Nanoencapsulation of MDM2 Inhibitor RG7388 and Class-I HDAC Inhibitor Entinostat Enhances their Therapeutic Potential Through Synergistic Antitumor Effects and Reduction of Systemic Toxicity.

Inhibitors of the p53-MDM2 interaction such as RG7388 have been developed to exploit latent tumor suppressive properties in p53 in 50% of tumors in which p53 is wild-type. However, these agents for the most part activate cell cycle arrest rather than death, and high doses in patients elicit on-target dose-limiting neutropenia. Recent work from our group indicates that combination of p53-MDM2 inhibitors with the class-I HDAC inhibitor Entinostat (which itself has dose-limiting toxicity issues) has the potential to significantly augment cell death in p53 wild-type colorectal cancer cells. We investigated whether coencapsulation of RG7388 and Entinostat within polymeric nanoparticles (NPs) could overcome efficacy and toxicity limitations of this drug combination. Combinations of RG7388 and Entinostat across a range of different molar ratios resulted in synergistic increases in cell death when delivered in both free drug and nanoencapsulated formats in all colorectal cell lines tested. Importantly, we also explored the in vivo impact of the drug combination on murine blood leukocytes, showing that the leukopenia induced by the free drugs could be significantly mitigated by nanoencapsulation. Taken together, this study demonstrates that formulating these agents within a single nanoparticle delivery platform may provide clinical utility beyond use as nonencapsulated agents.

Development of Pegylated Nano-Phytosome Formulation with Oleuropein and Rutin to Compare Anti-Colonic Cancer Activity with Olea Europaea Leaves Extract.

Olive leaf extract is a valuable source of phenolic compounds; primarily, oleuropein (major component) and rutin. This natural olive leaf extract has potential use as a therapeutic agent for cancer treatment. However, its clinical application is hindered by poor pharmacokinetics and low stability. To overcome these limitations, this study aimed to enhance the anticancer activity and stability of oleuropein and rutin by loading them into PEGylated Nano-phytosomes. The developed PEGylated Nano-phytosomes exhibited favorable characteristics in terms of size, charge, and stability. Notably, the anticolonic cancer activity of the Pegylated Nano-phytosomes loaded with oleuropein (IC50=0.14 µM) and rutin (IC50=0.44 µM) surpassed that of pure oleuropein and rutin alone. This outcome highlights the advantageous impact of Nano-phytosomes to augment the anticancer potential of oleuropein and rutin. These results present a promising pathway for the future development of oleuropein and rutin Nano-phytosomes as effective options for passive tumor-targeted therapy, given their improved stability and efficacy.

Molecular Accounting and Profiling of Human Respiratory Microbial Communities: Toward Precision Medicine by Targeting the Respiratory Microbiome for Disease Diagnosis and Treatment.

The wide diversity of microbiota at the genera and species levels across sites and individuals is related to various causes and the observed differences between individuals. Efforts are underway to further understand and characterize the human-associated microbiota and its microbiome. Using 16S rDNA as a genetic marker for bacterial identification improved the detection and profiling of qualitative and quantitative changes within a bacterial population. In this light, this review provides a comprehensive overview of the basic concepts and clinical applications of the respiratory microbiome, alongside an in-depth explanation of the molecular targets and the potential relationship between the respiratory microbiome and respiratory disease pathogenesis. The paucity of robust evidence supporting the correlation between the respiratory microbiome and disease pathogenesis is currently the main challenge for not considering the microbiome as a novel druggable target for therapeutic intervention. Therefore, further studies are needed, especially prospective studies, to identify other drivers of microbiome diversity and to better understand the changes in the lung microbiome along with the potential association with disease and medications. Thus, finding a therapeutic target and unfolding its clinical significance would be crucial.

Intraoperative graft flow profiles in coronary artery bypass surgery: A meta-analysis.

