high-mobility group box 1 (RAGE/HMGB1) pathway. In conclusion, our results indicated that while OC-low EVOO demonstrated a beneficial effect against Aß-related pathology in 5xFAD mice, EVOO rich with OC could provide a higher anti-inflammatory effect by targeting multiple mechanisms. Collectively, diet supplementation with EVOO or OC could prevent, halt progression, and treat AD.

Motivators and barriers towards clinical research participation: A population-based survey from an Arab MENA country.

Jordan was the first Arab country to enact clinical research regulations. The country has a well-flourished pharmaceutical industry that leans heavily on clinical research (CR) for drug development and post-marketing surveillance. In this cross-sectional study, we sought to assess the public's awareness and attitude towards CR as well as their perceived motivators and barriers to CR participation. A population-based, self-administered questionnaire was distributed to the general public in Jordan. Among the 1061 participants in this survey, 74% reported being aware of CR. The majority (70%) agreed to the role of CR in health promotion. Online information and healthcare staff were the two main sources of CR information for the participants. About 25% of the participants received prior invitations to participate in CR with 21% agreeing to participate. However, most participants of the current study (63%) were willing to participate in future CR. Contributing to science, benefiting others, and promoting one's own health were the top motivating factors for participating in CR; while time constraints, fear of research procedure, and lack of interest were the most cited reasons for rejecting participation. Filling out questionnaire surveys, donating blood samples, and participating in physical examinations were the main CR contributions of the participants. Nearly 31% of the participants believed that CR is conducted in a responsible and ethical manner, while 57% did not have an opinion regarding the same matter. In addition, 49% and 44% were neutral with regards to the degree of harm and confidentiality posed by CR. While only 27% disagreed that CR exposes participants to some form of harm, 48% either strongly agreed (15%) or agreed (33%) that it maintains high level of confidentiality for participants. The current study provides insight into the public's perception of CR in Jordan as well as its motivating factors and perceived barriers towards participating in CR. We envisage to utilize this insight as an aid in the design of vigilant future awareness campaigns and recruitment strategies.

Oleuropein-Rich Olive Leaf Extract Attenuates Neuroinflammation in the Alzheimer's Disease Mouse Model.

Alzheimer's disease (AD) is the most common form of dementia among several neurodegenerative disorders afflicting the elderly. AD is characterized by the deposition of extracellular amyloid-ß (Aß) plaques, disrupted blood-brain barrier (BBB), and neuroinflammation. Several studies have demonstrated the health benefits of olive oil and olive leaf extract (OLE) due to their polyphenolic content. The main phenolic compound in OLE is glycosylated oleuropein (OLG), while the aglycon form of oleuropein (OLA) exists in much lower amounts. This work aimed to evaluate the effect of a low dose of OLG-rich OLE and the mechanism(s) that contributed to the observed beneficial effects against Aß pathology in the homozygous 5xFAD mouse model. Mice were fed with OLE-enriched diet (695 µg/kg body weight/day) for 3 months, starting at 3 months old. Overall findings demonstrated that OLE reduced neuroinflammation by inhibiting the NF-κB pathway and suppressing the activation of NLRP3 inflammasomes and RAGE/HMGB1 pathways. In addition, OLE reduced total Aß brain levels due to increased clearance and reduced production of Aß and enhanced BBB integrity and function, which collectively improved the memory function. Thus, the consumption of OLE as a dietary supplement is expected to stop and/or slow the progression of AD.

Targeting Angiogenesis in Breast Cancer: Current Evidence and Future Perspectives of Novel Anti-Angiogenic Approaches.

Angiogenesis is a vital process for the growth and dissemination of solid cancers. Numerous molecular pathways are known to drive angiogenic switch in cancer cells promoting the growth of new blood vessels and increased incidence of distant metastasis. Several angiogenesis inhibitors are clinically available for the treatment of different types of advanced solid cancers. These inhibitors mostly belong to monoclonal antibodies or small-molecule tyrosine kinase inhibitors targeting the classical vascular endothelial growth factor (VEGF) and its receptors. Nevertheless, breast cancer is one example of solid tumors that had constantly failed to respond to angiogenesis inhibitors in terms of improved survival outcomes of patients. Accordingly, it is of paramount importance to assess the molecular mechanisms driving angiogenic signaling in breast cancer to explore suitable drug targets that can be further investigated in preclinical and clinical settings. This review summarizes the current evidence for the effect of clinically available anti-angiogenic drugs in breast cancer treatment. Further, major mechanisms associated with intrinsic or acquired resistance to anti-VEGF therapy are discussed. The review also describes evidence from preclinical and clinical studies on targeting novel non-VEGF angiogenic pathways in breast cancer and several approaches to the normalization of tumor vasculature by targeting pericytes, utilization of microRNAs and extracellular tumor-associate vesicles, using immunotherapeutic drugs, and nanotechnology.

Blood-Brain Barrier Disruption Increases Amyloid-Related Pathology in TgSwDI Mice.

