Cyclin dependent kinase inhibitor 3 (CDKN3) upregulation is associated with unfavorable prognosis in clear cell renal cell carcinoma and shapes tumor immune microenvironment: A bioinformatics analysis

Cell cycle regulatory proteins plays a pivotal role in the development and progression of many human malignancies. Identification of their biological functions as well as their prognostic utility presents an active field of research. As a continuation of the ongoing efforts to elucidate the molecular characteristics of clear cell renal cell carcinoma (ccRCC); we present a comprehensive bioinformatics study targeting the prognostic and mechanistic role of cyclin-dependent kinase inhibitor 3 (CDKN3) in ccRCC. The ccRCC cohort from the Cancer Genome Atlas Program was accessed through the UCSC Xena browser to obtain CDKN3 mRNA expression data and their corresponding clinicopathological variables. The independent prognostic signature of CDKN3 was evaluated using univariate and multivariate Cox logistic regression analysis. Gene set enrichment analysis and co-expression gene functional annotations were used to discern CDKN3-related altered molecular pathways. The tumor immune microenvironment was evaluated using TIMER 2.0 and gene expression profiling interactive analysis. CDKN3 upregulation is associated with shortened overall survival (hazard ratio [HR] = 2.325, 95% confident interval [CI]: 1.703–3.173, P < .0001) in the Cancer Genome Atlas Program ccRCC cohort. Univariate (HR: 0.426, 95% CI: 0.316–0.576, P < .001) and multivariate (HR: 0.560, 95% CI: 0.409–0.766, P < .001) Cox logistic regression analyses indicate that CDKN3 is an independent prognostic variable of the overall survival. High CDKN3 expression is associated with enrichment within the following pathways including allograph rejection, epithelial–mesenchymal transition, mitotic spindle, inflammatory response, IL-6/JAK/STAT3 signaling, spermatogenesis, TNF-α signaling via NF-kB pathway, complement activation, KRAS signaling, and INF-γ signaling. CDKN3 is also associated with significant infiltration of a wide spectrum of immune cells and correlates remarkably with immune-related genes. CDKN3 is a poor prognostic biomarker in ccRCC that alters many molecular pathways and impacts the tumor immune microenvironment.Scopu

Vitamin D serum level predicts stroke clinical severity, functional independence, and disability—A retrospective cohort study

BackgroundStroke is a leading cause of mortality and disability and one of the most common neurological conditions globally. Many studies focused on vitamin D as a stroke risk factor, but only a few focused on its serum level as a predictor of stroke initial clinical severity and recovery with inconsistent results. The purpose of this study was to assess the relationship between serum vitamin D levels and stroke clinical severity at admission and functional independence and disability at discharge in Saudi Arabia.MethodologyA retrospective cohort study of adult ischemic stroke patients who had their vitamin D tested and admitted within 7 days of exhibiting stroke symptoms at King Abdulaziz Medical City (KAMC) Jeddah, Saudi Arabia. Based on vitamin D level, the patients were categorized into normal [25(OH)D serum level ≥ 75 nmol/L], insufficient [25(OH)D serum level is 50–75 nmol/L], and deficient [25(OH)D serum level ≤ 50 nmol/L]. The primary outcome was to assess the vitamin D serum level of ischemic stroke patients’ clinical severity at admission and functional independence at discharge. The National Institute of Health Stroke Scale (NIHSS) was used to assess the clinical severity, whereas the modified Rankin scale (mRS) was used to assess functional independence and disability.ResultsThe study included 294 stroke patients, out of 774, who were selected based on the inclusion and exclusion criteria. The mean age of the participants was 68.2 ± 13.4 years, and 49.3% were male. The patients’ distribution among the three groups based on their vitamin D levels is: normal (n = 35, 11.9%), insufficient (n = 66, 22.5%), and deficient (n = 196, 65.6%). After adjusting for potential covariates, regression analysis found a significant inverse relationship of NIHSS based on 25(OH)D serum level (beta coefficient: −0.04, SE: 0.01, p = 0.003). Patients with deficient serum vitamin D level also had significantly higher odds of worse functional independence in mRS score [OR: 2.41, 95%CI: (1.13–5.16), p = 0.023] when compared to participants with normal vitamin D level.ConclusionLow vitamin D levels were associated with higher severity of stroke at admission and poor functional independence and disability at discharge in patients with acute ischemic stroke. Further randomized clinical and interventional studies are required to confirm our findings

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Nanocrystallization Improves the Solubilization and Cytotoxic Effect of a Poly (ADP-Ribose)-Polymerase-I Inhibitor