BACKGROUND: Conduits used in coronary artery bypass artery grafting (CABG) have different properties and flow profiles. We compared intraoperative mean graft flow (MGF) between arterial and venous conduits, off-pump CABG (OPCABG) and on-pump CABG (ONCABG) procedures, skeletonized and pedicled internal mammary artery (IMA) grafts, and pulsatility index (PI) between OPCABG and ONCABG, in pairwise meta-analyses. METHODS: Following a systematic literature search, all studies comparing MGF in arterial and venous grafts, were included. The primary endpoint was comparison of pooled MGF between arterial and venous grafts. Secondary endpoints were comparisons of pooled MGF in OPCABG vs ONCABG, anastomosed skeletonized vs pedicled IMA grafts, free skeletonized vs pedicled IMA grafts and PI in OPCABG versus ONCABG. RESULTS: A total of 25 studies with 4443 patients were included. Compared with venous grafts, arterial grafts had lower MGF (standardized mean difference [SMD], -0.28; 95% confidence interval [CI, -0.34; -0.22]; P < .001). OPCABG was associated with significantly lower MGF compared to ONCABG (SMD, -0.29; 95%CI, -0.50; -0.08]; P = .01). No differences were found in MGF between skeletonized vs pedicled IMA after anastomosis (SMD, 0.32; 95%CI [-0.08; 0.71]; P = .11) or in free flow (SMD, 0.76; 95%CI [-0.14; 1.65]; P = .10). No difference was found in PI between OPCABG and ONCABG. At meta-regression, age was associated with higher MGF, while OPCABG was associated with lower MGF. CONCLUSIONS: Intraoperative flow of venous conduits is higher than that of arterial grafts. Compared to OPCABG surgery, graft flow is higher in ONCABG. In skeletonized and pedicled IMA conduits, no difference in flow profiles was found.

The role of human rhinovirus in COPD exacerbations in Abu Dhabi: molecular epidemiology and clinical significance.

This study aimed to describe the molecular epidemiology and seasonality of human rhinovirus (HRV) in chronic obstructive pulmonary disease (COPD) and its association with COPD exacerbations in Abu Dhabi, the United Arab Emirates (UAE). Sputum specimens were collected for analysis from all COPD patients who visited a medical center from November 2021 to October 2022. The real-time quantitative polymerase chain reaction (qPCR) test was used to detect HRV. Of the 78 COPD patients included in the study, 58 (74%) patients presented with one or more exacerbation episodes. The incidence of COPD exacerbation peaked over the winter and substantially decreased during the summer. HRV positivity in patients during exacerbation (E1) was 11/58 (19%) and 15/58 (26%) two weeks after the exacerbation episode (E2). There was no significant difference in the HRV load in these patients. No statistically significant difference was observed in the detection of HRV during exacerbation compared to patients with stable COPD. This is the first study to assess the association between HRV detection by qPCR and COPD exacerbations in the UAE. The high sensitivity of the detection technology helped collect reliable epidemiologic data. Few studies have provided similar Middle East data. This study's pattern of COPD exacerbations and HRV detection parallels that of temperate countries. This information can help with future, more extensive surveillance of respiratory viruses in the UAE and the Middle East and their association with COPD exacerbations.

Knowledge and Practice of Healthcare Professionals in the Medical Care of Asthma Adult Patients in Jordan with a Particular Reference to Adherence to GINA Recommendations.

Purpose: This study aimed to evaluate Jordanian healthcare professionals' knowledge, skills, and experience in dealing with and treating adult asthmatic patients and assess healthcare professionals' compliance with the Global Initiative for Asthma (GINA) guideline recommendations for asthma treatment and management in Jordan. Patients and Methods: A cross-sectional survey was conducted in Jordan between May and June 2023. This study included physicians, pharmacists, and nurses working in clinical settings and directly interacting with asthma patients in Jordan's private and governmental healthcare facilities who were eligible to participate in this research. Three primary sections of an online survey were constructed using Google Forms and included demographic data, a diagnosis and management of the illness, and a list of worldwide medical references for asthma. Results: A total of 300 healthcare professionals, including pharmacists (103), nurses (87), Doctor of Pharmacy (28), and physicians (82), took part in this research. The survey respondents' general knowledge of the nature and symptoms of asthma is quite high, exceeding 84% and 86%, respectively. The survey also showed a high degree of awareness of asthma diagnosis. It was also revealed that around one-quarter of participants consistently reported the severity of asthma. The most frequent factor influencing the decision to take controller or maintenance medicines is symptom severity (reported from 86% of participants). The GINA guidelines were selected as the asthma information source by almost half of the participants. Finally, 47% of participants were aware of the GINA's 2019 adjustments of the recommendations. Conclusion: This study showed that Jordanian healthcare professionals understand the nature, symptoms, and diagnoses of asthma disease. However, many of the survey participants lack adherence, awareness, and understanding of the GINA recommendations about asthma management. More research is required to assess the adherence to the evidence-based recommendations and evaluate the impact of training courses.