In Alzheimer's disease (AD), several studies have reported blood-brain barrier (BBB) breakdown with compromised function. P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are transport proteins localized at the BBB luminal membrane and play an important role in the clearance of amyloid-ß (Aß). The purpose of this study was to investigate the effect of pharmacological inhibition of Aß efflux transporters on BBB function and Aß accumulation and related pathology. Recently, we have developed an in vitro high-throughput screening assay to screen for compounds that modulate the integrity of a cell-based BBB model, which identified elacridar as a disruptor of the monolayer integrity. Elacridar, an investigational compound known for its P-gp and BCRP inhibitory effect and widely used in cancer research. Therefore, it was used as a model compound for further evaluation in a mouse model of AD, namely TgSwDI. TgSwDI mouse is also used as a model for cerebral amyloid angiopathy (CAA). Results showed that P-gp and BCRP inhibition by elacridar disrupted the BBB integrity as measured by increased IgG extravasation and reduced expression of tight junction proteins, increased amyloid deposition due to P-gp, and BCRP downregulation and receptor for advanced glycation end products (RAGE) upregulation, increased CAA and astrogliosis. Further studies revealed the effect was mediated by activation of NF-κB pathway. In conclusion, results suggest that BBB disruption by inhibiting P-gp and BCRP exacerbates AD pathology in a mouse model of AD, and indicate that therapeutic drugs that inhibit P-gp and BCRP could increase the risk for AD.

Association of DNA repair gene polymorphisms with colorectal cancer risk and treatment outcomes.

Colorectal cancer (CRC) is the third most common carcinoma worldwide. Despite the progress in screening and treatment, CRC remains a leading cause of cancer-related mortality. Alterations to normal nucleic acid processing may drive neoplastic transformation of colorectal epithelium. DNA repair machinery performs an essential function in the protection of genome by reducing the number of genetic polymorphisms/variations that may drive carcinogenicity. Four essential DNA repair systems are known which include nucleotide excision repair (NER), base excision repair (BER), mismatch repair (MMR), and double-strand break repair (DSBR). Polymorphisms of DNA repair genes have been shown to influence the risk of cancer development as well as outcomes of treatment. Several studies demonstrated the association between genetic polymorphism of DNA repair genes and increased risk of CRC in different populations. In this review, we have summarized the impact of DNA repair gene polymorphisms on risk of CRC development and treatment outcomes. Advancements of the current understanding for the impact of DNA repair gene polymorphisms on the risk and treatment of CRC may support diagnostic and predictive roles in patients with CRC.

Immunotherapy for HER2-positive breast cancer: recent advances and combination therapeutic approaches.

Cancer immunotherapy has evolved dramatically with improved understanding of immune microenvironment and immunosurveillance. The immunogenicity of breast cancer is rather heterogeneous. Specific subtypes of breast cancer such as estrogen receptor (ER)-negative, human EGF receptor 2 (HER2)-positive, and triple-negative breast cancer (TNBC) have shown evidence of immunogenicity based on tumor-immune interactions. Several preclinical and clinical studies have explored the potential for immunotherapy to improve the clinical outcomes for different subtypes of breast cancer. This review describes the immune microenvironment of HER2-positive breast cancer and summarizes recent clinical advances of immunotherapeutic treatments in this breast cancer subtype. The review provides rationale and ongoing clinical evidence to the use of immune checkpoint inhibitors, therapeutic vaccines, and adoptive T cell immunotherapy in breast cancer. In addition, the present paper describes the most relevant clinical progress of strategies for the combination of immunotherapy with standard treatment modalities in HER2-positive breast cancer including chemotherapy, targeted therapy, and radiotherapy.

Crizotinib, a MET inhibitor, inhibits growth, migration, and invasion of breast cancer cells in vitro and synergizes with chemotherapeutic agents.

MET is a receptor tyrosine kinase known for its pleiotropic effects in tumorigenesis. Dysregulations of MET expression and/or signaling have been reported and determined to be associated with inferior outcomes in breast cancer patients rendering MET a versatile candidate for targeted therapeutic intervention. Crizotinib is a multi-targeted small-molecule kinase inhibitor for MET, ALK, and ROS1 kinases. This study evaluated the anti-proliferative, cytotoxic, anti-migratory, and anti-invasive effects of crizotinib in breast cancer cells in vitro. Cell viability was assessed by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) colorimetric assay. In vitro wound-healing assay was used to examine the effect of crizotinib on breast cancer cell migration. The expressions of Ki-67, MET, and phospho-MET receptors were characterized using immunofluorescence staining. Results showed that crizotinib has significant anti-proliferative activity on all mammary tumor cells with IC50 values of 5.16, 1.5, and 3.85 µM in MDA-MB-231, MCF-7, and SK-BR-3 cells, respectively. Crizotinib induced cytotoxic effects in all breast cancer cells examined. Combined treatment of small dose of crizotinib with paclitaxel or doxorubicin exhibited a highly synergistic inhibition of growth of MDA-MB-231 and MCF-7 cells with combination index values <1 while no significant effect was observed in SK-BR-3 cells compared with individual compounds. Treatment with crizotinib demonstrated a remarkable reduction in the expression of Ki-67 protein in all 3 tested cell lines. Crizotinib inhibited migration and invasion of MDA-MB-231 cells in a dose-dependent fashion. Crizotinib reduced MET receptor activation in MDA-MB-231 cells when treated at effective concentrations. In conclusion, crizotinib suppressed proliferation, migration, and invasion of breast cancer cells in vitro. The results of this study demonstrated that combined treatment of crizotinib with chemotherapeutic agents resulted in a synergistic growth inhibition of specific breast cancer cell lines.