Olaparib (OLA) is an anticancer agent that acts by inhibiting the poly (ADP-ribose)-polymerase-I (PARP-I). Due to its low solubility and low permeability, it has been placed as a BCS Class-IV drug and hence its clinical use is limited. In this study, we develop the nanocrystals of OLA as a way to improve its solubility and other performances. The OLA-NCs were prepared by antisolvent precipitation method through homogenization and probe sonication technique using a novel amphiphilic polymeric stabilizer (Soluplus&reg;). Particle characterization resulted approximately 103.13 nm, polydispersity-index was 0.104 with positive zeta-potential of +8.67 mV. The crystal morphology by SEM of OLA-NCs (with and without mannitol) exhibited nano-crystalline prism-like structures as compared to the elongated OLA-pure. The DSC, XRD and FTIR were performed to check the interaction of Soluplus, mannitol and OLA did not exhibit any physical interaction among the OLA, Soluplus&reg; and mannitol that is indicated by the presence of parent wave number peak. Two-fold increased solubility of OLA was found in PBS with Soluplus&reg; from the NCs (69.3 &plusmn; 6.2 &micro;gmL&minus;1) as compared to pure drug (35.6 &plusmn; 7.2 &micro;gmL&minus;1). In vitro release of drug from OLA-NCs was higher (78.2%) at 12 h at pH 6.8 and relatively lower (53.1%) at pH 1.2. In vitro cellular cytotoxicity and anticancer effects were examined on MCF-7 cells. OLA-NCs were found effectively potent to MCF-7 cells compared with OLA-pure with approximately less than half IC50 value during MTT assay. Estimation of p53, Caspase-3 and Caspase-9 in MCF-7 cells indicated that OLA-NCs have significantly (p &lt; 0.05) increased their expressions. After single oral dose in rats, 12 h plasma drug concentration-time profile indicated approximately 2.06-, 2.29-, 2&ndash;25- and 2.62-folds increased Cmax, AUC0-12 h, AUC0-&infin; and AUMC0-&infin;, respectively, from the NCs as compared to OLA-pure. Storage stability indicated that the OLA-NCs was physically and chemically stable at 4 &deg;C, 25 &deg;C and 40 &deg;C up to 6-months. Overall, OLA-NCs were deliberated; its potential feasibility to overwhelm the formulation challenges related to poorly soluble drugs and its future clinical applications

Analysis of Electricity and Water Consumption in Existing Mosque Buildings in the UAE

According to the World Economic Forum, the building sector is responsible for 40% of global energy consumption and 33% of greenhouse gas (GHG) emissions, and this is expected to increase due to population growth and the subsequent impact on the environment, economy and health. To tackle the problem, countries have set new construction codes, policies and regulations for the construction of new buildings in an effort to make them greener. However, there is a need to enhance the status of the existing buildings, especially mosques, as they are the main contributors to energy usage and water consumption in the United Arab Emirates (UAE). Therefore, this research seeks to fill this gap, aiming to evaluate the energy usage and water consumption practices employed in the existing mosque buildings within the UAE and to provide recommendations for improving the sustainability of mosques, with a focus on the environmental and economic pillars. The methodology relies mainly on data collected from 146 existing mosque buildings that have undergone energy saving audits across the UAE. Descriptive statistical analysis is performed to analyze the data from the period of 2018–2019 in order to determine the most significant factors related to energy inefficiency in existing mosque buildings in the UAE and to determine the most cost-effective and energy-saving corrective measures for energy and water conservation. The findings further enhance the standard of experience for mosque visitors (social aspect); reduce energy bill expenses, providing an acceptable return on investment from the proposed energy conservation measures for stakeholders (economic); and reduce the overall energy consumption, which can reduce the total CO2 emissions from mosque buildings (environmental)

Hyaluronan Polymer Length, Grafting Density, and Surface Poly(ethylene glycol) Coating Influence <i>in Vivo</i> Circulation and Tumor Targeting of Hyaluronan-Grafted Liposomes

Hyaluronan-grafted liposomes (HA-liposomes) preferentially target CD44-overexpressing tumor cells <i>in vitro via</i> receptor-mediated endocytosis. We investigated the pharmacokinetics and biodistribution of HA-liposomes with various sizes of HA (MW 5–8, 50–60, and 175–350 kDa) in mice. Incorporation of negatively charged HA on the liposome surface compromised its blood circulation time, which led to decreased tumor accumulation in CD44+ human breast cancer MDA-MB-231 xenografts compared to PEGylated liposomes (PEG-5000). Clearance of HA-liposomes was HA polymer length-dependent; high MW (175–350 kDa, highest ligand binding affinity) HA-liposomes displayed faster clearance compared to low MW (5–8, 50–60 kDa) HA-liposomes or PEGylated liposomes. Surface HA ligand density can also affect clearance of HA-liposomes. Thus, HA is not an effective stealth coating material. When dual coating of PEG and HA was used, the PEG-HA-liposomes displayed similar blood circulation time and tumor accumulation to that of the PEGylated liposomes; however, the PEG-HA-liposomes displayed better cellular internalization capability <i>in vivo</i>. Tumor histology showed that PEG-HA-liposomes had a more direct association with CD44+ cancer cells, while PEGylated liposomes located predominantly in the tumor periphery, with less association with CD44+ cells. Flow cytometry analysis of <i>ex vivo</i> tumor cells showed that PEG-HA-liposomes had significantly higher tumor cell internalization compared to PEGylated liposomes. This study demonstrates that a long blood circulation time is critical for active tumor targeting. Furthermore, the use of the tumor-targeting ligand HA does not increase total tumor accumulation of actively targeted liposomes in solid tumors; however, it can enhance intracellular delivery