Etiologies of Acute Bronchiolitis in Children at Risk for Asthma, with Emphasis on the Human Rhinovirus Genotyping Protocol.

This research aims to determine acute bronchiolitis' causative virus(es) and establish a viable protocol to classify the Human Rhinovirus (HRV) species. During 2021-2022, we included children 1-24 months of age with acute bronchiolitis at risk for asthma. The nasopharyngeal samples were taken and subjected to a quantitative polymerase chain reaction (qPCR) in a viral panel. For HRV-positive samples, a high-throughput assay was applied, directing the VP4/VP2 and VP3/VP1 regions to confirm species. BLAST searching, phylogenetic analysis, and sequence divergence took place to identify the degree to which these regions were appropriate for identifying and differentiating HRV. HRV ranked second, following RSV, as the etiology of acute bronchiolitis in children. The conclusion of the investigation of all available data in this study distributed sequences into 7 HRV-A, 1 HRV-B, and 7 HRV-C types based on the VP4/VP2 and VP3/VP1 sequences. The nucleotide divergence between the clinical samples and the corresponding reference strains was lower in the VP4/VP2 region than in the VP3/VP1 region. The results demonstrated the potential utility of the VP4/VP2 region and the VP3/VP1 region for differentiating HRV genotypes. Confirmatory outcomes were yielded, indicating how nested and semi-nested PCR can establish practical ways to facilitate HRV sequencing and genotyping.

Alteration of the Respiratory Microbiome in Hospitalized Patients with Asthma-COPD Overlap during and after an Exacerbation.

The immediate aim of this study was to comparatively examine the bacterial respiratory microbiome of patients in a stable state and during an exacerbation of asthma-COPD (chronic obstructive pulmonary disease) overlap (ACO). This prospective observational study took place in Jordan between 1 September 2021 and 30 April 2022. Sputum samples from patients with recognized ACO were acquired within 48 h of the exacerbation onset and again at 3 weeks following the exacerbation. The next-generation sequencing Illumina MiSeq was employed and uncovered significantly high bacterial diversity in the sputa. The results showed a significant decrease in the taxonomic richness in the sputum samples collected during the exacerbation episodes compared with those collected from patients in a stable state (p = 0.008), with an increase in the taxonomic evenness (p < 0.005). This change in the composition of the airway bacterial community suggests that the replacement of a significant portion of the airway microbiome with certain microorganisms may play a role in the decrease in microbial diversity observed during an ACO exacerbation. Greater knowledge of this link could allow for a more focused administration of antibiotics, especially during exacerbations, improving clinical efficacy and patient outcomes.

Practices, perceptions and trust of the public regarding online drug purchasing: a web-based survey from Jordan.

OBJECTIVES: Online purchasing, including drugs, increased dramatically in the last decade especially through the COVID-19 pandemic. The aim of this study was to investigate the frequency and attitudes of consumers concerning online drug purchasing and assess their perceptions regarding the benefits and disadvantages. DESIGN: A web-based survey conducted through a self-administered questionnaire that was approved by the Institutional Review Board (IRB) committee, ethical approval number: IRB/Al-Ahliyya Amman University/3/13/2021-2022. Cronbach's alpha for the attributes of benefits and disadvantages was 0.608 and 0.744, respectively. Primary outcome measures were extent of trust of the public in online drug purchasing using Likert scale. Multivariate linear regression was used to assess predictors of the trust score. SETTINGS: Hashemite Kingdom of Jordan. PARTICIPANTS: Inclusion criteria; residents of the Hashemite Kingdom of Jordan 18 years or older. The questionnaire was distributed through snowball effect via different social media. RESULTS: A total of 428 participants filled the questionnaire, their average age was 29.7±11.2. Almost all participants, 419 (98.6%) use the internet daily but only 79 (18.6%) participants shop online regularly. Fifty participants (11.8%) purchased drugs online and they had higher benefits score of online purchasing compared with those who did not buy drugs online, 12.5±3.7 and 10.9±3.1, respectively, p=0.002. Participant who purchased drugs online had an increase in trust score of 0.847 compared with those who did not purchase drugs online, p<0.001. In the multivariate model, participants with education level of high school or higher than high school, compared with those with education lower than high school had an increase in trust score of 1.336 (p=0.026) and 1.137 (p=0.039), respectively. CONCLUSION: The public recognises the risks in buying drugs online. Awareness campaigns and regulations that control and monitor online drug purchasing should be implemented.

The Effect of Weekly 50,000 IU Vitamin D3 Supplements on the Serum Levels of Selected Cytokines Involved in Cytokine Storm: A Randomized Clinical Trial in Adults with Vitamin D Deficiency.

This research aimed to evaluate the effects of high-dose cholecalciferol (VD3) supplements (50,000 IU/week) on selected circulating cytokines associated with cytokine storms in adults with vitamin D deficiency. This clinical trial, based in Jordan, included 50 participants receiving vitamin D3 supplements (50,000 IU/week) for 8 weeks; the exact number was assigned to the control group. Interleukin-6 (IL-6), interleukin-1ß (IL-1ß), interleukin-10 (IL-10), tumor necrotic factor-α (TNF-α), and leptin were measured in serum at baseline and 10 weeks (wash out: 2 weeks). Our results revealed that vitamin D3 supplementation significantly increased the serum levels of 25OHD, IL-6, IL-10, IL-1ß, and leptin compared with baseline. In contrast, the serum level of TNF-α insignificantly increased in the group receiving vitamin D3 supplementation. Although the observations of this trial may refer to a potential negative effect of VD3 supplementation during cytokine storms, further trials are required to clarify the potential benefits of VD3 supplement during cytokine storms.

Human Rhinovirus: Molecular and Clinical Overview / Rinovirus humano: descripción molecular y clínica

Human rhinoviruses (HRVs) are associated with a wide spectrum of clinical manifestations, ranging from mild cold symptoms to more severe respiratory illnesses, significantly burdening global healthcare systems. At the molecular level, HRVs belong to the Picornaviridae family and are classified into three species: HRV-A, HRV-B, and HRV-C. Advances in genomic sequencing and phylogenetic analysis have revealed a remarkable genetic diversity within HRV species, with over 160 serotypes identified. This genetic variability contributes to the ability of HRVs to evade host immune responses and facilitates their continuous circulation in the population. This review provides an overview of the molecular and clinical aspects of HRV infections.(AU)

The first study characterizing the respiratory microbiome in cystic fibrosis patients in Jordan

Cystic fibrosis (CF) is most commonly seen in Caucasians and is uncommon in the Middle East. This study, based in Jordan, aimed to describe the association between lung exacerbation in CF patients and the respiratory microbiome composition. Using the 16S rRNA marker-gene sequencing, we investigated the microbiota in sputa during exacerbation (E1) and 14 days after the exacerbation (E2) of two CF patients admitted to the hospital. Detected genera with high abundance in the E1-related sputa of the first patient included Achromobacter and Streptococcus. At E2, Achromobacter and Staphylococcus were the highest abundant genera. Regarding the second patient, Veillonella and Streptococcus, were the highest abundant genera at E1. Whereas, Streptococcus and Veillonella were the highest abundant genera. This is the first study, based in Jordan, to report and describe the respiratory microbiome during and after the exacerbation of CF patients. This study suggests that pulmonary exacerbation in CF patients can result in alterations in their respiratory microbiome. A better knowledge of this link could allow more focused use of antibiotics, especially during exacerbations, improving clinical efficacy and patient outcomes. (AU)