The relationship between hydroxychloroquine plasma concentration and COVID-19 outcomes in rheumatoid arthritis patients in Saudi Arabia

Background: The drug hydroxychloroquine (HCQ) is widely used to treat rheumatoid arthritis (RA) and has been repurposed for the treatment of COVID-19. This study aims to determine whether HCQ concentration levels in individuals with RA alter the incidence of COVID-19 or its complications. Methods: We collected plasma samples from 13 individuals with confirmed rheumatoid arthritis (RA) to measure HCQ concentration levels. The study included individuals at least 18 years old who had been taking HCQ for at least six months at daily doses ranging from 200 to 400 mg. Results: The study enrolled a total of 13 RA patients. All patients were chronic HCQ users. Among the 13 patients, 7 patients were receiving HCQ at a dose of 200 mg per day, and 6 patients were receiving HCQ at a dose of 400 mg per day. COVID-19 confirmed cases accounted for approximately 46% of all patients. Half of the infected patients (n = 3) were taking a daily dose of 200 mg daily, while the other half were taking 400 mg daily. COVID-19 symptoms ranged from mild to moderate, and the intensity of the symptoms was not severe enough to necessitate hospitalization. COVID-19 symptoms in RA patients included headache, fever, fatigue, dry cough, and loss of taste or smell. Conclusions: Our findings indicated that there was no correlation between HCQ concentrations in rheumatoid arthritis patients and the occurrence of COVID-19 or its complications

Ribociclib-Loaded Ethylcellulose-Based Nanosponges: Formulation, Physicochemical Characterization, and Cytotoxic Potential against Breast Cancer

In the present study, ribociclib-loaded nanosponges (RCNs) composed of ethylcellulose and polyvinyl alcohol were developed using an emulsion-solvent evaporation method. Preliminary evaluations of the developed RCNs (RCN1 to RCN7) were performed in terms of size, polydispersity index (PDI), zeta potential (ZP), entrapment efficiency (EE), and drug loading (DL), which allowed us to select the optimized formulation. RCN3 was selected as the optimized carrier system with particle size (363.5±4.8 nm), PDI (0.292±0.012), zeta potential (−18.5±0.05 mV), EE (81.35±1.64%), and DL (21.96±0.28%). Further, the optimized nanosponges (RCN3) were subjected to FTIR, XRD, DSC, and SEM studies, and results confirmed the proper encapsulation of the drug within the porous polymeric matrix. In vitro drug release studies showed that the drug release was significantly enhanced with a maximum drug release through RCN3 formulation (81.85±0.37%) and followed the Higuchi model. Moreover, the RCN3 system showed greater cytotoxicity than free ribociclib (RC) against MDA-MB-231 and MCF-7 breast cancer cell lines. The percentage of apoptosis induced by RCN3 was found significantly higher than that of free RC (p<0.05). Overall, ribociclib-loaded ethylcellulose nanosponges could be a potential nanocarrier to enhance the effectiveness of ribociclib in breast cancer treatment

Exploitation of Design-of-Experiment Approach for Design and Optimization of Fast-Disintegrating Tablets for Sublingual Delivery of Sildenafil Citrate with Enhanced Bioavailability Using Fluid-Bed Granulation Technique

Sildenafil citrate undergoes first-pass metabolism, resulting in poor oral bioavailability at 25–41% of the administered dose. This study aimed to design and optimize fast-disintegrating tablets for the sublingual delivery of sildenafil citrate to improve bioavailability and facilitate rapid onset of action. The design-of-experiment (DoE) approach using 32 full factorial design was conducted to develop a new formulation of sildenafil fast-disintegrating sublingual tablets (FDSTs) using the fluid-bed granulation technique. The levels of partially pre-gelatinized starch (5–15%) and microcrystalline cellulose (10–60%) were selected as independent formulation variables. The prepared FDSTs were investigated for physical properties. Further, the optimum formulation was chosen for in vivo study in rabbits. Regression analysis showed that independent variables have a significant (p &lt; 0.05) influence on critical attributes of FDSTs. The optimized formulation showed acceptable mechanical strength (friability &lt; 1.0%) with very fast disintegration (14.561 ± 0.84 s) and dissolution (94.734 ± 2.76% after 15 min). Further, the optimized formulation demonstrated a significant increase (p &lt; 0.01) in Cmax and AUC0–∞ with short tmax compared to the market product (Viagra®). Based on these results, using the DoE approach, a high level of assurance was achieved for FDSTs’ product quality and performance